Endocrine Tumours -
Molecular Radiation on Target
Peptide Receptor Radionuclide Therapy with
Lutetium-octreotate
Jaap J.M. Teunissen
CIP-gegevens Koninklijke Bibliotheek, Den Haag© Teunissen, J.J.M., 2008
ISBN/EAN: 978-90-9023552-3
Printed by: PrintPartners Ipskamp, EnschedeLay-out: Karlijn van den BergCover: Vincent Beijersbergen
All rights reserved. No part o�� this thesis may be reproduced orights reserved. No part o�� this thesis may be reproduced or transmitted in any ��orm, by any means, electronical or mechanical, without prior written permission o�� the author.
Endocrine Tumours -
Molecular Radiation on TargetPeptide Receptor Radionuclide Therapy
with Lutetium-octreotate
Endocriene tumoren –
Doelgerichte moleculaire straling
Peptide receptor radionuclide therapie met Lutetium-octreotaat
Proe��schri��t
ter verkrijging van de graad van doctor aan de Erasmus Universiteit Rotterdam
op gezag van de rector magnificus
Prof. dr. S.W.J. Lamberts
en volgens besluit van het College voor Promoties.
De openbare verdediging zal plaatsvinden op woensdag 10 december 2008 om 13:45 uur
door
Jacobus Johannes Marius Teunissen
geboren te Arnhem
Promotiecommissie:
Promotor: Pro��. dr. E.P. Krenning
Overige leden: Pro��. dr. ir. M. de Jong Pro��. dr. F.H. de Jong Dr. W.W. de Herder Copromotor: Dr. D.J. Kwekkeboom
Voor Papa
CONTENTS
Chapter 1 General introduction
1.1 Management o�� patients with neuroendocrine tumours 1.2 Peptide receptor radionuclide therapy (PRRT)�� 1.3 Aims and outline o�� the thesis
Chapter 2 Outcome o�� PRRT with [177Lu-DOTA0,Tyr3]octreotate in patients with gastroenteropancreatic tumours
2.1 Treatment o�� patients with gastroenteropancreatic tumours with the novel radiolabelled somatostatin analogue [177Lu-DOTA0,Tyr3]octreotate2.2 Radiolabeled somatostatin analog [177Lu-DOTA0,Tyr3]octreotate in patients with endocrine gastroenteropancreatic tumors
Chapter 3 Quality o�� Li��e in patients with gastroenteropancreatic tumors treated with [177Lu-DOTA0,Tyr3]octreotate
Chapter 4 E����ects o�� therapy with [177Lu-DOTA0,Tyr3]octreotate on endocrine ��unction
Chapter 5 Comparison o�� [177Lu-DOTA0,Tyr3]octreotate and [177Lu-DOTA0,Tyr3]octreotide: which peptide is pre��erable ��or PRRT?
Chapter 6 Radiolabelled somatostatin analogues in di����erentiated thyroid carcinoma
6.1 Peptide receptor radionuclide therapy ��or non-radioiodine-avid di����erentiated thyroid carcinoma6.2 Staging and treatment o�� di����erentiated thyroid carcinoma with radiolabeled somatostatin analogs
Chapter 7 Summary and general discussion
Chapter 8 Samenvatting en algemene discussie
Abbreviations
Dankwoord
Curriculum Vitae
List o�� publications
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1General introduction
1.1Management o�� patients with neuroendocrine tumours
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�Thediscoveryoftheneuropeptidesomatostatin(SS) in1973byGuilleminandco-workersattheSalkInstitute1andtheextensiveworkonthefunctionofpeptides,includingSS,bythegroupofSchallyet al.2,forwhichbothreceivedtheNobelprizein1977,wasanimportantsteptowardsthecurrentknowledgeofneuroendocrinetumours.Almosttwodecadeslater,itscounterpart,thesomatostatinreceptor(SSTR)wascharacterizedbyYamadaet al.3,4.Furthermore,thewidespreadpresenceandfunctionswithinthebodyofboththehormoneanditsligandhasbeenintensivelystudied.Thepolypeptidesomatostatincomprisesseveralpeptidesformedafterdifferentposttranslationalprocessingofthepre-prosomatostatinproteinencodedbyasinglegene.Onlytwoofthesesmallpeptides,somatostatin-14andsomatostatin-28,arebiologicallyactiveandarethemostcommonsomatostatinpeptidespresentin theperipheralandcentralnervoussystem(CNS).Thesomatostatin-14andsomatostatin-28isoformsconsistof14and28aminoacids,respectively.Theentiresomatostatin-14sequenceispresentintheC-terminusofsomatostatin-28.Thepredominantbiologicallyactiveisoformissomatostatin-14.Therelativeproportionsofsomatostatin-14andsomatostatin-28differamongvarioussomatostatin-producingtissues.However, somatostatin-14 and somatostatin-28displayoverlappingphysiologicalfunctions.Bothsomatostatin-14andsomatostatin-18areproducedbyneuroendocrine,inflammatory,andimmunecellsinresponsetoions,nutrients,neuropeptides,neurotransmitters,thyroidandsteroidhormones,growthfactors,andcytokines5.
ThesomatostatinpeptidesexerttheirregulatorybiologicalroleafterbindingtoanSSTR.Atpresent,fivedifferenthumanSSTRs,namedSSTR1,SSTR2,SSTR3,SSTR4andSSTR5havebeenidentifiedandcloned3,4.AllfiveSSTRsbelongtothesuperfamilyofG-protein-coupledreceptorswithseventransmembranedomainsandhavebeenidentifiedthroughouttheCNS,endocrineandexocrineglands.Allfivesubtypesbindsomatostatin-14andsomatostatin-28withhighaffinity.AlthoughthedifferentSSTRsubtypesare40%to60%structurallyhomologous,eachsubtypehasitsspecificroleinsignallingbetweencellsandthedifferenttissues.Themostprominentrole,however,istheinhibitoryeffectofsomatostatinonthesecretionofhormonesinvariousorganssuchastheinhibitionofgrowthhormone,prolactinandthyroidstimulatinghormonewithinthepituitaryorinhibitionofglucagonandinsulinreleasewithinthepancreas.
SomatostatinreceptorsareexpressedinvarioustissuessuchastheCNS,anteriorpituitary, theendocrineandexocrinepancreas, thegastrointestinal tract andtheadrenals,butneuroendocrinetumoursalsofrequentlyexpresssomatostatinreceptors.Table1summarizesthecharacteristicsofsomatostatinreceptorexpressioninneuroendocrinetumours.
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�Table 1.Somatostatinreceptorexpressioninneuroendocrinetumours
ReceptorincidencePancreaticandgutendocrinetumours:80-100%Insulinomas:50-70%
Receptordensity Commonlyhigh
Receptordistribution Commonlyhomogeneous
Receptorexpression Well-differentiatedtumour>undifferentiatedtumour
Receptorsubtypeexpressionfrequency SSTR2>>SSTR1=SSTR5>SSTR3>>SSTR4
Receptorlocalisation Usuallycellmembranebound,especiallySSTR2
Adapted from Reubi 7
Thereceptordensityishighinthemajorityofcasesbutmayvarybetweenthetumours.UndifferentiatedendocrinetumoursexpresslessoftenSSTRsandifso,thedensityisreportedtobelow6,7.TheSSTRmostcommonlyexpressedinendocrinetumoursistheSSTR2.
Incidence Theage-standardisedincidenceofcarcinoids,themostcommongastroentero-pancreatic neuroendocr ine tumour (GEP-NET), descr ibed as the age-standardised incidence per 100,000 inhabitants per year, is approximately1-2/100,0008.ThelowestpercentageofpatientsisreportedinItaly,whereasthehighestnumberhasbeenreportedintheUSA9,10.AslightpreponderanceinwomenwasreportedinEurope,whereasintheUSAahigherincidencewasfoundamongblackpeople8. Interestingly,theincidentalfindingofcarcinoidtumoursduringautopsiesismuchhigherandisreportedtobeabout1%11.InarecentDutchstudy,theprimarysiteofNETswasreportedtobewithinthegastrointestinaltract(62%),especiallytheappendix(27%),followedbythesmallbowel(13%).Thereafter,thelungsandmediastinumarethesecondmostcommonlocalisationofneuroendocrinetumours.
Modlinet al.12,whousedtheSurveillance,Epidemiology,andEndResultsdatabase(SEER,1973–1991)registry,reportedtheoverallincidenceofnonlocalisedcarcinoidsatthetimeofdiagnosisas45.3%inatotalof5468carcinoidpatients.Thefrequentlyduringsurgeryincidentallyencounteredappendicealcarcinoidwasdemonstratedtobenonlocalisedin35.4%.Carcinoidsoriginatingfromdifferentanatomicalsites,likethepancreas,smallintestineorcolon,wereencounteredmorefrequentlywithmetastasisatdiagnosis(76.1%,70.7%and71.2%,respectively).PancreaticNETs
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�ofwhichupto40%arenon-functioning,haveabout50%hepaticmetastasesatdiagnosis13.Intwelvepercentofpatientswhopresentwithmetastaticdisease,theprimarysiteremainsunknown8.
Histology and classificationInthelastcenturyseveralclassificationsofGEP-NETshavebeenapplied.Obern-dorfer,whowasthefirsttocharacterizethesetumours,reportedtheexistenceofrareepithelialtumoursinthegutthathavearelativelymonotonousstructureandexhibita lessaggressiveor indolentnaturethangutderivedcarcinomas 14.Thelattercharacteristicfeatureofthetumourmadehimchoosethename‘carcinoid’.Until1963,allGEP-NETstumourswerereferredtoascarcinoids.Atthattime,WilliamsandSandlerdividedthecarcinoidsintofore-,mid-andhindgutcarcinoids,accordingtotheirembryologicorigin15.Thisclassificationwasneverfullyacceptedbycliniciansmainlybecauseofthewiderangeofdifferencesofmorphology,functionandbiologythatcouldbefoundwithinonesingleclassoftumours.In1980,thefirstWorldHealthOrganization(WHO)classificationofendocrinegastrointestinaltumourswasintroduced.Endocrinetumoursweresubdividedbasedoncelltypeintoenterochromaffincell,gastrincellandunspecifiedcarcinoids16.Thisclassificationcausedmisunderstandingbetweenpathologistsandcliniciansbecauseforthelattergroupthetermcarcinoidwasmainlyreservedforpatientswhohadsymptomsduetothesecretionofhormonesbythetumour.Obviously,theWHOdefinitiondidnotcoverthewholemorphological,biologicalandclinicalspectrumofGEP-NETs.AmorestructuredWHOclassificationwasintroducedin200017,18.Thenewclassificationisbasedonacombinationofpathologicalandclinicalfeatureswithparametersspecificforeachorganfromwhichtheendocrinetumoursoriginate.AllGEP-NETsaregrosslydividedintothreemaincategories:(1)well-differentiatedendocrinetumours,furthersubdividedintotumourswithbenignandwithuncertainbiologicalbehaviour;(2)well-differentiatedendocrinecarcinomasorlowgrade;and(3)poorlydifferentiatedendocrinecarcinomasorhighgrade(Table2).
Becausepoorlydifferentiated tumourshaveahighlyaggressivecourse, theseneoplasmsareprofoundlydifferentfromtheothersubgroupsand,therefore,requireamoreaggressivetherapeuticapproach(seefurther inthischapter).Afurtherdistinctionwasmadeaccordingtothespecificorganlocalisations.Thestomach,duodenum(andproximaljejunum),ileum(includingthedistaljejunum),appendix,colon-rectum,andpancreasweredistinguished.Besides thehistopathologicalcharacteristicsandprimarysiteoforigin,theendocrinetumoursareclassifiedintowhetherbiologicallyactivesubstances/hormonesareproducedandsecretedandtherebydistinguishedintofunctioningornon-functioningendocrinetumours.
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�Table 2.WHOclassificationofgastroenteropancreaticendocrinetumours
Tumour SiteWell differentiated endocrine tumour (Benign behaviour)
Well differentiated endocrine tumour (Uncertain behaviour)
Well differentiated endocrine carcinoma (Low grade malignant)
Poorly differentiated endocrine carcinoma (High grade malignant)
Pancreas Confinedtopancreas<2cm
Confinedtopancreas≥2cm
WelltomoderatelydifferentiatedGrosslocalinvasionand/ormetastases
SmallcellcarcinomaNecrosiscommon
<2mitosesper10HPF >2mitosesper10HPF Mitoticrateoftenhigher(2-10per10HPF)
>10mitosisper10HPF
<2%Ki-67positivecellsNovascularinvasion
>2%Ki-67positivecellsorvascularinvasion
Ki-67index>5% >15%Ki-67positivecellsProminentvascularand/orperineuralinvasion
Stomach Confinedtomucosa-submucosa≤1cm.Novascularinvasion
Confinedtomucosa-submucosa>1cmorvascularinvasion
WelltomoderatelydifferentiatedInvasiontomuscularispropriaorbeyondormetastases
Smallcellcarcinoma
Duodenum, upper jejunum
Confinedtomucosa-submucosa≤1cm.Novascularinvasion
Confinedtomucosa-submucosa>1cmorvascularinvasion
WelltomoderatelydifferentiatedInvasiontomuscularispropriaorbeyondormetastases
Smallcellcarcinoma
Ileum, colon, rectum
Confinedtomucosa-submucosa≤1cm(smallintestine)
Confinedtomucosa-submucosa>1cm(smallintestine)
WelltomoderatelydifferentiatedInvasiontomuscularispropriaorbeyondormetastases
Smallcellcarcinoma
≤2cm(largeintestine).Novascularinvasion
>2cm(largeintestine)orvascularinvasion
Appendix Non-functioningConfinedtotheappendicealwall
Enteroglucagon-producingConfinedtosubserosa
WelltomoderatelydifferentiatedInvasiontomesoappendixorbeyondormetastases
Smallcellcarcinoma
≤2cm.Novascularinvasion
>2cmorvascularinvasion
HPF, high power field. Adapted from Ramage et al. 2005 19
16
�Functioningendocrinetumoursorcarcinomasarestilltraditionallynamedaccordingtothehormone(s)thatareproducedsuchasgastrinomas,insulinomasandvasoactiveintestinalpeptide-omas (‘VIPomas’) 20.The termcarcinoid is reserved for thefunctioningwell-differentiatedendocrinetumours,whichproduceandsecreteserotoninandtherebycausetheso-calledcarcinoidsyndrome.Thetermmalignantcarcinoidisreservedforthefunctioningwell-differentiatedendocrinecarcinomas.Poorlydifferentiated(usuallysmallcell)endocrinecarcinoma,whichischaracterisedbyhighgrademalignancy,isnolongerassociatedwiththetermcarcinoid.
WiththeuseofthenewWHOclassificationtheindividualtumourwithintheheterogeneousgroupofendocrinetumourscanbebetterclassifiedaccordingtotheirhistology,biologicalbehaviourandclinicalpresentation.Mostoftheendocrinetumours, includingthosedescribedwithinthis thesisarewell-differentiated,slowgrowingandhavearelativegoodprognosis.Withrespecttothetumoursdescribedinthisthesis,theterms‘endocrine’and‘neuroendocrine’canbeconsideredsynonymous.Sincetheresultsdescribedwithinthepresentthesisarecomparedwithstudiesfromthepast,thetumournomenclaturemaydifferfromthemostrecentWHOdefinitions.WherepossiblethenewWHOclassificationisused.
TREATMENT
Evaluation of therapy outcomeThetreatmentofGEP-NETsisextremelyvariableanddifferenttreatmentmodalitiesarecurrentlyusedanddeveloped.Tohave insight inandforcomparisonwiththereportedoutcomesof thedifferenttreatmentoptions, it isnecessarytobefamiliarwiththemethods,whichareusedtomeasureandcomparetheoutcomesoftreatment.
Themostobvioustreatmentoutcomeorendpointofastudy,especiallyinearlyphaseIIclinicaltrials,istumourreduction.However,itisoftennotclearwhichtumourresponsecriteriahavebeenusedorwhatismeantwithpartialresponseorremission(PR),stabledisease(SD)orprogressivedisease(PD)mentionedinthethosestudies.Moststudiesdiscussedinthisgeneralintroductionuseestablishedcriteria,suchasthecriteriaoftheWHO,ResponseEvaluationCriteriainSolidTumours(RECIST)orcriteriadefinedbytheSouthwestOncologyGroup(SWOG).DefinitionsofthesedifferentcriteriaareshowninTable3.
Theuseofthistypeofcriteriaallowsbettercomparisonofresultsamongpatientstreateddifferently.However,tofullyunderstandandcompareclinicaltrialsitisimportanttorealizethesedifferences.Themostimportantdifferencebetweenthesecriterialieswithinthemethodofmeasuringthetumours(bidimensional
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�versusunidimensional).Thismayleadtodifferentresponseoutcomeinthesamepatientwhenothercriteriaareused.Asthedefinitionofprogressivediseaseisalsodifferentinallcriteria,differencescanbeexpectedespeciallywhenestablishingthenumberofpatientswithPD21.Also,althoughoutcomeoftherapybasedontumoursizemeasurementseemstobestraightforward,ithasthedisadvantagethatitdoesnottakeintoaccountthatinhibitionoftumourgrowth,resultinginSD,canbealsoofsignificantclinicalbenefitandviceversa;thatresponsedoesnotperseimplyclinicalbenefitwheninformationaboutside-effects,qualityoflifeandtimetoprogression(TTP)islacking.Furthermore,onlymorphologicalinformationonradiological imagingiscurrentlyusedinassessingtumourresponsesfollowingthementionedcriteria,whereasinformationofmetabolicresponseassessedbymolecularimaging(e.g. Fluorodeoxyglucose-PositronEmissionTomography,FDG-PET)isnottakenintoaccount,butmaybepossiblyatleastasimportant.Inseveralstudies,itisreportedthatmetabolicresponsehadadditionalvaluetomorphologicalresponsedata 22,23. InthemanagementofGEP-NETs, forexample,controversyexistsintheclinicalimportanceoftheoccurrenceofabdominalfibrosiscommonlyseenincarcinoidpatients.Thisevidenceofdiseasewillremainstableinfollow-upbuthasnomeaningintermsofdiseaseactivity.Nonetheless,itwillbeincludedintheassessmentofmorphologicalresponse.It isthereforenotunlikelythatinthefuturethecurrentcriteriaforresponseevaluationinGEP-NETswillincluderesponsecriteriabasedonbothmorphologicalresponseandassessmentofmetabolicresponsebymolecularimagingoreventhatresultsofmolecularimagingcanserveasasurrogatemeasureoftherapeuticefficacy.
Inmostphase III trialsandsomephase II trialsmorestringentendpoints likesurvival,progressionfreesurvival(PFS),andTTPareused.Theseendpointsaremorelogicalwhenconsideringtumourresponseintermsofmetabolicactivity,especiallysincemoreandmorecancertherapeuticsarebasedontheinhibitionoftumourcellgrowthratherthantheinductionoftumourcelldeathorapoptosisinconventionalcytotoxicstrategies.Furthermoretheseendpointshavetheadvantageofassessingthetherapeuticefficacywithinaspecificpatientpopulationratherthanfortheindividualpatient.Obviouslyhowever,thesetrialsrequiretheinclusionofmorepatientsandlonger,carefullymonitoredfollow-up.Therefore,dataonPFSandTTPareoftenlackinginreportsonanti-tumouractivityofrecentlydevelopedanti-canceragents.Thedifferentandmostcommonlyuseddefinitionsofsurvivalandcorrespondingendpoints,aregiveninTable4.
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�Table 3.DefinitionofresponseaccordingtoWHO,RECISTandSWOGcriteria.
CriteriaTumour size measurement
CR PR SD PD
WHO a
Sumofproducts(bidimensional)
Disappearanceofallknowndisease
Confirmation≤4weeks
≥50%decreaseofalllesions;nonewlesion,noprogressionofanylesions
Confirmation≤4weeks
NeitherPRnorPDcriteriaaremet
Confirmation≤4weeks
≥25%increaseofasinglelesion;newlesion(s);noCR,PR,orSDdocumentedbeforeincreaseddisease
RECIST b, c
Sumofmaximumdiametersoftargetlesions
(unidimensional)
Completedisappearanceofalltargetandnon-targetlesions
Confirmation≤4weeks
≥30%decreaseofalltargetlesions;nonewlesion(s);noprogressionofdisease
Confirmation≤4weeks
NeitherPRnorPDcriteriaaremet
Confirmation≤4weeks
≥20%increase,newlesion(s);noCR,PR,orSDdocumentedbeforeincreaseddisease
SWOG d Sumofproductsoftheperpendiculardiametersofallmeasurablelesions(bidimensional)
Completedisappearanceallmeasurableandevaluabledisease
Confirmationat6weeks
≥50%decreaseofatleastonemeasurablelesion;noprogressionofevaluabledisease;nonewlesions
Confirmationat6weeks
NeitherCR,PRnorPDcriteriaaremet
Confirmationat6weeks
≥50%orincreaseof10cm2increase,orclearworseningofanyevaluabledisease,orreappearanceofanylesionwhichhaddisappeared,orappearanceofanynewlesion/site,orfailuretoreturnforevaluationduetodeathordeterioratingcondition
WHO, World Health Organization; SWOG, Southwest Oncology Group; RECIST, Response Evaluation Criteria in Solid Tumours; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease(a) Cancer 1981; 47:207-214(b) J Natl Cancer Inst 2000; 92:205-216(c) target lesions, all measurable lesions up to a maximum of five lesions per organ and 10 lesions in total,
representative of all involved organs(d) Investigational New Drugs 1992; 10: 239-253
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�Themostimportanttreatmentoutcomeiswhetherthestudiedtherapycanalterthenaturalhistoryofprogressionofthepatients’diseaseorincreaseofsurvival.Methodstostudythelatterendpointcanbefoundinsurvivalanalysisstudies.However,theslowlyprogressiveorindolentnatureofthediseasepresentinmostpatientsmakesthatsurvivalanalysisofGEP-NETsrequiresastudywithalongfollow-upperiod.Furthermore,thiscanbeadisadvantageintermsofdeterminingtheeffectivenessoftherapywithinalimitedperiodoftime.Also,carefulmonitoringduringfollow-up,preferablyinthehospitalwherethepatientwastreated,isnotalwayspracticallyfeasible.Inanidealsituation,survivalanalysiscontainsamatchedcontrolgroup,whichinsomestudiesis,forpracticalandethicalreasons,notavailable.Analternativeoptionistolookathistoricalcontrols.However,thismethoddoesnottakeintoaccounttheproblemofadifferentpatientmixandhistoricaltime-framedependentfactorssuchasdifferencesinavailabletherapeuticoptionsforthediseaseordevelopmentofmoresensitivediagnosticmodalities.
Table 4.Definitionofsurvivalandendpointsforclinicaltrials
Survival Term Definition† Endpoint
Overall survival (OS) Thepercentageofsubjectsinastudywhohavesurvivedforadefinedperiodoftime.Usuallyreportedastimesincediagnosisortreatment.
Deathfromanycause
Disease-specific survival
Thepercentageofsubjectsinastudywhohavesurvivedaparticulardiseaseforadefinedperiodoftime.Onlydeathsfromthediseasebeingstudiedarecounted.Subjectswhodiedfromsomeothercausearenotincludedinthecalculation.Usuallyreportedastimesincediagnosisortreatment.
Deathfromthediseasestudied
Time to progression (TTP)
Ameasureoftimeafteradiseaseisdiagnosed(ortreated)untiltheprogressivediseaseoccurs.
Progressivediseaseaccordingtotrialresponsecriteria
Progression-free survival (PFS)
Onetypeofmeasurementthatcanbeusedinaclinicalstudyortrialtohelpdeterminewhetheranewtreatmentiseffective.Itreferstotheprobabilitythatapatientwillremainalive,withoutthediseasegettingworse.
Progressivediseaseorcancer-relateddeath
Disease-free survival Lengthoftimeaftertreatmentduringwhichnocancerisfound.Canbereportedforanindividualpatientorforastudypopulation.
Relapse
Survival rate Thepercentageofpeopleinastudyortreatmentgroupwhoarealiveforagivenperiodoftimeafterdiagnosis.Thisiscommonlyexpressedas5-yearsurvival.
NA
† these definitions were quoted from the National Cancer Institue (NCI) website: www.cancer.gov; NA, not applicable
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�Otherfactors,whichareimportanttoreport,includechangesindisease-relatedsymptoms,adversereactions/complicationsandside-effects.Inmostcases,exceptforlife-threateningcomplications,thesefactorsarenotinfluencingtheprimaryendpointsofthestudy,suchasresponsetotreatment,TTPorsurvival,butareimportantinjudgingtheinfluenceofthetherapyonnormaldailylifeandnon-intendedeffectsoftherapy.Together,theseeffectshavetheirimpactontheso-calledqualityoflife.
Qualityoflifeisanentitythatisdifficulttodefine,andhence,difficulttoassess.Probablyoneofthemainreasonsforthisisthatitdiffersforanygivenindividual.Nonetheless,standardisedmethodstoassessqualityoflifehavebeendevelopedduringthelastdecades.Theseassessmentsofqualityoflifehavebecomeacommonlyandincreasinglyusedendpointinmanyoncologytrials.
Oneof the currentlyusedmethods to assessqualityof life is theQLQ-C30questionnairedevelopedbytheEuropeanOrganizationofResearchandTreatmentofCancer(EORTC)andcanbeusedforevaluationinalltypesofcancers.Forspecificcancersadd-onmoduleshavebeendevelopedincludingaseparatemoduleforGEP-NETs 24.BesidestheEORTCQLQ-C30questionnairemanyother instrumentshavebeendeveloped.However,despitethemanydifferentmethodsavailabletomeasurequalityoflife,reportsonGEP-NETsoftenlacktheassessmentofqualityoflife.Comparisonofchangesinqualityoflifebetweentreatmentsis,therefore,notpossible.
SurgeryResectionoftheprimarytumouristheonlycurativetreatmentoptionandremainsthecornerstoneinthetreatmentofpatientswithGEP-NETs.Surgerywithcurativeintentcanbesuccessful,especiallyinappendicealcarcinoids.Theappendixisoneofthemostcommonsinglesiteforcarcinoidtumour9.Althoughrare,itisconsideredthemostcommontypeofappendicealprimarymalignantlesion,andisfoundin0.3-0.9%ofpatientsundergoingappendectomy25.Smallappendicealendocrinetumours(<1cm)haveanexcellentprognosiswitha5-yearsurvivalrateof94%afterappendectomy.Largertumours(>2cm)requirerighthemicolectomy.Hemicolectomyshouldalsobeconsideredintumours1–2cminsizeif(a)themesoappendixisinvolved;(b)angioinvasionisdemonstrable;and(c)ahighproliferativeindex/Ki-67levelisapparent,and(d)whentumoursarelocatedatthebaseoftheappendixwithpositivemargins26,27.The5-yearsurvivalrateforpatientswithmorethanlocaldiseaseis85%27.Incontrast,surgerywithcurativeintentisoftennotpossibleinpatientswithendocrinetumoursinadjacentareassuchastheileumanddistaljejunum.Atthetimeofdiagnosisthetumoursarecommonlylargerthan2cmandhavealreadyinvadedthemuscularispropria.Typicalfindingsatlaparotomyarea
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�smallprimarytumourwithlargemesentericmetastaseswithmarkedsurroundingmesentericfibrosisordesmoplasticreactionduetolocaleffectsofserotoninandgrowthfactorsproducedbythetumour28.Theprimarytumourandmesentericmetastasesshouldberemovedbywedgeresectionofthemesenteryandlimitedintestinalresection,andlymphnodemetastasesoughttobeclearedasefficientlyaspossiblebydissectionintheareaofthemesentericarteryanditsbranches.Thisapproachhasbeenrecommendedsincewithoutthismanagementpatientsareatrisktodevelopabdominalcomplications,suchas intestinalobstructionduetoextensivemesentericdesmoplasticreactionorencasementofmesentericvessels.The lattermaycauseperiodic intestinal ischemiaorsegmentalgangrenewithsubsequentriskofperforation.Iftheprimarytumourandmesentericmetastasesappearradicallyremoved,thepatientsmayremainsymptom-freeforalongperiodoftime.However,after5-10yearsoffollow-up,tumourrecurrencesoccurfrequentlywithlivermetastasesinmorethan80%ofpatientswithlongfollow-up29.Besidesfrequentrecurrenceafterinitialresectionwithcurativeintent,cumulativeanalysisofalltypesofendocrinetumoursshowedthatin45%ofcasesmetastaseswerealreadyevidentatthetimeofdiagnosis12.
Inthecaseofmetastases,ofwhichlivermetastasesaremostfrequent,surgerywiththeintentiontocureisunlikelytosucceed.Inthesecasessurgeryoftheprimarytumourinapalliativesettingcanbebeneficialtothepatientintermsofimprovementofqualityoflife.Hightumourloadoftheprimarymaycausesignificantmorbidity,includingsecretionofhighamountsofhormonesandriskofmechanicalbowelobstruction,anddecreasedsurvival.
Thespectrumofclinicalpresentationinpatientswithlivermetastasesmayrangefrompatientswithprogressive liverdisease,accompaniedbyextremeclinicalsyndromessecondarytoincreasedhormoneproduction,tocasesinwhichpatientshavebeenknowntolivefordecadeswithremarkablylargelivermetastaseswithoutsymptomatology.Yaoet al.30indicatedthatsurgeryinpatientsinwhomthetumourwasstill insituandwhohadalso liver involvementwitha limitednumberofmetastases,mightberewardingintermsofextendedsurvival.Sixteenpatientshadcompletesurgicalresectionoftheirmetastasesofwhomtenhadsynchronousresectionoftheirprimarytumour.Thetotalgrouphada5-yearsurvivalof70%.Patientswithalimitednumberoflivermetastases(<5)hadafavourabledisease-freesurvivalof46monthscomparedto20monthsinpatientswithmorethan4livermetastases.Itwasconcludedthateveninpatientswithhepaticmetastasessurgeryhastobeconsidered.
Furthermore,ifthetumourbulkintheliveristooextensiveforcompleteresection,surgerymightalsohaveaplaceinpalliation.Severalstudieshavepointedoutthat
22
�forpatientsinwhomcytoreductivesurgeryortumourdebulkingofmorethan90%ofthetumourcanbeachieved,surgeryshouldbeofferedasitmayprolongsurvivalandalterthenaturalhistoryofthediseaseprocess31,32.Recently,anewpleaforthisaggressivesurgicalapproachofadvanced-stagecarcinoidtumourswaspublishedbyBoudreauxet al. 33.Thisapproachincludedsurgicalresectionoftheprimarytumourwhenpossibletopreventlifethreateningabdominalcomplications(suchasintestinalobstruction,ischaemiaorperforation),prophylacticcholecystectomytonegatethepossibilityoffuturegallstonedevelopmentassociatedwithlong-termoctreotidetherapyandstageddebulkingascomorbiditieswouldallow.Inpatientsinwhomsuchanapproachwasperformedmajorcomplicationswasencounteredin17%,minorcomplicationsin39%.Nonetheless,accordingtotheauthors,thesesurgicalinterventionsinpatientswithadvanced-stagediseaseprovidedsignificantimprovementsinqualityoflifeandpatientsurvival.However,despitethesestudiesthatadvocateanaggressiveapproach,suchanapproachhasnotbeenimplementedinallspecialisedcentres.IntheNetherlands,forexample,majorsurgeryinGEP-NETssuchasdescribedbyBoudreauxisnotwidelyaccepted.Reasonfora lessaggressiveapproachisprobablyacombinationoffactorsincludingthereportedhighcomplicationrate,thelackofrandomisedcontrolledstudiesandlackofqualityoflifedata.Therefore,althoughtheresultsofabovementionedaggressivesurgicalapproachcouldbenefitpatientswithGEP-NETsintermsofoutcome,survivalandqualityoflife,randomisedcontrolledstudieswithlongfollow-up,includingproperlydesignedqualityoflifeassessmentarenecessary.
Liver transplantationOrthotopic liver transplantation (OLT)hasbeenprogressivelyabandoned forthemanagementofhepaticmetastaticdiseaseofmostcarcinomasbecauseoftheunacceptablehighrecurrenceratewhichdoesnotjustifythecostoftheprocedureandtheutilizationofscarcedonororgans.However,inpatientswithGEP-NETs,thetumoursareusuallyslow-growing(withtheexceptionofpatientswithpoorlydifferentiatedendocrinetumours).Moreover,metastasesareoftenonlyconfinedtotheliverand,therefore,OLTcanbeavaluabletreatmentoption.Especiallysincethequalityoflifeofthesepatientsisoftenpoorduetopainanddebilityrelatedtohepatomegalyand/orhormoneproduction,endocrineGEPtumoursareoneofthefewmalignancieswherehepaticmetastasesarenotacontraindicationtolivertransplantation.Obviously,partialhepatectomy,followedbydebulkingorcytoreductivesurgeryarethefirstoptionsthathavetobereviewedinanypatient.Inmostcases,however,partialhepatectomyisnotpossiblebecauseofmultifocalandbilaterallocalisationofdiseasewhichispresentinapproximately90%ofpatientswhopresentwithlivermetastases34.Whenmedicaltherapyorinterventions(localablation/hepaticarterialembolisation)alsofailtocontrolthediseaseintermsofprogressionand/orsymptoms,theoptionofanOLTcomesinview.
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�Most reportsonOLTaresinglecentrestudies thatdescribea limitednumber(maximumof 19)ofpatientswith amedian follow-up ranging from 11 to 54months35.Therefore,theoutcomeofOLTintermsofsurvivalratescanonlybebasedonthethreelargemulti-centrestudieswith30ormorepatientsincluded36-38.AlthoughtheprimarygoalofOLTinmostcasesiscure,documentedrecurrence-free5-yearsurvivalratesinthesestudieswererelativelylow,rangingfrom17to24%37,38.Reported1-and5-yeartruesurvivalratesaftertransplantationrangefrom58-68%and35-47%39,respectivelyandarehigherthanhistoricalcontrols,whichhavedocumented5-yearsurvivalratesofapproximately30%40.However,randomisedstudiesarelackingandsincethepublicationofthesestudiesseveralnewtherapeuticstrategiesonOLThaveevolved,whichincreasetheoverallsurvival,especiallywithinthegroupofpatientswithdistantmetastases9.
Interestingfindingswerereportedinthelargestretrospectivemulti-centreanalysistodate38.Fourfactorsrelatedtooutcomewereidentified.Subsequently,aproportionalhazardsmodelindicatedthatageatorabove50andsynchronousupperabdominalexenterationorWhipple’sprocedurewereindependentfactorsofpooroutcome,whereaslocationoftheprimarytumour(lungorbowel)andpre-OLTsomatostatinanaloguetreatmentwerefavourableprognosticfactors.Patientswithfavourableprognosticindicatorshadanoverall5-yearssurvivalof65%andmediansurvivalofmore than8years. In contrast,patientswhohadextendedoperationwithabdominalexenterationorWhipple’soperationhad1-and5-yearsurvivalof50%and31%,respectively.Theroleoftumourbiologyasdeterminedbythreedifferentimmunohistochemicalmarkers,Ki-67,E-cadherinandp53,wasreportedinthelargestsinglecentrestudy41.UsingthecombinationofKi-67andE-cadherintheauthorswereabletoshowsignificantdifferencesbetweenlong-termsurvivorsandpatientswhodiedearlyafterOLT.
IncontrasttotherelativelygoodresultsofOLT,thepostoperativemortalityishigh,reportedtobe10%at30daysand14%at60days38.ThishighmortalityrateisprobablyoneofthereasonswhyOLThasnotbeenimplementedinthemanagementofpatientswithGEP-NETsinmosttransplantationcentres,includingthoseintheNetherlands.Furthermore,surgeonsoftenhesitatetoperformOLTatthetimemetastaticspreadisevident,becauseoftheriskofearlytumourspreadsecondarytotheeffectsofimmunosuppressionafterOLT.
Inconclusion,livertransplantationformetastaticGEP-NETsiscontroversial.Whenconsidered,theoverallconsensusisthatOLTshouldbeconsideredonlyincarefullyselectedindividuals,basedonthepatients’age(<50years),extensionofintendedsurgeryandKi-67/E-cadherinexpression.However,theexactrole,includingfindingoptimalhistopathologicalclinicalcriteriatopredictclinicaloutcomeandtheexact
24
�timingofOLT,needtobedefinedinlargemulti-centrebasedprospectivestudies.
Furthermore,treatingphysiciansshould,atthepointofdefiningthebesttreatmentfortheindividualpatient,alwaysrealizethatalthoughnotimpossible,cureafterOLTisimprobable.ThismeansthatOLTinapatientwithextendedhepaticdiseasewillusuallybeconsideredasthelastpossibleoptionforeffectivepalliationandimprovementofsurvival.Furthermore,itmaybequestionedwhetheratthattimeofdiseaseevolution,thepatientisstillacandidateformajorsurgery.
LOCAL THERAPY
External Beam RadiationExternal beam radiation therapy (EBRT)neverhad an important role in themanagementofpatientswiththerelativelyradioresistantGEP-NETs.Furthermore,thelocationofliverandabdominalmetastaseslimitstheuseoftraditionalEBRT.Therefore,reportsontheeffectivenessofEBRTinpatientswithneuroendocrinetumoursare limited.However,occasionally,EBRThasbeenappliedfor locallyinoperable carcinoid andpancreatic islet cell carcinomas 42,43. Small seriesofpatientstreatedwithEBRTofwhichthelargestincludedatotalofsixtypatientsindicatedthatonlyinselectedpatientssubstantialsymptomaticimprovementcanbeachieved44,45.ThesereportsshouldberegardedseparatelyfromthosethatdescribeEBRTinpatientswithbrainandbonemetastaseswhohavespinalcordcompressionorbonepaindueto localtumourexpansion. Inthosecases,EBRTremainsthestandardpalliativetherapy45.
Hepatic Artery (Chemo) Embolisation Hepaticarteryembolisation(HAE)inGEP-NETsisbasedonthefactthatmetastasesreceivemostoftheirbloodsupplyfromthehepaticartery.Incontrast,thenormalhepaticparenchymareceives20-25%ofitsbloodsupplyfromthehepaticarteryand75-80%fromtheportalvein.HAEwillinducetumournecrosisbyselectiveinductionoftemporarybutcompleteischaemiainhypervascularlivermetastasesbyblockingbranchesofthehepaticarteryandthustheoxygensupply.
The combinationof localiseddeliveryof a cytotoxic compound followedbyembolisationiscalledhepaticarterychemoembolisation(HACE).Thisintravasculartechniquemakesitpossibletodeliveracytotoxicdruginverycloseproximitytothetumourcells.ForHACE,thecytotoxicagentmostoftenusedisdoxorubicin(Adriamycin).However,othercytotoxinsand/orcombinationshavealsobeenused46,47-49.
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�Candidatesforembolisationarepatientswhohaveadvancedstagediseasewithmultiple livermetastases thatarenotamenable tosurgical cure.However, inHA(C)E,despiteadvancesininterventionaltechniques,carefulpatientselectionisrequired,asdisease-andalsotreatment-relatedadverseeffectsmaybesignificant.Absolutecontraindicationsincludeportalveinthrombosis,liverfailureandbiliaryreconstruction(i.e.afteraWhippleprocedure).Relativecontraindicationscanbetumourloadexceeding50%oftheliver,contrastallergy,moreextrahepaticthanhepaticdisease,andpoorperformancestatusofthepatient50,51.
Theembolisationprocedureisinmostpatientsfollowedbyacomplexofsymptomsandreactionssuchasmildandtransientnauseaandvomiting(50–70%),abdominalpain(50–60%),feverupto38.5°C(30–60%)andraisedlivertransaminases(100%)oftenreferredtoasthepost-embolisationsyndrome52.Suchsymptomsareeasilycontrolled,butpatientsshouldbemadeawarethatsuchsymptomsmightpersistforseveraldays.Majorcomplicationsarerarelyseen,butrenalandliverfailureandbleedingpepticulcershavebeenobserved.
Furthermore,embolisationmayleadtoseriouscomplicationsinindividualpatients(gallbladderischaemia,pancreatitis,liverabscess,vasculardamageandaneurysmformation,hepatorenalsyndromeandhormonalcrisis).Themortalityrateinthemajorseriesislessthan5%53.Consideringtheriskofcomplicationsandrelativelyhighmortalityrate,chemoembolisationhastobeperformedinexperiencedhandsandspecialisedcentres,whicharenotwidelyavailable.
AlthoughHACEhasnotbeencomparedinarandomisedmannerwithHAEtodate,encouragingresultssuggestthatembolisationcombinedwithintra-arterialchemotherapyisatleastaseffectiveaswithoutchemotherapy.TumourresponseratesafterchemoembolisationaregiveninTable5.
Objective tumour response rates arewidely variable and range from 33 to79%46-49,55-58.Mediandurationofresponsevariedfrom6–21months.Differencesinnumberofpatientsandtumourtypestudied,protocolandtumourresponseevaluationcriteriausedandchoiceofcytotoxiccompoundemployedvariedwidelywhichmakesinterpretationandcomparisonbetweenthedifferentstudiesverydifficult.Furthermore,inmostpatientschemoembolisationwasnotperformedasfirst-linetherapy.Thesepatientshadadditionalmedicaltherapy(e.g.octreotides.c.)beforeorduringtreatmentwhichcanbeaconfoundingfactorintheobservedresults.Interestingly,inthelargeststudytodate,predictorsofefficacywereidentified57.Arterialenhancementonabdominalcomputedtomographyandbodymassindex(BMI)werefactorsthatwerepositivelycorrelatedwithTTPinmultivariateanalysis,thussuggestingthatthecytoreductiveeffectonthetumourbyHACErequires
26
�hypervascularityofthetumour.ThequestionwhytheBMIhasaneffectontumourresponseafterHACE ismorecomplicated.Severalhypothesesarementionedincluding(a)aninversecorrelationofBMIwithtumouraggressivenessand(b)higherdosagesgiventopatientswithelevatedBMIastheinjecteddoseofchemotherapywasbasedonthebodysurfacearea.Still,noclearevidencefortheseexplanationsispresentand,therefore,theresultsarestillunderdebate.Furthermore,althoughitwasnotarandomisedstudy,resultswithstreptozotocinsuggestedanatleastequaltherapeuticefficacycomparedtodoxorubicin.StreptozotocinwasthereforerecommendedtobeusedwithHACE,therebysavingthecardiotoxicdoxorubicinforpossiblenecessarysubsequentintravenouschemotherapy.
Radioembolisation Thetechniqueofradioembolisationinvolvestheadministrationofmicrosphereslabelledwith radioactive isotopes to induce hepatic artery occlusion andsimultaneouslydeliverlocalirradiation.Thistechnique,developedbythegroupofGrady59inthesixties,wasinitiallyintroducedasasafeprocedureinthemanagementoflivermetastasisofcarcinoidtumoursin197160.Themethod,reintroducedin1994bythegroupofShapiro61,wasperformedintwenty-fourpatientswithlivermetastasis,includingsixpatientswithmetastaticGEP-NETs.InthispreliminaryphaseIstudyin1994,glassmicrospheresloadedwith90Ywereused.Althoughencouragingdatawerepresented,itwasuntilrecentlythatmorereportsonradioembolisationinpatientswithmetastasizedGEP-NETstreatedwith90Y-microsphereswerepublished62,63.IneightpatientswithunresectableneuroendocrinehepaticmetastasesMurthyet al.63reportedonePR,fourcasesofSD,andthreecasesofPD.Mediansurvivaltimeswere14months(range,3-15months)fromthetimeoftreatmentand36.5months(range,16-105months)fromthetimeofdiagnosisofhepaticmetastases.
Inanotherreport,hundredthirty-sevenpatients,including19patientswithGEP-NETsunderwent225administrationsof90Ymicrospheresbyarterialinfusion62.BasedonWHOcriteria,43%ofalllesionsdemonstratedPR,47%hadSDand10%hadPD.Limitationsofthisstudyincludedtheheterogeneousgroupstudied,withoutspecifiedtumourresponsespersubgroup.Furthermore,thereportedresponseperlesionwasstudiedratherthantheclinicallymorerelevantresponseperpatient.Unfortunately,themediansurvivalrateof25.9monthsforneuroendocrinetumoursinasubgroupanalysiswastheonlyspecificdatagivenonGEP-NETs.FutureresearchontheuseofradiolabelledmicrospheresinthecohortofpatientswithGEP-NETs,aswasmentioned,willbeimportanttodelineateitsroleinthemanagementofGEP-NETpatients.
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�
Tab
le 5
. Chem
oembo
lisation
ingastroenteropancreaticneuroendo
crinetumou
rs
Ref
eren
ces
No
. Pat
ien
ts/
Tu
mo
ur
Ty
pe
*C
hem
oth
erap
y†
Sust
ain
ed r
elie
f (%
)in
sym
pto
mat
ic
pat
ien
ts
5-H
IAA
dec
reas
e(>
50%
, CA
RC
on
ly)
Per
cen
tage
Ob
ject
ive
Res
po
nse
(cri
teri
a)
Med
ian
res
po
nse
d
ura
tio
n(m
on
ths)
Therasse,199
347
23/CARC
DOX
100
9135
(WHO)
‗‗
Ruszniewski,199346
18/C
ARC,5/ICC
DOX
7357
33(W
HO)
21
Perry,19
94
4815/C
ARC,15/IC
CDOX
90‗‗
79‡
(WHOin19
/24pts)
‗‗
Clouse,199
455
14/C
ARC
§DOX
9069
78
(WHO)
8.5
Diaco,199
556
10/C
ARC
CDDP,
MMC,D
OX
||100
‗‗60
(unkn
own)
42.5
(mean,6pts)
Ruszniewski,200058
8/CARC,7/ICC
STZ(1.5g/m
2 )67
5053
(WHO)
10.5
Roche,2003
4910/C
ARC,4other
DOX
7075
71
(WHO,includ
ingMR)
‗‗
Marrache,200757
31/C
ARC,36
other**
DOX(23),
STZ(4
4)
9165
37
(RECIST)
14.5
NA
, not
app
licab
le; *
CA
RC
, car
cino
id t
umou
rs; I
CC
, isl
et c
ell t
umou
r; †
, DO
X, d
oxor
ubic
in (
adri
amyc
in )
; STZ
, str
epto
zoci
n; M
MC
, mit
omyc
in C
; CC
DP,
cis
plat
in;
5-H
IAA
, 5-h
ydro
xyin
dole
acet
ic a
cid;
‡, >
50
% d
ecre
ase
of h
orm
onal
secr
etio
n an
d/or
> 5
0%
dec
reas
e in
tum
our
size
; §, m
ostl
y ca
rcin
oid;
all
14 tu
mou
rs w
ere
func
tion
ally
ac
tive
; ||,
incl
udin
g se
quen
tial
intr
a-ar
teri
al 5
-fluo
rour
acil
and
daily
oct
reot
ide
acet
ate
adm
inis
trat
ion
; **,
36
pati
ents
incl
udin
g IC
C; p
artl
y ad
apte
d fr
om O
’Too
le
200
3 54
28
�Alsorecently,90Y-lanreotidehasbeenusedintra-arteriouslywithintheliverof23patientswithGEP-NETs,withencouragingresults.Itwasreportedthat3outof19(16%)evaluablepatientshadPR,12(63%)hadSDand4(21%)hadcontinueddiseaseprogression.Fourpatientsdiedbeforetherapyevaluationcouldbeperformed.However,sincethesepatientsmostprobablydiedbecauseofthetreateddisease,theyshouldhavebeenincludedinthereportedresults.Thecorrectedoutcomewouldbe3outof23(13%)patientshavingPR,12outof23(52%)SD,and4outof23(17%)PDdespitetreatment.Symptomaticcontrolwasobservedin14outof23(61%)64. Intrahepatic-arterial injectionofradiolabelledsubstancesmayachievehigherintratumouralconcentrationsandmaybeofvalueintreatingisolatedhepaticlesions.However,inthemanagementofdisseminatedGEP-NETs,whichisthecaseinmostpatients,radioembolisationisprobablylesshelpful,especiallyinthelong-termcontrolofthedisease.
Local ablative therapy Local,imaging-guidedablationtechniques,suchasradiofrequencyablation(RFA),laser inducedthermotherapy(LITT)orcryotherapyarewidelyusedto inducetumourreductionininoperablehepatocellularcarcinomasandlivermetastasesfromcolorectalcarcinomas65,66.RFAusesradiofrequencywavesthatareconvertedtoheat.Itisappliedwithanelectrodedirectlyinthecentreofatumourandsubsequentlyresultsincellulardestructionattemperaturesabove60°C.LITTisbasedonalmostthesameprincipleexceptthatwiththistechniquetheheatisinducedbyalaserbeam.Hepaticcryotherapyorablationinvolvesfreezingandthawingoflivertumoursbymeansofacryoprobeinsertedintothetumours.Allthesetechniqueshavetheadvantagethatnormallivertissueispreserved.
A fewsmall seriesandcase reportsof thesedifferent techniqueshaveshownexcellentresultswithtumourresponsesinupto97%ofpatientswithneuroendocrinehepaticmetastases67-70.Furthermore,thelargeststudyof34patientstreatedwithRFA,including18withcarcinoid,9withisletcelltumoursand7withmedullarythyroidcarcinoma,showedsymptomreliefin95%ofpatientswithsignificantorcompletesymptomcontrol in80%,withameandurationof 10months(range6–24months)67.Disadvantagesofthesetherapies,however,include(a)highrateofreportedcomplications,suchasabscess formation, haemorrhage and biloma, (b)abscessformation,haemorrhageandbiloma,(b)livermetastasesaretreatedonly,and(c)onlyintrahepatictumourswithrelativelysmallvolumearetreated.InlargeclinicaltrialswithRFA,itwasdemonstratedthateradicationoftumourswithdiameteroflessthan4cmismorelikelythanthatoflargertumours71.However,recentlyVeenendaalet al.70reportedthatwiththeuseofsimultaneousmultiplefibreLITTorbipolarRFA,ablationoftumoursaslargeas7cmindiameterandupto7lesionsinonesessionisfeasible.Still,numerouslesionsandcloseproximitytothemainvesselsoftheliverremainthemostimportant
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�reasonsnottoperformLITTorRFA,andtostartothertherapies.Cryotherapywasalsoreportedsuccessfulintermsofsymptomcontrolandobjectivetumourresponses65,72,73.Thistypeoftherapycanthereforeberegardedasanimportantsupplementtosurgicalresectionandallowsregionaldestructionof lesionsnotamenabletoresection.
Unfortunately,carefullyconducted(large)prospectivestudiesforthesedifferentlocaltherapiesarelacking.Nonetheless,withanoverallcomplicationrateof5-10%andamortalityrateof0.5%forRFAandLITTinlargestudieswithnon-neuroendocrinetumours74-76,localtherapeuticmodalitiessuchasthesecanbeconsideredinselectedpatientswitha limitednumberof localhepaticrecurrencesornewmetastasesdevelopingduringfollow-upifotherinclusioncriteriaaremetaswell.
MEDICAL THERAPY
Somatostatin analoguesWhensurgery isno longer anoption inpatientswithmetastaticdiseaseandsymptomsoccur,mostpatientsare treatedwithsomatostatinanalogues.Theoctapeptideanaloguesofsomatostatin,ofwhichoctreotideandlanreotidearethemostcommonlyused,arecyclicpeptidesthatareresistanttopeptidasedegradation.Consequently,aprolongedhalflifeof1.5-2hoursisachieved,whichisconsiderablylongerthanthatofthenativeformsofsomatostatin(1-2minutes).Furthermore,thesesomatostatinanaloguesdifferfromnativeformsofsomatostatinintheiraffinitytothedifferentreceptorsubtypesastheseanaloguesexhibithighaffinitytotheSSTR2and5,moderateaffinitytotheSSTR3andverylowaffinitytotheSSTR1andSSTR4,whereasthenativesomatostatinformshavehighaffinitytoallsomatostatinreceptorsubtypes.However,sinceSSTR2isexpressedinmorethan80%oftheclassicalmidgutcarcinoidtumoursandin50-80%oftheendocrinepancreatictumours,thesestablesomatostatinanaloguesaresuitablefortherapy.Besidesprovidingsymptomaticreliefbysuppressionofhypersecretionofhormonesandtherebyimprovementormaintenanceofthepatients’qualityoflife,therapywithsomatostatinanaloguescan inhibit tumourgrowth.Theefficacyofsomatostatinanaloguetherapycanbedividedintosubjective,biochemicalandobjectivetumourresponses.Inthefirsttrialin25symptomaticcarcinoidpatientswhoweretreatedwithoctreotidesubcutaneously(150µgthree-timesdaily),symptomaticimprovement(reductionofflushingand/ordiarrhoea)wasobservedin22/25(88%)patients.Biochemicalresponse,whichwasdefinedasa50%ormoredecreaseof5-hydroxyindoleaceticacid(5-HIAA)levels,wasobservedin17/25(72%)ofpatients.Themediandurationofthebiochemicalresponsewas12months(range1tomorethan18months) 77.Thecauseofdiminishedeffectivenessofoctreotideanaloguesinthelong-term,awell-recognisedphenomenon,hasnotbeennotfullyelucidatedyet78.However,as
30
�somatostatinreceptorscintigraphywiththesimultaneoususeofoctreotideanalogsinpatientsisrelativelyunaffectedandthereforewithdrawalprobablynotmandatory79,80,itislikelythatthisphenomenonoftachyphylaxisortherapyresistanceisbasedonapost-membranereceptordefectratherthaninvolvingthesomatostatinreceptoritself.
Inameta-analysis,whichcompiledthestudiesthatfollowedthefirsttrial,Gordenet al.81reportedsymptomaticimprovementin92%andbiochemicalresponsesin66%.Reductionoftumoursizewasnotedinonly8%andstablediseasein85%.
Besideadministrationofsomatostatinanaloguesbydailyinjection,slow-releaseformulationsbecameavailable,whichcanbeconsideredanimportantimprovementinthedailymanagementofpatients.Long-actingreleaseSandostatin(Sandostatin-LAR®;onceevery2-4weeks)andlanreotideprolongedrelease(Lanreotide-PR®;onceeverytwoweeks)inwhichoctreotideorlanreotidehavebeenincorporatedintomicrospheresofabiodegradablepolymer,areabletocontrolthesymptomsaswellastheshort-actingformulations,howeverwithouttheburdenofdailysubcutaneousinjections82.
Commonearlyside-effects,especiallywiththedailyformulation,includenausea,abdominalcramps,loosestools,mildsteatorrhoeaandflatulence.Mostside-effectsstartquicklyafteradministrationandaredose-dependent,butsubsidespontaneouslyafterthefirstweeksoftreatment83.Persistentside-effectsofsomatostatinanaloguesarefew.However,paradoxicaldiarrhoeacanoccur.Furthermore,inductionofgall-stoneshasbeenreportedinupto13-60%inpatientswithacromegalyonlong-termoctreotidetreatment84.However,inmanyofthesepatientsbilesludgeispresentinsteadoffullblownstones.Furthermore,onlyinasmallminorityofpatientswithrealstones,thesebecomesymptomatic.
Patientswithfunctioningtumoursoftenusethelongactingreleaseformulation(LAR)ofoctreotide,likeSandostatin-LAR,withdosesupto30mg/month.However,upto40%ofthepatientsneedrescuemedicationseveraltimesaweekfortheacutecontrolofsymptoms83.Wolteringet al.85demonstratedthatdosesof30mg/monthleadtoplasmalevelsof5xtheKdofoctreotidefortheSSTR2(Kd≈1x10-9mol/L),butfailtoachievetheplasmaconcentrationsthatwillcompletelysaturatetheSSTR2.Itwasconcludedthatthiscouldexplaintheneedforhigherdosesinsomepatientsandthatfrequentmeasurementofoctreotidebloodlevelscouldguideoctreotidetherapy.Furthermore,theuseofLAR,atdosesof60mg/monthwasadvocatedinthosepatientswithpoorsymptomcontrolortumourgrowthdespitenormallydosedLARtherapy.
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�In summary, somatostatinanaloguesarehighlyeffective in the symptomaticmanagementofpatientswithovertsymptomsofGEP-NETs.However,itisstillcontroversialwhethertreatmentwithsomatostatinanaloguesmustbestartedinordertoinduceinhibitionofproliferationofthetumour, ifprogressionoccursinpatientswithoutsymptomsorwithnon-functionaltumours.Thedoseshouldthenpreferablybewithinthehighrangeofthenormaldosagescheme.However,itmustbestressedthatbecauseofthesmallchancesofsuccessinrelationtothehighcosts,theuseofsomatostatinanaloguesasananti-neoplastictherapyisquestionedbymany86.
InterferonInterferon(IFN)-alphawasintroducedintheearly1980sasatreatmentoptioninpatientswithGEP-NETsbythegroupofÖberg87.Inarecentmeta-analysistheyreportedtheresultsoftreatmentwithrecombinantIFN-alpha88.Themediandoseusedwas5millionunitsofIFN-alphaeveryotherdaysubcutaneously.Themedianbiochemicalresponseratefrompooledstudieswas44%andthemediantumourresponserate11%.However,nosurvivalanalysiswasavailable,asmostpublishedstudieswerenotrandomisedcontrolled.Furthermore,frequentadversereactionstoIFN-alphaincludedtemporary‘flu-like’symptoms,chronicfatiguesyndromeandmentaldepression.Thelattertwocandevelopinvaryingseverityatvariousgradesinupto50%ofpatients.Auto-immunereactionswerealsoreportedandoccurredin15-20%ofpatients.Mostfrequentofthesewasthyroiddysfunction.Thesignificantlyhigherincidenceandseverityofadverseeffects,andlowerbiochemicalresponseratecomparedwithsomatostatinanaloguesmakesIFN-alphanotthefirstchoiceofmedicaltherapyinpatientswithGEP-NETs.
CombinedtherapywithIFN-alphaandsomatostatinanalogueswasproposedtoincreasetheantiproliferativetherapeuticeffect.SeveralstudiesindeedreportedencouragingresultsoftheadditionofIFN-alphatooctreotide89,90.However,incontrast to thesestudies, the firstprospective, randomized,multi-centre trialthatstudiedtheeffectofsomatostatinanalogue(lanreotide),IFN-alphaandtheircombinationfortherapyofmetastaticGEP-NETsindicatedthatnosignificantlyhigherantiproliferativeeffectcouldbeachievedwiththeadditionofIFN-alphatolanreotide91.Whenboththerapieswerecomparedassingletherapy,nodifferenceswereevident.However,treatmentwithlanreotidewasgenerallywelltoleratedandonlyafewminorside-effectsoccurred.IFN-alpharelatedside-effectsweremorecommonthanthoseattributabletolanreotide91.
Systemic ChemotherapyTheuse of chemotherapy in patientswithGEP-NETs is limited because ofdisappointingresultsandhigh incidenceofmajorside-effects.Mostobjective
32
�responseswerereportedinwell-differentiatedpancreaticorduodenaltumours.Single-agentchemotherapydemonstratedlackofobjectiveresponsesandhightoxicityandwasthereforereplacedbycombinationalchemotherapyinstudiesthatfollowed.Thebestresultswereobtainedwiththecombinationofstreptozotocinwitheitherdoxorubicinorfluorouracil(5-FU).Objectiveresponsesforthecombinationofstreptozotocinwith5-FUinGEP-NETsaspublishedbyMoertelet al.rangedfrom45to63%92,93,whereasthecombinationofstreptozotocinanddoxorubicinhadsimilarobjectiveresponsesinupto69%92,94.However,theseimpressiveresultswereneverreproducedinlaterstudies.Interestingly,Chenget al.95whoreportedontheeffectofcombinationtherapywithstreptozotocinanddoxorubicinhadonly1outof16(6%)patientswithmajorobjectiveresponsebystandardCTcriteria.
ThedifferencebetweentheirresultsandthosefromMoertelet al.92wasexplainedbythedifferencesintheresponsecriteriaused,whichincludedclinicalmeasurementofhepatomegalyonphysicalexamination,ormeasurementonradionuclideliver-spleenscanning,asanindicatorofamajorobjectiveresponseintheearlystudiesbyMoertelet al.93,96.Nonetheless,othershavereportedrelativelyhigherobjectiveresponseratesof36%-55%94,97,98.Meandurationofresponsesinthestudiesthatusedstreptozotocinanddoxorubicinrangedfrom14-22months.Atthismoment,thecombinationofdoxorubicinandstreptozotocinisregardedasthestandardchemotherapyinpatientswithprogressivewell-differentiatedendocrinepancreaticorduodenalcarcinoma98,99.Inpatientswithwell-differentiatedcarcinoidofmidgutoriginthebestresults,intermsofthehighestobjectiveresponse,wasalsoreportedwithdoxorubicinandstreptozotocin100.Fortypercentofpatientshadanobjectiveresponse.Theseresults,however,wereonlyestablishedinasmallnumberofpatientsandwereneverreproducedsincethen.
Withtheuseofstreptozotocinanddoxorubicinmajorside-effectshavetobetakenintoaccount.Streptozotocincaninducerenalimpairment.Renalinsufficiencyinupto30%ofpatientstreatedwithstreptozotocinwasreported.Therefore,thekidneysaredoselimiting93.Obviously,carefulmonitoringofrenalfunctionisnecessarytopreventrenaldamage.Cardiacfunctionisthedoselimitingfactorforchemotherapywithdoxorubicin.Developmentofdoxorubicin-associatedcardiomyopathy isdose-dependentandcongestiveheartfailurewasreportedinmorethan4percentofpatientswhohadreceivedacumulativedoseof500-550mgofdoxorubicinpersquaremeter.Incidencerosetomorethan18percentatdosesover550mgm-2101.
Otherchemotherapeuticagents, likedimethyltriazenoimidazolecarboxamide(DTIC)ordacarbazineprovedtohaveminimalactivityinpatientswithmetastaticcarcinoidtumoursorneuroendocrinepancreatictumours102-104.AnoverviewofthemoststudiedchemotherapymodalitiesisgiveninTable6.
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�
Tab
le 6
. Resultsandside-effectsofchem
otherapyinpatientswithneuroendo
crinetumou
rs
Regim
en
Tumou
rTy
pes
No.of
Patients
PRand
CR(%)
MedianRespo
nse
Duration(mon
ths)
Haematologic
ToxicityGrade
3and4(%
)
Nausea
andVom
iting
(%)
OtherM
ajorSide-effects
Stud
y
Doxorub
icin
CARC
3321*
4NA
NA
—Moertel96
5-FU
CARC
1926*
3NA
NA
—Moertel96
STZ/5-FU
CARC
4333*
7NA
NA
—Moertel96
STZ
NEP
4236*
170
83Renaltoxicity,29%
;liverfailure,2%
Moertele
t al.
93
STZ/5-FU
NEP
4263*
1729
85Renaltoxicity,31%
Moertele
t al.
93
STZ/5-FU
NEP
3345*
725
81Diarrhoea,33%
;renalin
sufficiency,7%
Moertele
t al.
92
STZ/doxorub
icin
NEP
3669
*20
580
Diarrhoea,5%;renalin
sufficiency,4%;
heartfailure,9%
Moertele
t al.
92
STZ/doxorub
icin
NEP
166
>18
19NA
Diarrhoea,19%
;cardiactoxicity,19%
ChengandSaltz
95
DTIC
CARC
1513
4NA
NA
—VanHazele
t al.
104
DTIC
CARC
5616
329
88Diarrhoea,23%
Buk
owskie
t al.
102
DTIC
CARC/N
EP
714
NA
NA
0—
Ritzele
t al.
103
5-FU
/IFN
-αCARC/N
EP
2421
1342
NA
Diarrhoea,8%
Andreyeve
t al.
105
Mitoxantron
eCARC
359
1432
26—
Neijte
t al.
106
Paclitaxel
CARC/N
EP
244
361
63Diarrhoea,54%
;neurologictoxicity,61%
Anselle
t al.
107
Abb
revi
atio
ns: P
R, p
arti
al r
emis
sion
; CR
, com
plet
e re
mis
sion
; DT
IC, d
imet
hylt
riaz
enoi
mid
azol
e ca
rbox
amid
e; 5
-FU
, fluo
rour
acil;
STZ
, str
epto
zoto
cin;
CA
RC
, car
cino
id;
NEP
, neu
roen
docr
ine
panc
reat
ic t
umou
r; N
A, n
ot a
vaila
ble;
IFN
-α, i
nter
fero
n-al
pha.
* R
espo
nse
eval
uati
on in
clud
ing
bioc
hem
ical
res
pons
es a
nd p
hysi
cal e
xam
inat
ion
for
eval
uati
on o
f hep
atom
egal
y.A
dapt
ed f
rom
Kw
ekke
boom
et
al. 10
8
34
�Inrecentyears,newchemotherapeuticagentsandregimenshavebeenevaluated,includinghighdosepaclitaxeladministeredwithgranulocyte-colonystimulatingfactor, docetaxel, gemcitabin and irinotecan in combinationwith 5-FU andLeucovorin107,109-111.However,mosttherapystrategiesprovedtobedisappointinginGEP-NETpatientsandsomeofthemhadconsiderablytoxicityprofiles.Promisingistheuseoftemozolomide,acytotoxicalkylatingagentthatwasspecificallydevelopedasanoralandlesstoxicalternativetoDTIC,incombinationwiththalidomide.Thiscombinationalregimenwasusedin29patientswithmetastaticcarcinoid(n=15),pheochromocytoma(n=3),orpancreaticneuroendocrinetumours(n=11)112.RadiologicresponseaccordingtoRECISTcriteriawasdocumentedin5(45%)patientswithpancreaticNETs,1(33%)patientwithpheochromocytomaand1(7%)patientwithacarcinoidtumour.Therefore,thisstudysuggestsmoreefficacywiththisregimeninpatientwithpancreaticNETsthanincarcinoidtumours.
Poorlydifferentiatedendocrinecarcinomas(PDEC)arepreferentiallytreatedwiththecombinationofetoposideandcisplatin.Highresponserateswithobjectivetumourresponseinupto65%ofpatientswerereported 113,114.However,thedurationofresponsewasoftenverylimitedandrarelyexceeded10months.Inaddition,reportedpercentagesofnephrotoxicityandneutropeniawerehigh.InthemostrecentphaseIIclinicalstudyin78patientswithPDEC,patientsweretreatedwithathree-drugregimenofpaclitaxel,carboplatin,andetoposide115.Forty-one(56%)patientshadmajorresponses(ofwhom15%completeresponse).Survivaldatashowedmedian,2-year,and3-yearsurvivalratesof14.5months,33%,and24%,respectively.
Clearly,thecombinationofcisplatin/carboplatinandetoposidewithorwithoutanadditionalchemotherapeuticagentiscurrentlythemosteffectivetherapeuticregimenofsystemicchemotherapyforPDECprovidedthepatienthasadequateorganfunctionandperformancestatus.
Inconclusion,withinthecurrentlypublishedEuropeanguidelinesfortheManagementofpatientswithGEP-NETsasproposedbytheEuropeanNeuroendocrineTumourSociety(ENETS)chemotherapyusingcombinationsofstreptozotocin,doxorubicinand5-FUisindicatedinpatientswithprogressiveadvancedmetastaticorsymptomaticdiffusemetastaticforegutNETswithlivermetastases,notinNETsfrommidgutorigin 116. Also, in colorectalNETswithmoderately towell-differentiatedhistopathologychemotherapyhasnorolewithinthetherapeuticarmamentarium117.Cisplatin/carboplatinplusetoposideisrecommendedinpatientswithNETswithpoorlydifferentiated(i.e.above20%Ki-67positivecells)tumoursregardlessoftheoriginoftheprimary118,119.
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�INTERNAL RADIOTHERAPY
Meta- [131I] Iodobenzylguanidine (MIBG) TherapyMeta-iodobenzylguanidine(MIBG)isanarkyl-guanidinederivative,structurallysimilartonoradrenaline,whichutilizesthevesicularmonoaminetransportersandisincorporatedintovesiclesorneurosecretorygranulesinthecytoplasm120.However,it isnotsignificantlymetabolized.MIBGshowslittlebindingtopost-synapticreceptorsandcauseslittleornopharmacologicalresponse121.Itmaybelabelledby123Iforimagingor131Iforbothimagingandtherapy.
MIBGscintigraphyhasbeenusedformanyyearstovisualizecarcinoidtumoursasitisconcentratedinendocrinecells122.Thismethodwasinitiallydevelopedtodetecttumoursarisingfromchromaffincellssuchasphaeochromocytomas,paragangliomasandneuroblastomaswithoverall reportedhigh sensitivityof approximately90%andspecificityashighas99%122,123.Althoughwithlowersensitivity,MIBGscintigraphywasthereafterutilizedtodetectneuroendocrinetumours.However,MIBGscintigraphyincarcinoidtumours,includingtheinitiallyuseddiagnostic131I-MIBGscintigraphy,hasshownlowersensitivitythan111In-octreotidescintigraphy.Inarecentreview,thecumulutiveresultsoftwentyyearsofexperiencewithMIBG,includingMIBGscintigraphy,mediandetectionrateandsensitivityof50%and76%,respectively,wasshown 124. Incontrast, the largest review, that includedpooledimagingdatafrom35centerswithintotalmorethan1200patientswithcarcinoidtumours,describedthat111In-octreotidescintigraphyhasamediandetectionrateof89%(range67%to100%)andamediansensitivityof84%(57%to93%)125.Furthermore, imagingwith 123I-MIBGhasapoorsensitivityinidentifyingisletcelltumours126.Interestingly,withinthefewstudiesthatcompared123I-MIBGandsomatostatinreceptorscintigraphyincarcinoidtumours,acomplementaryroleof123I-MIBGscintigraphyhasbeennotedeitherasadifferentintensityorasadifferentpatternofuptakeinnon-octreotideavidregions126,127.Inonereportinwhichadirectcomparisonbetweenthesetwoimagingmodalitieswasperformed,comparableresultswithsensitivitiesofabout84%weredemonstrated,whereasthecombinationofthesescansincreasedthesensitivityto95%127.Itwasconcludedthat111In-octreotidescintigraphyismoresensitiveindetectingmetastaticlesionsfromGEP-NETsthan123I-MIBGscintigraphy,withthelatterimagingmodalityusefulintheoccasionalpatientwhohasMIBG-avidlesions,butdidnotshowanyuptakewiththeinitiallyperformed111In-octreotidescintigraphy128.
BesidesdiagnosticandstagingpurposesofMIBGscintigraphyinGEP-NETs,itcanalsobeusedtoidentifypatientsfor 131I-MIBGtherapy. 131I-MIBGtherapyhastheadvantagethatthetreatmenttargetsallsitesofdisease,includingdistantmetastases,aswasshownon 123I-MIBGscintigraphyperformedbeforetherapy.Treatment
36
�protocolsvarybetweendifferentcentres.Theusuallyprescribeddosesof131I-MIBGrangebetween7.4and11.2GBq(200–300mCi),administeredat3-6monthsinterval.Occasionally,dosesupto14.8GBq(400mCi)pertreatmentareused.Tominimizethyroidal131Iuptake,potassiumiodide(120-150mg/d)isgivenbefore,during,andseveraldaysafterthetherapy.
Reportedtumourresponsesafter 131I-MIBGtherapyinpatientswithmetastaticcarcinoiddiseaserangefrom13-35%129-132,withobjectivetumourshrinkagein15%and13%ofpatientsinthetwolargeststudiescomprising52and75patients,respectively,whocouldbeevaluatedwithCT/MRI129,132.
Ingeneral,biochemicalresponse,whichwasdefinedassignificantreductioninthetumourmarkerlevelssuchaschromograninAor5-HIAA,didnotfollowthetumourresponseandwasdemonstratedin37-46%130,132.
Symptomaticcontrolwasdemonstratedinevenahigherproportionofpatients.In49to87%131I-MIBGtherapypatientshadadecreaseofsymptoms130,132-134.Furthermore,besidesthisobviouspalliativeeffect, 131I-MIBGtherapyalsoprovedtobecost-effective.Pathiranaet al.133evaluated12patientswithcarcinoidsyndromeandfoundasignificantreductioninoctreotidedosagesin8patientsafter 131I-MIBGtherapy,whichresultedindecreaseduseofoctreotideandtherebyminimizedcosts,evenincludingthecostsofthe131I-MIBGtherapies.
Althoughsymptomalleviationhasbeenwelldescribedinthemajorityofpatients,andpartialtumourresponsesdooccur,completeradiographicresponseshavenotbeenreportedwith131I-MIBGtreatment.
Reportsonsurvivalinpatientswithneuroendocrinetumours(includingcarcinoids)treatedwith131I-MIBGarefew.Recently,twostudiesreportedsurvivalbenefitwhenpatientswithcarcinoidtumourweretreatedwithatleast15GBq131I-MIBGgivenover6months132,135.Furthermore,symptomaticresponsetotreatmentinpatientswhohadprogressivediseasewasassociatedwithanimprovementofmediansurvivalof44months(5.76versus2.09years)comparedwithpatientswhohadnosymptomaticresponse 132.Interestingly,objectivetumourresponseandreductionofhormonelevelsdidnotcorrelatewithimprovedsurvivalinthestudiedpatients.Withinthesamestudy,adirect,lineardosedependentrelationwasfoundbetweeninitialdoseandsurvival.Aninitialdoseof400mCi131I-MIBGwasrecommendedforfurtherstudies.
Ingeneral,131I-MIBGtreatmentiswelltoleratedwithside-effectslimitedtonauseaorvomitingin24-72hrafteradministration,mildhepaticdysfunctionwithspontaneous
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�recoveryandtemporarymyelosuppression4-6weekspost-therapy.Onlyincidentallypatientsmaydevelopsignificantside-effectssuchasseveremyelosuppression,especiallywhenextensivemetastaticspreadwithinthebonemarrowispresent,orhepaticfailureinpatientswithwidespreadlivermetastases136.Furthermore,thefrequencyandseverityofmosthaematologicalside-effectsareclearly(cumulative)dosedependent130,132.
Methodstoenhance131I-MIBGuptakewiththeintenttoincreasetheeffectivenessoftherapywereexploredandincludedtheuseofpremedication,suchasnifedipineandunlabelledMIBG,ortheintra-arterialdeliveryofthedose.Blakeet al.137founda2-foldincreaseintumouruptakeafterpremedicationwithnifedipineinpatientswithmalignantphaeochromocytoma.Hoefnagelet al. 138achievedanimprovedtumourtonon-tumour(T/NT)ratioincreaseof7.8–111.4%at24hron131Ilabelled(‘hot’)MIBGscintigraphyin17of24patientswithcarcinoidtumoursbypre-treatingthemwithcoldMIBG.Theauthorsclaimthatthiscouldbeanadvantageconsidering131I-MIBGtherapyincarcinoidpatientswithinitiallowuptakeonMIBGscintigraphy,facilitatinghigher 131I-MIBGuptakeinmetastaticlesionsafterpre-treatingwithcoldMIBG.However,thedemonstratedincreasewasbasedonanincreaseofT/NTratiosinsteadofabsoluteuptakevalues.Therefore,adecreaseofbackgrounduptake,whichislikelyaftercoldMIBG,couldhaveaccountedfortheobservedincreaseofT/NTratioaswell.
Inanotherstudy,intra-arterialtreatmentcomparedtointravenousadministrationof131I-MIBGinpatientswithmostlycarcinoidsresultedinupto4-foldhighertumouruptake(mean1.7-fold)of131I-MIBGinlivermetastases139.Again,thereportedhighertumouruptakewasinfactahighertumourtowhole-bodyactivityratioinsteadofabsolutetumouruptake.Intra-arterialtreatmentwith131I-MIBGwasclaimedtobeasafealternativetostandardintravenousapplication.
Innoneof theabovementionedstudies thepotentialbenefitof theenhanced131I-MIBGuptakeintermsofeffectivenesswasstudied.Randomisedstudiesbetweenunenhancedversusenhanced131I-MIBGdelivery,whichalsoincludemeasurementofabsoluteuptakevaluesarewarrantedtoassesthetruepotentialbenefitofthesetherapeuticstrategies.
Inconclusion,internalirradiationtherapywith131I-MIBGisgenerallysafeandwelltoleratedwithonlyafewacuteandlong-termadverseeffects. 131I-MIBGtherapyappearstooffereffectivepalliationwithsymptomaticcontrol.Despitethefactthatobjectivetumourresponsescanbefoundonlyinaminorityofpatients,studiessuggestthattheremaybeasurvivalbenefit.
38
�Peptide Receptor Radionuclide TherapyAsmentionedearliersomatostatinreceptorsarepresentonthemajorityofGEP-NETs.Besidestargetedtherapywithsomatostatinanalogueslikeoctreotideorlanreotide,thetumourscanbevisualisedinpatientsusingtheradiolabelledsomatostatinanalogue[111Indium-DTPA0]octreotide(OctreoScan®).Thenextlogicalstepafterthesuccessfulimagingwastotrytouseradiolabelledsomatostatinanaloguesasatreatmentinthesepatients.Peptidereceptorradionuclidetherapy(PRRT)withradiolabelledsomatostatinanaloguesisarelativelynewandpromisingtreatmentmodalityforpatientswithinoperableormetastasisedGEP-NETs.Chapter1.2ofthisthesisgivesareviewoftheroleandtherapeuticplaceofPRRTinthewholearmamentariumoftreatmentmodalitiesinthemanagementofpatientswithendocrinetumours.
MOLECULAR THERAPYRecently,therehasbeenincreasinginterestintheuseofmolecularlytargetedtherapyforpatientswithmetastasisedendocrinetumours.EspeciallymoleculartargetswithinthetumourcellsuchastheBcl-2andBaxgene,whicharebothinvolvedinthecascadeofapoptosisandvascularendothelialgrowthfactor(VEGF)whichisinvolvedinangiogenesis,butalsoplateletderivedgrowthfactor(PDGF),epithelialgrowthfactorreceptor(EGFR)andmammaliantargetofrapamycin(mTOR)whicharefactorsknowntobeinvolvedincontrolofgrowth,havebecomemoleculartargetsfortherapy.Targetedtherapieswithinhibitorsandantibodiesagainstthesemoleculartargetsarecurrentlyclinicallytested.AsummaryofthedifferenttherapiesandstageofclinicaltrialsisgiveninTable7.
Therapywithimatinib(Glivec®),areceptortyrosinekinase(TK)inhibitor,whichtargetsthe activated portion of the BCR-ABL oncoprotein and the tyrosine kinasestheactivatedportionoftheBCR-ABLoncoproteinandthetyrosinekinasesofthec-kitreceptorandPDGFreceptor,hasbeensuccessfullyappliedinpatientswithchronicmyeloidleukaemia140andingastrointestinalstromaltumours141.BothPDGFandPDGFreceptorsareexpressedinendocrinetumours.Therefore,theeffectofimatinibwasevaluatedinaphaseIItrial inpatientswithadvancedcarcinoidtumours.Oneoutof27patientshadanobjectiveresponse,17hadstabledisease,and9hadprogressivediseaseasevaluatedbytheRECISTcriteria142.
Therapywhichtargetsangiogenesis iscurrentlyclinicallyevaluatedandcanbegroupedbymechanismoftargeting:(1)bycounteractingVEGFwithmonoclonalantibodies,suchastheVEGFblockinghumanizedmonoclonalantibodybevacizumab(Avastin®);(2)smallmoleculesthatinhibitthereceptorTKdomainsoftheVEGFandPDGFreceptor, suchas sunitinib (Sutent®), sorafenib (Nexavar®) and (3)othercompoundswithdifferentantiangiogenicmechanisms,suchasthalidomide(Thalomid®)orendostatin143.
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�Althoughnotyetpublishedinpeer-reviewedjournals,severaltrialsareplannedoralreadyongoing.Thepreliminaryresultsofthesetrialsareingeneralpromisingandhavebeenpresentedonscientificmeetings.
ThefirstpreliminaryreportedclinicaltrialonbevacizumabtherapyinGEP-NETswasperformed in44patientswithadvancedcarcinoid tumourswhowereonstabledosesofoctreotide.Patientswererandomizedtoadditionallyreceiveeitherbevacizumab15mg/kgonanevery3weeksbasisorpegylatedinterferonalpha-2bweekly(0.5µg/kg)during18weeks 145.Bevacizumabwassuperiortopegylatedinterferonalpha-2bbothintermsofprogressionfreesurvivalandsuppressionoftumourbloodflowmeasuredbyfunctionalcomputedtomographyscan.ThisresultledtotheplannedphaseIIItrialinwhichpatientswithadvancedpoor-prognosiscarcinoidtumourundercontrolwithdepotoctreotidewillberandomizedtoreceiveeitheradditionallyinterferonalpha-2bsubcutaneouslyorbevacizumab.
Smallmulti-TKinhibitors,suchassunitinib,sorafenibandvalatanib,arecurrentlyinvestigatedfortheireffectinpatientswithGEP-NET.Clinicalresultshavebeenonlypublishedforsunitinibwhichhasbeenapprovedinpatientswithmetastaticrenalcellcarcinoma146.PreliminarydataofalargephaseIItrialwith106patientsreporteda15%objectiveresponseinpatientswithmetastaticisletcellcarcinomasand2%objectiveresponseinpatientswithcarcinoidtumours,alongwithhighratesofdiseasestabilization(75%forisletcellcarcinomasand93%forcarcinoids)147.Thesestudiessuggestthattyrosinekinaseinhibitionmaybeausefultherapeuticstrategyinthisdisease.However,whetherthesepatientshadprogressivediseaseatstudyentry,whichisimportanttojudgetheoutcomeofstablediseaseinrelativeslow-growingtumourswasnotindicated.Furthermore,unfortunately,nodefinitivepeer-reviewedpublicationfollowedthispreliminaryreportyet.
Gefitinib,asmall-moleculeinhibitoroftheEGFRtyrosinekinasedomain,iscurrentlystudiedinpatientswithGEP-NET,andpreliminarydatashowedthatoneof40patientswithcarcinoidshadPR148.Withinthegroupofisletcellcarcinomas(n=31),2hadPRand1MR.Inpatientswithcarcinoiddisease,23of38(61%)andinpatientswithisletcellcarcinomas,9of29(31%)wereprogression-freeat6months,whichwasconsideredpromising.Inaddition,32%(12/38)ofcarcinoidand14%(4/29)ofisletcellcarcinomapatientshadalonger(atleast4months)TTPthantheTTPdocumentedpriortostudyentry.Side-effectswithhigh-gradetoxicitywereinfrequent.Clearly,gefitinibcanbepromisinginthetreatmentofGEP-NETsinthefuture.
40
�Table 7. Moleculartargetedagentsingastroenteropancreaticneuroendocrinetumours
Agent Generic name (Trade Mark) Stage of development
VEGFmonoclonalantibody
Bevacizumab(Avastin®). Inphase-IIIdevelopment
Smallmulti-tyrosinekinaseinhibitor
Sunitinib(Sutent®) Phase-IIcompleted
Vatalanib Phase-IIinprogress
Sorafenib(Nexavar®) Phase-IIinprogress
Pazonpanib Phase-IIinprogress
PDGFR/c-kit/bcr-ablinhibitor
Imatinib(Glivec®) Phase-IIcompleted
EGFRinhibitor
Gefitinib(Iressa®) Phase-IIcompleted
mTORinhibitor
Everolimus(RAD001;Certican®) Inphase-IIIdevelopment
Temsirolimus(CCI-779) Phase-IIcompleted
Other
Bortezomib(Velcade®) Phase-IIcompleted
VEGF,vascularendothelialgrowthfactor;PDGFR,platelet-derivedgrowthfactorreceptor;EGFR,epidermalgrowthfactorreceptor;mTOR,mammaliantargetofrapamycin
Adapted from Yao et al. 144
Mammaliantargetofrapamycin(mTOR)isaserine/threonineproteinkinasethatisessentialinthecontrolofcellgrowth,proteinsynthesis,andautophagy.Inhibition ofInhibitionofmTORmayinhibitabnormalcellproliferation,tumourangiogenesis,andabnormalcellmetabolismandtherebypotentiallybeeffectiveasacancertherapy149.
Althoughnotpublishedtodate,thefirstphaseIIhumanclinicaltrialswithmTORinhibitorsinlow-gradeGEP-NETsarecurrentlyunderway.Preliminarydataontheuseof10mgoforaleverolimusdailycombinedwith30mgintramusculardepotofoctreotideevery4weeksshowedthat10outof60(17%)patientshadPR,45(75%)hadSDand5(8%)hadPD150.Thisoutcomeismorethancouldbeexpectedfromtheuseofalong-actingoctreotideformulaalone.However,aneffectofoctreotide
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�treatment,whetherdirectorsynergisticalwitheverolimuscannotbeexcluded.Everolimuswaswelltoleratedincombinationwithoctreotide.Toevaluatetheeffectinlargerpatientgroupsfurtherresearchinclinicaltrialsisplanned.
Inthefirstpublishedstudywithtemsirolimus,twooutof36(6%)patients(21withcarcinoid,15withisletcellcarcinoma)whoreceivedintravenoustemsirolimusonaweaklybasis,achievedPRbyRECISTcriteria.Twenty-threeoutof36(64%)ofpatientshadPRorSD151.Surprisingly,theauthorsconcludedthattemsirolimusappearstohavelittleactivityanddoesnotwarrantfurthersingle-agentevaluationinadvancedneuroendocrinecarcinomas.However,aswasclearlyexplainedbyO’DonnellandRatain152,64%patientswithtumourcontrolaftertherapyanda1-yearprogressionfreerateof40%inagroupoftreatedpatientsthathadprogressivediseaseatentryofthestudyissuggestiveofdrugactivitybeyondthenaturalcourseofdiseaseandthusaneffectivetherapy.Furthermore,theoutcomecomparesfavourablywithagentslikesomatostatinanaloguesandinterferon-alphathatwerepreviouslystudiedinGEP-NETs.Therefore, itwasconcludedthatfurtherresearchontheeffectivenessoftemsirolimusasasingle-agenttherapyinGEP-NETsshouldnotbeabandoned.Theauthorsmadeclearthatsingle-armstudieshavetobecarefullyanalysedorevenabandonedandthatrandomisedtrialsaresuperiorforstudyingnewtherapeuticagents.
Inconclusion,therecentdevelopmentsinmolecularlytargetedtherapyingeneraloncologyhaverenewedtheinterestoftreatmentofpatientswithGEP-NETswithsystemictherapy.Preliminaryresults frommostlyphase IIclinicalstudiesarepromising,butlargeconfirmatorystudiesarewarranted.
CONCLUDING REMARKSThisreviewindicatesthevarietyoftherapeuticapproachesandthemultitudeoftechniquesthatcanbeemployedinthetreatmentofpatientswithGEP-NETs,especiallywhenmetastaticdiseaseisevident.AtthatmomentthemanagementofGEP-NETspatientsisadifficult,butchallengingtask.AnexampleofanalgorithmforclinicaldecisionmakingisgiveninFigures1aand1b.Figure1adisplaysthemanagementofpatientswithlimited(resectable)disease,whereasinFigure1bthetherapeuticalstrategiesarepointedoutwiththeintenttodecreasethetumourburdenasmuchaspossibletoestablishanincreaseofpatients’well-beingandsurvival.Nonetheless,notalwaysthebest therapeuticaloptionischosenastherapeuticdecisionsareoftenbaseduponthetechniquelocallyavailableand/orontheevidencelevelofexpertopinion.Therefore,therapeuticmanagementdecisionsforthisgroupofpatientshastobeplacedinamultidisciplinaryteam-basedsetting,sothatthebesttherapeuticaloptionforeachindividualpatientcanbechosen.Specialistswithinsuchateamshouldideallyincludeanendocrinologist,oncologist,(endocrinespecialised)
42
�surgeon,(intervention)radiologist,nuclearmedicinephysicianandpathologist.Furthermore, inpatientswithseverepain,aradiotherapistoranaesthesiologistshouldbeconsultedforoptimalpalliation.Also,sincethepatientsaresufferingfromararedisease,treatmentandfollow-upshould,ifpracticallyfeasible,beperformedinatertiary(university)referralhospitalwithfacilitiesforexperttreatment.Inthisway,thefullspectrumoftreatmentmodalitiescanbeofferedandappliedsothatoptimalmanagementofpatientswiththesetumoursisguaranteed.
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�
Figu
re 1
a.Initialm
anagem
entofgastroenteropancreaticneuroendo
crinetumou
rs(GEP-NETs)
44
Figure 1b.Managementofmetastaticgastroenteropancreaticneuroendrocrinetumours(GEP-NETs)
Abbreviations: IFN-α, interferon-α; RFA, radiofrequency ablation; LIT T, laser-induced Interstitial thermotherapy; PD, progressive disease; SD, stable disease; MR, minor response; PR, partial response
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1.1
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1.2Peptide receptor radionuclide therapy
Jaap J.M. Teunissen, Dik J. Kwekkeboom, Marion de Jong, Jan-Paul Esser, Roel�� Valkema
and Eric P. Krenning
Best Practice & Research Clinical Gastroenterology 2005; 19: 595–616
AbstractPeptidereceptorradionuclidetherapyisanewtreatmentmodalityforpatientswithinoperableormetastasisedneuroendocrinegastroenteropancreatictumours.Afterthesuccessfulimplementationofsomatostatinreceptorscintigraphyindailyclinicalpractice,thenextlogicalstepwastoincreasetheradiationdoseoftheadministeredradiolabelledsomatostatinanalogueinanattempttoinducetumourshrinkage.Sincethen,anincreasingnumberofpatientshasbeensuccessfullytreatedwiththisapproach,resultinginasubstantialnumbersofpatientwithobjectivetumourshrinkage.Seriousside-effectshavebeenrare.Thisarticlereviewstheeffectivenessofthedifferentradiolabelledsomatostatinanaloguesused,thecurrentlyknownside-effectsandthesurvivaldataavailable.Furthermore,clinicalissues,includingindicationandtimingoftherapy,arediscussed.Finally,importantdirectionsforfutureresearcharebrieflymentionedto illustratethat,althoughthecurrentlyavailableresultsalreadysuggestafavourableoutcomecomparedwithothersystemictherapies,newstrategiesarebeingdevelopedtoincreaseefficacy.
Abstract INTRODUCTIONSomatostatin receptor (SSTR) scintigraphy,whichwasdeveloped in the late1980s,hasbecomeanimportantimagemodalityinpatientswithSSTR-positivetumours1,2.Thisisnotonlybecauseofitshighsensitivityforvisualisingsomatostatin-positivetumoursandtherebyitsabilitytolocaliseotherwiseundetectabledisease,butalsobecauseoftheselectionofknownmetastaticdiseaseforpeptidereceptorradionuclidetherapy(PRRT)withradiolabelledsomatostatinanalogues.Thisnewmodalityoftargetedtherapyisverypromising,especiallyinpatientswithinoperableormetastaticgastroenteropancreatic(GEP)tumours(i.e.gastrointestinalcarcinoidsandfunctioningandnon-functioningpancreaticendocrinetumours).
RADIONUCLIDES AND SOMATOSTATIN ANALOGUES IN PEPTIDE RECEPTOR RADIONUCLIDE THERAPY SeveralradiolabelledsomatostatinanaloguesarecurrentlyusedtotreatpatientswithSSTR-positivemetastasisedGEPtumours.Theseconjugatesallconsistofasomatostatinanalogue,suchasoctreotideoroctreotate,acomplexingmoiety(orchelator)andaradionuclide.Thechelator,whichisattachedtothesomatostatinanalogue,allowsastableconnectionbetweentheanalogueandtheradionuclide.Thebasicprincipleoftumour-targetingaftersystemicadministrationoftheconjugateinvolvesbindingtoSSTRs,whichareexpressedonthecellsurfaceofthetumourcell,followedbyeffectiveinternalisationoftheradionuclide-peptidecomplex3–5.TheemittedradiationcandamagetheDNA,whichmaysubsequentlyleadtotheinductionofcelldeath.Inclinicalpractice,differentcombinationsofradionuclidesandsomatostatinanaloguesareusedtotargettheSSTR-positivetumour.TheseanaloguesdifferfromeachotherintheiraffinityforthevariousSSTRsubtypes.Thisvariableaffinityisimportantbecauseitcanhavegreatinfluenceontheclinicaleffectivenessoftheradiolabelledsomatostatinanalogue.Theavailableradionuclidesandsomatostatinanaloguesusedwillbediscussed.
Radionuclides in peptide receptor radionuclide therapyIndium(111In),yttrium(90Y)andlutetium(177Lu)havebeenthemostfrequentlyusedradionuclidesfortargetedradiotherapyinthevariousclinicaltrialsoverthepastdecade.Differencesinthephysicalpropertiesoftheseradionuclides,whichareimportantfortheeffectivenessofthetherapy,relateto,forexample,emittedparticles,particleenergyandtissuepenetrationrange(Table1).
111In,coupledviathechelatorDTPAtoD-Phe1-octreotide([111In-DTPA0]octreotide;111In-octreotide),wasusedinthefirstclinicaltrialsinwhichpatientswithmetastasisedGEPtumoursweretreatedwithradiolabelledsomatostatinanalogues6–8.
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Table 1.Physicalcharacteristicsoftheradionuclidesusedinpeptidereceptorradionuclidetherapy
Radionuclides Emitted ParticleParticle energy
(mean keV)
Maximum Tissue Penetration Range
(~ number of cells *)
Half-life (days)
Indium(111In) Augerelectronsγ-radiation
3and19keV171and245keV
10µm(<1) 2.8
Yttrium(90Y) β-radiation 935keV 12mm(~600) 2.7
Lutetium(177Lu) β-radiationγ-radiation
130keV113and208keV
2mm(~100) 6.7
* Number of cells based on an average tumour cell size of 20 μm; ~, approximately
Besidesγ-radiation,whichmakes111Inasuitableradionuclideforimaging,itemitsbothAugerandconversionelectronswithamedium-to-shorttissuepenetrationrange (0.02–10 and 200–500µm, respectively). In vitro PRRT studieswith[111In-DTPA0]octreotide showed that the therapeuticeffectwasdependentoninternalisation,whichenablestheAugerelectronstoreachthenucleus9.TheseresultssuggestthattheAugerelectronsandnottheconversionelectronscanbeheldresponsibleforthereportedtumourresponseswith111In-labelledsomatostatinanalogues.InanattempttoincreasetheefficacyofPRRT,clinicaltrialsthatfollowedusedβ-emittingradionuclides,suchas90Yor177Lu.Radionuclidesemittingβ-radiationhavegreatertherapeuticpotentialsincetheemittedparticlerangeexceedsthecelldiameter10–12.
Furthermore, theability to irradiateneighbouringcells is anadvantagewithtumours,suchasbreastcarcinomas, thatarecharacterisedbyaheterogeneousSSTRtissuedistribution,withregionsofhighdensitynexttoregionsthatlackreceptorexpression13.Asexpected,theclinicalandpreclinicalstudiesinwhich90Y-or 17 7Lu-coupled somatostatin analogueswereuseddemonstratedmoreeffectivenessintermsoftumourshrinkagethanwasreportedwithsomatostatinanaloguescoupledto111In14–17.O’Donoghueet al.12,whousedamathematicalmodeltoexaminetumourcurabilityanditsrelationshiptotumoursizefor22β-emittingradionuclides,calculatedanoptimaltumourdiameterforcureof34and2mmfor90Yand177Lu,respectively.Withrespecttothesecalculations,thepreclinicalstudiesbydeJonget al.14,18,inwhichLewisratsbearingSSTR-positivepancreaticCA20948tumoursofdifferentsizes(0.1–15cm2)weretreatedwith[177Lu-DOTA0,Tyr3]octreotate
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(177Lu-DOTATATE)and[90Y-DOTA0,Tyr3]octreotide(90Y-DOTATOC)areofspecialinterest.Aftertreatmentwith177Lu-DOTATATE(totalcumulativedose555MBq,maximumestimatedtumourdose60Gy),ahighercureratewasobservedinthegroupofratsbearingsmalltumours(<1cm2)thanintheratsbearinglargertumours(>1cm2,meanapproximately5cm2).Incontrast,treatmentwithasingledoseof370MBq90Y-DOTATOC, leadinguptoamaximumof60Gy in themedium-sized(3–9cm2)tumours,showedlesscurewithinthegroupofratsbearingsmall(<1cm2)tumourscomparedwiththeratsbearingmedium-sizedtumours(Figure1) 19.Theseresultssuggestedthattreatmentwithacombinationof90Y-and177Lu-labelledsomatostatinanaloguescanbemoreeffectiveinthetreatmentofmultipletumoursthatdifferinsizethancanoneoftheanaloguesseparately.Recently,deJonget al. 20 reportedtheresultsofsuchacombinationversussingleanaloguetherapy. Inratsbearingbothasmall (<0.5cm2)anda largetumour(7–9cm2),significantlybettersurvivalwasobservedafterPRRTwiththecombinationof185MBq(half-dose)90Y-DOTATOCand278MBq(half-dose)177Lu-DOTATATEthanafterasinglefulldoseof370MBq90Y-DOTATOCor555MBq177Lu-DOTATATE.TotranslatetheseresultstotheclinicalsettingwithpatientswithGEPtumours,90Y-labelledsomatostatinanaloguesmaybemoreeffectiveinlargertumours,whereas177Lu-labelledsomatostatinanaloguesmaybemoreeffectiveinsmallertumours,withthecombinationofbothradionuclidesasthemostsuitabletherapyfortheclinicalsituationinwhichmostpatientshavetumourmetastasesvaryinginsize.
Unfortunately,randomisedcontrolledclinicalstudiescomparingthetherapeuticefficacyof90Yand177Lusomatostatinanaloguesorcombination-basedregimensarestilllacking.
Somatostatin analogues in peptide receptor radionuclide therapyThevarious111In-,90Y-or177Lu-labelledsomatostatinanaloguesdifferintheiraffinityfortheexpressedSSTRs.FivehumanSSTRsubtypes(SSTR1–SSTR5)thatbindnativehumansomatostatin(SS14)anditshigh-affinity28aminoacidprecursor(SS28)havebeencloned21–23.However,theiraffinitiesforsyntheticsomatostatinanaloguesdifferconsiderably.The‘cold’analogueoctreotide,whichisfrequentlyusedtocontrolsymptomsrelatedtohormoneoverproductionbyGEPtumours,bindswithhighaffinitytoSSTR2andwith lowaffinitytoSSTR3andSSTR5,whereasitdoesnotbindtoSSTR1andSSTR424,25.Furthermore,autoradiographystudiesbyReubi et al. 26demonstratedthat,afterlabellingoctreotide,viaDTPA,with111In,theaffinitiestoSSTR2andSSTR5werediminished(Table2).
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60
Figure 1. Curerate(expressedaspercentageofcuredrats)foundingroupsofratsbearingCA20948 tumours of different indicated sizes after treatmentwith 370MBq [90Y-DOTA0,Tyr3]octreotideor555MBq[177Lu-DOTA0,Tyr3]octreotate (maximumestimatedtumourdoseof60Gyforbothtreatments).CR,completeresponse;PR,partialresponse.(ModifiedfromdeJonget al. 14).
However,despitethechangeinaffinities,SSTR2remainsthereceptorsubtypeforwhich[111In-DTPA0]octreotidehasthehighestaffinity.Hoflandet al.27demonstratedthattheuptakeof[111In-DTPA0]octreotideintheSSTR-positiveorgansofmicewaspredominantlydeterminedbySSTR2.Moreover,Johnet al.28demonstratedthatapositive[111In-DTPA0]octreotidescintigraminpatientswithneuroendocrinetumoursismainly theresultofSSTR2expression,whereasSSTR1,SSTR3,SSTR4andprobablySSTR5arelessimportant.RadiolabelledsomatostatinanaloguesthathadahigheraffinityforSSTR2thandid111In-octreotide,andwerethereforepotentiallymoreeffectivefortherapy,thusbecameavailable.Smallstructuralchangesintheradioligandmolecule,forexampleadifferentradionuclide,chelatororpeptide,revealeddistinctdifferencesinthebindingpropertiesoftheanalogueforthevariousSSTRsubtypes(Table2)26.
Inanimalexperiments,several111In-labelledsomatostatinanaloguesshowedahigherspecificuptakethan 111In-labelled[DTPA0]octreotideinSSTR-positiveorgans5.Furthermore,theanalogue[DOTA0,Tyr3]octreotatehasaninefoldhigheraffinityforSSTR2comparedwith[DOTA0,Tyr3]octreotide,whereastheaffinitiesforSSTR3andSSTR5werefoundtobelower26.InlinewiththehigheraffinityforSSTR2,biodistributionstudieson 111In-octreotideand 177Lu-DOTATATEscintigraphyshowedathree-tofourfoldhighertumouruptakeinfouroutoffivepatientswith
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somatostatin-positivetumours,ofwhomthreehadGEPtumours29.AsmostGEPtumoursareknowntopredominantlyexpressSSTR2,allclinicalstudiesselectedaradiolabelledsomatostatinanalogueforPRRTwithat leastahighaffinityforSSTR2.
CLINICAL STUDIES Theoutcomeofseveralphase Iandphase IIPRRTstudies, inwhichdifferentradiolabelledsomatostatinanalogueswereused,hasbeenpublished.Inaddition,ithasbecomeapparentthatthebonemarrowandkidneysarethemostimportantdose-limitingorgansinthistypeoftherapy.
Table 2. Affinityprofiles (IC50)a forhumanSSTR1-SSTR5(hSSTR1-5)ofa seriesofsomatostatinanalogues
Peptides hSSTR1 hSSTR2 hSSTR3 hSSTR4 hSSTR5
SS-28 5.2±0.3(19) 2.7±0.3(19) 7.7±0.9(19) 5.6±0.4(19) 4.0±0.3(19)
Octreotide >10,000(5) 2.0±0.7(5) 187±55(3) >1,000(5) 22±6(5)
DTPA-octreotide
>10,000(6) 12±2(5) 376±84(5) >1,000(5) 299±50(6)
111In-octreotide >10,000(5) 22±3.6(5) 182±13(5) >1,000(5) 237±52(5)
DOTATOC >10,000(7) 14±2.6(6) 880±324(4) >1,000(6) 393±84(6)90Y-DOTATOC
>10,000(4) 11±1.7(6) 389±135(5) >10,000(5) 114±29(5)
DOTALAN >10,000(7) 26±3.4(6) 771±229(6) >10,000(4) 73±12(6)
90Y-DOTALAN >10,000(3) 23±5(4) 290±105(4) >10,000(4) 16±3.4(4)
DOTA-OC >10,000(3) 14±3(4) 27±9(4) >1,000(4) 103±39(3)
90Y-DOTA-OC >10,000(5) 20±2(5) 27±8(4) >10,000(4) 57±22(4)
DTPA-Tyr3-octreotate
>10,000(4) 3.9±1(4) >10,000(4) >1,000(4) >1,000(4)
111In-DTPA-Tyr3-octreotate
>10,000(3) 1.3±0.2(3) >10,000(3) 433±16(3) >1,000(3)
DOTA-Tyr3-octreotate
>10,000(3) 1.5±0.4(3) >1,000(3) 453±176(3) 547±160(3)
90Y-DOTA-Tyr3-octreotate
>10,000(3) 1.6±0.4(3) >1,000(3) 523±239(3) 187±50(3)
Modified from Reubi et al. 26
a All values are IC50 ± SEM in nM. The number of experiments is in parenthesis.
1.2
62
[111In-DTPA0]octreotide The first radiolabelled somatostatin analogue therapy inGEPpatientswithadvanced-stagediseasewas basedon the administrationofhighdosages of111In-octreotide,which at that timewas available for diagnostic purposes(Table3)6,7,30,31.
Thetotalcumulativedosevariedfrom3.1GBqupto160.0GBq.InareportbyValkemaet al. 6,inwhichtheoutcomeof 111In-octreotidetreatmentin50patientswithSSTR-positivetumourswasreviewed,15outofthe26(58%)GEPpatientshadastabilisationoftheirmetastaticdisease,andtwooutof26(8%)showedminorremission,definedasareductionintumoursizeofbetween25%and50%.Patientswithstablediseaseandminorremission(17outof26;65%)wereconsideredtohaveshownabeneficialtherapeuticeffectasallpatientshaddocumentedprogressivediseaseatstudyentry.InanotherreportbyAnthonyet al.30,2outof26(8%)patientshadapartialremission,whereas21outof26(81%)hadstabledisease.Buscombeet al.31reportedtheoutcomeof111In-octreotidetherapyin12GEPpatientstreatedwithcumulativeactivitiesashighas36.6GBq.Sevenoutofthe12(58%)patientshadstabledisease6monthsafterthelasttherapy,2(17%)demonstratedpartialremissionand3(25%)hadprogressivediseasedespitetreatment.
Table 3.Peptidereceptorradionuclidetherapywith111In-octreotideinpatientswithGEPtumours
Response a
Authors [Ref.] No. of patients
PD before therapy Cum dose (GBq)
PR MR b SD PD
Valkemaet al.[6] 2624/26(92%)(clinicaland/orimagingbased)
4.7-160.0 02(8%)
15(58%)
9(35%)
Anthonyet al.[30] 26100%(clinicaland/orimagingbased)
6.7-46.62(8%)
N/I20(77%)
4(15%)
Buscombeet al.[31] 12100%(biochemicalorimagingbased)
3.1-36.62(17%)
N/I7(58%)
3(25%)
Cum dose, cumulatieve dose of 111In-octreotide; N/I, not indicateda Criteria of Tumour Response: PR (partial remission), > 50%reduction of tumour size; SD (stable disease), < 25% reduction or increase of tumour size; PD (progressive disease), > 25% increase of tumour size. b Modification of SWOG criteria including MR (minor remission), between 25 and 50% reduction in tumour size.
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AlltheclinicalPRRTstudiesreportedencouragingandpromisingresults,especiallyintermsofclinicalbenefitandbiochemicalresponses.Reportedcasesofobjectivetumourshrinkagewere,however,few.Theseoutcomessuggestedthattheanti-tumoureffectof111In-octreotideisnotidealforPRRT,atleastforvisibleGEPtumours.However,experimentaldatainratshaveshownthathighdosesof111In-octreotidecaninhibitthegrowthoflivermetastasesafterinjectingSSTR2receptor-positivetumourcellsintotheportalvein32.TheseresultssuggestthatPRRTwith111In-labelledanaloguesmightbeeffectiveinthetreatmentofmicro-metastasesormetastaticspreadduringinitialsurgery.Clinicalstudiesthatcouldconfirmtheseobservationsare,however,lacking.
[90Y-DOTA0,Tyr3]octreotide, [90Y-DOTA]lanreotide and [90Y-DOTA0,Tyr3]-octreotate IntheclinicaltrialsthatfollowedthePRRTwith111In-labelledanalogues,90Y-labelledanalogueswereused.AsummaryofthesestudiesisshowninTable4.
In1998,Otteet al.33reportedthefirstresultsof10patientswithSSTR-positivetumourstreatedwith90Y-DOTATOC.Twooutof10patientshadpartialremissionandsixstabledisease;intwopatients,18F-deoxyglucosepositronemissiontomography,afterasingledoseof90Y-DOTATOC,showedasubstantialreductionof18F-deoxyglucoseuptakeinthetumour.Inthestudiesthatfollowed,theresponserates(completeandpartialremission)inpatientswithGEPtumours,whoweretreatedwitheither6.0GBq/m2or7.4GBq/m2,were10out37(27%)and8outof37(22%),respectively16,34.Todeterminewhetheradecreaseinthenumberoftreatments,butatthesametimemaintainingthemaximumcumulativedoseof7.4GBq/m2duetoanincreaseofdosagepertreatment,couldincreasetheobjectiveresponseanotherstudywasperformed35.Twelveoutof35patients(34%)hadcompleteorpartialremission,whichindicatedahigherpercentageoftumourregression.Noincreaseinthenumberofside-effectswasreported.Althoughtheseresultssuggestedthatanincreaseofdose,andasaconsequenceadecreaseinthenumberoftherapeuticinjections,couldbemorebeneficial,itmustbestressedthatthiswasnotarandomisedcontrolledtrialandthenumberoftreatedpatientswaslow.Nonetheless,thevariationofprotocolcharacteristics,suchasthenumberoftreatments,thedosespertreatmentorthelengthoftreatmentinterval,areofgreatinterestandmayplayanimportantroleinthereportedoutcomeofPRRTstudies.Randomisedcontrolledstudiesontheeffectsofthesevariablesarethereforeneeded.
Clinicalstudiesperformed inMilanalsoused90Y-DOTATOCtotreatvariousSSTRpositivetumours 36–40.Recently,Bodeiet al. 40 reportedtheirexperiencewith90Y-DOTATOC,inwhichatotalof141patientswithvarious,SSTRpositivetumoursweretreated.Anobjectiveresponse(completeorpartialremission)of26%
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64
wasobserved.Moreprecisely,23%ofpatientswhohadprogressivediseasebeforetherapy(113outof141;80%)hadcompleteorpartialremission,whereasinthegroupwithstabledisease(28outof141;20%),32%hadcompleteorpartialremission.Unfortunately,thespecifiedtreatmentoutcomeaccordingtotumourtypewasnotgiven.Itwas,however,reportedthatmostofthepatientswhohadafavourableoutcomehadneuroendocrineGEPtumours.InamoredetailedstudyfromMilan,theoutcomeoftherapyin40patientswithSSTR-positivetumourswasreported39.Thecumulativedoseof90Y-DOTATOC,whichwasgivenintwocycles,rangedfrom5.9to11.1GBq.InthegroupwithGEPtumours,thistherapyregimenresultedinpartialremissionin6outof21patients(29%),whereas11outof21(52%)hadstablediseaseand4/21(19%)hadprogressivedisease.Valkemaet al.41reportedthepreliminaryresultsofamulticentrephaseIstudyperformedinRotterdam,BrusselsandTampa.Theobjectivewastodefinethemaximumtoleratedsingleandfour-cycledosesof90Y-DOTATOC6,11,14.Escalatingdosesupto14.8GBq/m2infourdosesorupto9.3GBq/m2inasingledosewereadministeredtoatotalof60patients.Fourofthe54(7%)patientswhoweretreatedwiththeirmaximumalloweddosehadpartialremission,7outof54(13%)hadminorremission,and33outof54(61%)showedstabilisationoftheirdisease.Anti-tumoureffectintermsofimprovementofresponse,accordingtotheSWOG(SouthwestOncologyGroup)tumourresponsecriteria,includingstablediseaseandminorremissioninpatientswithprogressivediseaseatthestartoftherapy,wasreportedas65%41.Themediantimetoprogressionofthatsamegrouphadnotbeenreachedat26months42.
InaEuropeanmulticentrestudy(MAURITIUS),another90Y-labelledsomatostatinanalogue, 90Y-DOTA-lanreotide,wasused to treat39GEPpatients.The totalcumulativedoserangedfrom1.9GBqto8.6GBq(50–232mCi)of 90Y-DOTA-lanreotide15.Eightoutof39(20%)patientsshowedminorremission,and17outof39(44%)hadstabledisease.ThefirstresultsofthetherapeuticefficacyinpatientswithSSTR-positivetumourswiththesomatostatinanalogue[90Y-DOTA0,Tyr3]octreotate(90Y-DOTATATE)wererecentlyreportedbyBaumet al. 43,44.Twenty-eightoutof75(37%)patientshadpartialremission,and39outof75(52%)demonstratedstablediseaseaftertherapy.Therefore,90Y-DOTATATEmightalsobeapromising90Y-labelledsomatostatinanalogue.Despitethedifferencesinsomatostatinanaloguesandprotocolsusedinthevarious90Y-basedPRRTstudies,thereportedresultsoftherapyintermsofcompleteandpartialremissionpercentages,rangingupto37%(Table4),indicatedanimprovementintherapeuticeffectivenesscomparedwiththestudieswith111In-labelledoctreotide.
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Table 4.Peptidereceptorradionuclidetherapywith90Y-and 177Lu-labeledsomatostatin
analoguesinpatientswithGEPtumours
Response *
Authors [Ref.]
No.of
PatientsPD at
baselineCR PR MR ‡ SD PD CR + PR
[90Y-DOTA0, Tyr3]octreotide
Otteet al.1999[48]} 16 N/I 01
(6%)N/I
14(88%)
1(6%)
1/16(6%)
Waldherret al.2001[34] 3734/37(84%)
1(3%)
9(24%)
N/I23
(62%)4
(11%)10/37(27%)
Waldherret al.2002[16] 3737/37(100%)
1(3%)
7(19%)
N/I26
(70%)3
(8%)8/37(22%)
Waldherret al.2002[35] 3535/35(100%)
2(6%)
10(29%)
N/I19
(54%)
4(11%)
12/35(34%)
Bodeiet al.2003[39] 21 N/I 06
(29%)N/I
11(52%)
4(19%)
6/21(29%)
Valkema et al.2003[41] 5441/54§(76%)
04
(7%)7
(13%)33
(61%)10
(19%)4/54(7%)
[90Y-DOTA]lanreotide
Virgoliniet al.2002[15] 3939/39(100%)
0 08
(20%)17
(44%)14
(36%)0/39(0%)
[90Y-DOTA0,Tyr3]octreotate
Baum et al.2004[43,44] 7567/75(89%)
028
(37%)N/I
39(52%)
8(11%)
28/75(37%)
[177Lu-DOTA0,Tyr3]octreotate
Kwekkeboomet al.2003[45] 7629/76(38%)
1(1%)
22(29%)
9(12%)
30(39%)
14(18%)
23/76(30%)
* Criteria of Tumour Response (SWOG); CR (complete remission), no evidence of disease; PR (partial remission), > 50% reduction of tumour size; SD (stable disease), < 25% reduction or increase of tumour size; PD (progressive disease), > 25% increase of tumour size; ‡, modification of SWOG criteria including MR (minor remission), between 25 and 50% reduction of tumour size; N/I, not indicated; §, Valkema, personal communication
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[177Lu-DOTA0,Tyr3]octreotate Thefirstresultsof[177Lu-DOTA0,Tyr3]octreotate(177Lu-DOTATATE)therapyweredescribedinastudyof35patientswithneuroendocrineGEPtumours,whohadafollow-upof3–6monthsafterreceivingtheirfinaldose17.Patientsweretreatedwithescalatingdosagesfrom100to150,andamaximumof200mCi(3.7,5.6and7.4GBq,respectively)177Lu-DOTATATE,uptoafinalcumulativedoseof600–800mCi(22.2–29.6GBq),withtreatmentintervalsof6–9weeks.Theeffectsofthetherapyontumoursizewereevaluable in34patients.Threemonthsafter thefinaladministration,acompleteremissionwasfoundinonepatient(3%),apartialremissionin12(35%),stablediseasein14(41%)andprogressivediseaseinseven(21%),includingthreepatientswhodiedduringthetreatmentperiod.
Inanupdateonthistreatmentin76patientswithGEPtumours45,completeremissionwasfoundinonepatient(1%),partialremissionin22(29%),minorremissionin9(12%),stablediseasein30(40%),andprogressivediseasein14patients(18%).Theeffectof 177Lu-DOTATATEtherapyontumoursize,uptakeonpost-therapyscintigraphy,liverenzymesandthetumourmarkerchromograninAinapatientwhoshowedpartialremissionisshowninFigure2.Sixoutof32patientswhohadinducedstablediseaseortumourregressionafterthetherapyandwerealsoevaluatedafter12months(mean18monthsfromtherapystart)developedprogressivedisease;intheother26,thetumourresponsewasunchanged.Mediantimetoprogressionwasnotreachedat25monthsfromthebeginningoftherapy.Inamorerecentevaluationofresponseinatotalof131GEPtumourpatients,theseoutcomeswereconfirmed,withamediantimetoprogressionofmorethan36months46.
Comparison of the different treatments Treatmentwith90Y-and177Lu-labelledsomatostatinanaloguesisveryencouragingintermsoftumourshrinkage.However,directcomparisontoevaluatetheoptimaltreatmentremainsdifficult.Differencesintreatmentprotocol,suchasadministereddoses,dosingschemesandthetumourresponsecriteriaused,canberesponsiblefortheobserveddifferencesintreatmentoutcome.Therefore,randomisedcontrolledtrialsarenecessarytodefinetheoptimalPRRTandtreatmentscheme.
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Figure 2. Baselineandfollow-updataofapatientwithcarcinoidwithlivermetastases.(A)Post-therapyscintigraphyaftereachcycleisshown(toprow).Notethedecreaseofuptakeof[177Lu-DOTA0,Tyr3]octreotateonthelastscintigraphyscanincomparisonwiththefirst(blackarrowsindicatingtheindexlesion).At3and6monthsafterfourcyclesoftherapy,thepatienthadapartialremission(>50%decreaseintumourvolumeoncomputedtomography;whitearrowsindicatetheindexlesion)(bottomrow).(B)Regressionofthetumourmasswasaccompaniedbyadecreaseinserumconcentrationofalkalinephosphatase(referencerange0–119U/l),gamma-glutamyltranspeptidase(gamma-GT;referencerange0–49U/l)andthetumourmarkerchromograninA(referencerange10–100ng/ml).
A
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SIDE-EFFECTS AND RADIATION TOXICITY AdversereactionsobservedafterPRRTcanbedividedintodirectside-effectsandthemoredelayedeffectsof radiotoxicity.Directeffectscommonlymentionedduringandaftertherapyarenausea,vomitingandabdominalpain17,30,34.Ingeneral,theseside-effectsoccurinaminorityofpatientsandareeasilytreatedwithanti-emeticsorpainmedication.Mildhairlosswasobservedinpatientstreatedwith177Lu-DOTATATE,buthairgrowthhadnormalisedatfollow-up3–6monthsafterthelastadministration17.Besidethesemildside-effects,moreserioustoxicitymayoccur,especiallytothebonemarrow,kidneysandliver.Thereportedpercentagesoftheseside-effectsortoxicitiesareshowninTable5.
Table 5.Side-effectsinpatientswithsomatostatinreceptor-positive(GEPandnonGEP)tumourstreatedwithdifferentradiolabelledsomatostatinanalogues
Grade 3-4 Haematologic Toxicity §
Other Toxicities
Author [Ref.] Radioligand Number of
Patients
Platelets Haemo-globulin
White blood cells
Valkemaet al.[6] [111In-DTPA0]octreotide 50 10% 15% 2% 3AML/MDS
Anthonyet al.[30] [111In-DTPA0]octreotide 27 7% 11% 7%3Liver,1Renal
Bodeiet al.[39] [90Y-DOTA0,Tyr3]octreotide 40 7% 3% 7%
Otteet al.[48] [90Y-DOTA0,Tyr3]octreotide 29 3% 7% 0% 4Renal*
Waldherret al.[16] [90Y-DOTA0,Tyr3]octreotide 39 0 3% 0% 1Renal
Valkemaet al.[41] [90Y-DOTA0,Tyr3]octreotide 60 12% 1% 2%1MDS,1Liver,1Renal
Kwekkeboomet al.[45]
[177Lu-DOTA0,Tyr3]octreotate 200 3% 8% 13%1MDS,2Liver‡,1Renal
Percentages are based on patient numbers. AML: acute myeloid leukaemia; MDS: myelodysplastic syndrome §, Most of the mentioned haematologic toxicities were transient. See reference for more detailed information;*, No amino-acid infusion in half of the patients; ‡ personal communication, Kwekkeboom et al.
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Haematological toxicity Haematological toxicitiesofgrade3–4forhaemoglobin,whitebloodcellsandplateletswerereporteduptoamaximumof15%16,30,39,45,47,48.Ingeneral,thedecreaseinbloodcellcountwastransient,andtransfusionwasonlyoccasionallyneeded.Moreseriousside-effecswerereportedfromaclinicaltrialinwhich50patientsweretreatedwith111In-octreotide6.Leukaemiaandmyelodysplasticsyndromewerereportedinthreepatientswhohadbeentreatedwithtotalcumulativedosesofover2.7Ci(100GBq),withanestimatedcumulativebonemarrowradiationdoseofabout3Gy.Onepatient,whodevelopedacutemyeloidleukaemia17monthsafterthefirstdoseof111In-octreotide,hadhadchemotherapyandtreatmentwithinterferonbeforePRRT.Theothertwopatients,whohadhadnopreviouscytotoxictherapy,developedmyelodysplasticsyndromeaftermorethan3years.Noneofthe44patientswhoweretreatedwithacumulativedoselowerthan100GBqdevelopedmyelodysplasticsyndromeorleukaemia.InaphaseItrialwith90Y-DOTATOCinwhichtheobjectivewastodefinethemaximaltoleratedsingleandfour-cycledoses,onepatienthadmyelodysplasticsyndrome2yearsafterthestartofPRRT;thispatienthadalsohadpreviouschemotherapy41.InthereportbyKwekkeboom et al.45,whostudiedthepatientstreatedwith177Lu-DOTATATEasPRRT,onepatientinthewholegroupofpatientswhohadbeentreatedorwerebeingtreateduptothattime(201patients,637administrations)developedmyelodysplasticsyndrome.Thispatienthadalsopreviouslyreceivedchemotherapy.Insummary,haematologicaltoxicityinPRRTisingeneralmildandreversible,andtheriskofdevelopingmyelodysplasticsyndromeorleukaemiaislowifcertaindosinglimitsarerespected.
Renal toxicity Chelatedsomatostatinanaloguesareclearedpredominantlybythekidneys.Anaccumulationandretentionoftheseanalogueswithinthekidneyoccursbut isnotSSTRmediated49.Becauseoftherapidclearance,[111In-DTPA0]octreotidecanbesafelyappliedfordiagnosticusewithoutanydamagetothekidneys 1,50.Fortherapeuticuse,however, therenalaccumulationandtherelatively longrenaleffectivehalf-lifeof theradiopharmaceuticalcanbedose-limiting. Inexternalbeamradiationtherapy,renalabsorbeddosesof23Gy(fractionsof2Gy)maycausenephropathyin5%ofpatientsin5years,whereas28Gyleadstoa50%riskoverthesameperiod51.However,sincePRRTisappliedascontinuouslow-doseradiationwithintracellularaccumulation,amaximumcumulativedoselimitof23Gymaynotbeapplicable.Thefirstreportsonacute(6–12monthsafterradiationexposure)and late (1–5yearsafterexposure) renal side-effectsappearedafter theuseof90Y-DOTATOCinvariousclinicaltrials33,52–54.Theresultssuggestedthatacumulativedoseof90Y-DOTATOCofmorethan7.4GBq/m2mightbeariskfactorforrenalinsufficiency33.However,someyearslater,acasereportofapatientwhodevelopedlate-onsetrenalinsufficiencywithatotalcumulativedoseoflessthan7.4GBq/m2
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indicatedthatevenlessradiationcancauserenaldamageatalatertimepoint53.Incontrast,norenaltoxicitywasfoundinpatientstreatedwith[111In-DTPA0]octreotide6.Thedifferencebetween 111Inand 90Ywithregard to the inductionof radiationnephropathymaybeexplainedbythedifferenceintheparticlerangeemitted(10µmversusapproximately12mm,respectively).TheAugerelectronsemittedby111Inwithinthetubularcellsdonotreachtheradiosensitiveglomeruli.Thisparticlerangeadvantagemightalsobethereasonwhyonlyonepatientofagroupof201patientstreatedwith177Lu-DOTATATEdevelopedrenalfailure45.Althoughthenumberofpatientsreportedwithradiationnephropathywasrelativelylow,andthepotentialbenefitforthepatientsoutweighedtheriskofoccurrenceofthisseverecomplication,itbecameclearthatPRRT-inducedradiationnephropathywasdifficulttopredictwiththecurrentlyappliedmaximumcumulativedoselimits.Tworecentstudiesinwhichpatientsweretreatedwith90Y-DOTATOCprovidedmoreinsightintoindividualkidneydosimetryanditsimportanceinPRRT55,56.Thesestudiesindicatedthat,apartfromthetotalrenalradiationdose,thedosevolume,fractionationrateandclinicalparametersofhypertension,diabetesandagearerelevantriskfactorsfor thedevelopmentofa lossofrenal function.Kidneyprotectionmethodstopreventdamagetothekidneyfromhighabsorbeddoseswitheachadministrationareobviouslyofimportance.ThemostimportantmethodcurrentlyusedtoreducetherenaluptakeofradioactivityinPRRTistheuseofaminoacidsolutions,whichcanbeeasilyco-administeredduringtherapy.Preclinicalstudieshaveshownthattheinfusionofpositivelychargedaminoacids,mainlyL-lysineandL-arginine,areabletoreducethetubularreabsorptionofradiolabelledsomatostatinanaloguesinrats57.Clinicalstudieshaveprovedthatco-infusionwithacombinationoftheL-lysineandL-arginineoramixedaminoacidsolutiononthedayoftherapyledtoareductioninrenaluptakeofbetween20and47%29,39,58,59.Higherdosesofaminoacidsaremoreeffectivebuthavethedisadvantageofinducingahigherincidenceofside-effects,suchasnausea,vomitingand,especiallywithhigherdosesofL-lysine,hyperkalaemia59,60.
Liver toxicity MostpatientstreatedwithPRRTintheclinicaltrialsstudiedhadlivermetastases.Theextentofliverinvolvementrangedfromasinglelesiontodiffuseliverinvolvementwithpronouncedhepatomegaly.ItisthereforenotunlikelythatPRRTcaninducehepatocellularradiationinjury.Inclinicalpractice,however,itmaybedifficulttodistinguishanincreaseofliverfunctionparametersinducedbyradiationfromasubtleprogressionof livermetastases.Anthonyet al. 30reportedthreepatients(fromatotalof27),treatedwith 111In-octreotide,inwhomatemporaryincreaseinliverfunctionparameters(grade3livertoxicityonWorldHealthOrganizationtoxicitygrading)wasobserved.Allthreepatientshadatumourreplacementofmorethan75%of theirhepaticparenchymaandtreatment-associatednecrosis
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onthecomputedtomographyscans.Inpatientswithlessextensiveliverdisease,changesinliverfunctionparametersdidnotoccur.Asignificantincreaseinliverfunctionparametersaftertheadministrationof90Y-DOTATOCwasreportedintwostudies41,61.Valkemaet al.41reportedonetransientgrade3toxicityinagroupof60patientstreatedwith90Y-DOTATOC(phaseIstudy).Inanotherstudy,15patientswithprovenlivermetastases(ofwhom12hadextensiveliverinvolvement,definedas25%ormore)fromneuroendocrinetumoursweretreatedwiththreecyclesof120mCi(4.4GBq)each61.Inonlyfourofthese15patients,oneormoreofthethreeliverenzymesthatweremeasured-serumaspartateaminotransferase,alanineaminotransferaseandalkalinephosphatase-increasedatleastonegrade,accordingtotheWorldHealthOrganizationcommontoxicitycriteria,frombaselinetofinalfollow-upmeasurement(4–6weekspostcycle3).ItwasconcludedthatpatientswithdiffuseSSTR-positivehepaticmetastasescouldbetreatedwithacumulativeadministeredactivityof360mCi(13.2GBq)of90Y-DOTATOCwithonlyasmallchanceofdevelopingmildacuteorsubacutehepaticinjury.Inthegroupofpatientstreatedwith 177Lu-DOTATATE,significantlyincreasedliverfunctionparameters(grade4livertoxicity)wasevidentintwopatientsafterthefirstcycleoftreatment(D.J.Kwekkeboom,personalcommunication,2004).Onepatient,whosufferedfromarapidlygrowingneuroendocrinetumourwithextensiveliverinvolvement,clinicallyprogressedtoliverfailurewithin3weeksanddiedshortlythereafter.WhethertheaggressivenatureofthetumourorthePRRT-inducedtoxicityledtothisfatalconditionremainsunclear.Theotherpatient,whoafterthefirsttherapydevelopeddyspnoea,acuteabdominalpainandincreasedliverfunctionparameters,washospitalisedforseveralweeks.Gradually,theliverfunctionparametersandhyperbilirubinaemiareturnedtopre-therapylevels.Treatmentwith177Lu-DOTATATEwascontinuedfor6monthsafterthefirsttherapywithareduceddoseof1.9GBqfollowedbyathirdadministrationof4.1GBqwithoutanyacuteside-effects.
CLINICAL PRACTICE InpatientswithmetastasisedGEPtumours,forwhomsurgeryisnolongeranoption,PRRTcanbeaneffectivealternativetherapeuticmodalitywithlimitedside-effects.Theresultsintermsoftumourvolumereduction,asshowninthedifferentclinicaltrials,areveryencouragingandseemtocomparefavourablywithchemotherapy.Norandomisedcontrolledstudyhas,however,beenperformedtoconfirmthis.Althoughproveneffectiveinasubstantialpercentageofpatients,PRRThasnotbeenwidelyrecognisedasalternativesystemictherapy.Instead,the ‘wait-and-see’approachoftenremainsthemainstayofinitialmanagementinpatientswithunresectabledisease.Therationaleforthisapproachisfoundinthenaturalhistoryofwell-differentiatedGEPtumoursnotreceivingtreatment,inwhichtumourscanbeindolentformanyyearsandthewell-beingofpatients,evenwithmetastasised
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tumours,canbeunchangedformanyyears.However,thereportedstudiesonPRRTclearlyindicatethatpatientswithdocumentedprogressivediseaseorasubstantialincreaseinsymptomscanbenefitfromthistherapy.TherecognitionofthepossiblebenefitofPRRTforpatientswithGEPtumoursisincreasing,butitsimplementationwithinthewholetherapeuticarrayisratherpoor.FactorsthatcontributetothisincludethefactthatPRRTisarelativelynewtherapeuticmodality, thelackofapprovedradiopharmaceuticals,whichisinpartrelatedtoincreasedgovernmentaldemands,andtherapy-relatedcosts.
Indications for peptide receptor radionuclide therapyCandidatesforPRRTarethosepatientswithinoperableGEPtumourswhohaveprogressivediseaseorsymptomatologythatisdifficulttomanagewithmedication.Ifitisagreedthatthemalignancyisinoperable,thetumourhastobeSSTR-positive,basedontumouruptakeon111In-octreotidescintigraphy.Furthermore,theamountoftumouruptakehastobeequaltoorhigherthanthatofnormallivertissue(accordingtocriteriapreviouslydescribedbyKrenning et al.10).
Highuptakeduring111In-octreotidescintigraphyhasbeenshowntobecorrelatedwithtumourregressionafterPRRT17.Additionally,becauseoftheradiationtothebonemarrowandtheriskoftemporarybonemarrowsuppression,patientsneedtofulfilcertainminimalhaematologicalcriteria.Kidneyfunctionhastobedeterminedbeforetherapytoexcludepatientswithsignsofimpendingrenalfailure(glomerularfiltrationrate<40ml/minute).Thepresenceofbonemetastases,whichoccurinaminorityofpatients,isnoexclusioncriterion.Asarule,ifatumourresponseoccurs,alltumoursitesdecreaseinsize.However,cysticandbonelesionsseemtorespondinamoreprotractedwaythanthemorecommon,solidlivermetastases.Upuntilnow,nosystematicstudyhasbeenperformedtoaddresstheissueofapossibledifferentialresponseofmetastasesbasedontheirlocation.ThefullpatientselectioncriteriaaresummarisedinTable6.
Timing of therapyThereiscurrentlynoconsensusaboutwhentostartPRRTinpatientswithGEPtumours.Thestageofdiseaseatwhichthediagnosisismadeishighlyvariableandrangesfromalocalised,non-metastaticprimarytumourtomoreadvancedorend-stagediseasewithhepatomegalyandascites.Inarecentreportinwhichtherelationshipbetweendelayofdiagnosis,extentofdiseaseandsurvivalin115patientswithcarcinoidwasstudied,ameandelayinthediagnosisof66monthswasfound62.Itwasconcludedthatthediagnosisofcarcinoidisdifficult,andthereforeadelayofdiagnosisbyphysiciansiscommon.Strikingly,thedelayofthediagnosisdidnotcorrelatewiththeextentofthedisease.However,theextentofthediseasedidcorrelatewithsurvival.
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Table 6. CriteriaforpeptidereceptorradionuclidetherapyinpatientswithGEPtumours
Inclusion
Sufficienttumouruptakeon111In-octreotidescintigrams
Haematology
Plateletcount≥75-100x109/L
Whitebloodcellcount≥2-3.5x109/L
Haemoglobin≥5.0mmol/L
Kidneyfunction
Creatinin(serum)≤150µmol/Lorcreatinineclearance≥40ml/min
KarnofskyPerformanceStatus≥50
Lifeexpectancy>6months
Exclusion
Chemotherapywithin6weekspriortotreatmentstart
Pregnancy/lactation
Patientswithprimarytumoursandlymphnodemetastaseswerelesslikelytodieofcarcinoiddiseasethanpatientswithhepaticmetastases,carcinomatosisorextra-abdominalmetastases.Unfortunately,reportsonPRRTwithexplicitsurvivaldataarefew.Inthemulticentretrialwith111In-octreotide6,itwasreportedthatPRRTforend-stagepatientswithahighertumourburdenwaslesslikelytohaveafavourableoutcomethanforpatientswithlowertumourburdenorinabettergeneralcondition.Survivaldatainagroupof27patientstreatedwith 111In-octreotidepresentedbyAnthonyet al.30suggestedasurvivalbenefitinpatientstreatedwith111In-octreotide.Thenumberofpatientsstudiedwas,however, low,andthesurvivaldataofthetreatedgroupwerecomparedwithdatafromahistoricalcontrolgroup.Inthestudieswith177Lu-DOTATATE,itwassuggestedthat,becauseofthehighsuccessrateofthetherapy,thelowincidenceofside-effecsandthehighmediantimetoprogression(>36months),itsusecanbeadvocatedinpatientswithmetastasised,unresectableGEPtumourswithoutwaitingfortumourprogression17,63.
AnotherargumentinfavourofearlytreatmentisthatneuroendocrinetumourscandedifferentiateinthecourseofthediseaseandtherebylosetheexpressionofSSTRs.Treatmentwithradiolabelledsomatostatinanalogueswillthenbeimpossible17.However,whetherearly treatmentwouldbenefitpatientswithmetastasised,unresectableGEPtumoursintermsoflongersurvivalremainstobestudiedandshouldimplyrandomisationintogroupswithandwithoutPRRT.Atthismoment,
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whenthereseemstobeproofthatPRRTisaneffectivetherapy,suchasurvivalstudyseemsunethical.
Anotherissue,regardingthequestionwhetherweshouldtreatpatientswithPRRTornotatanearlystageofthedisease,isthebenefitintermsofclinicalresponseandqualityoflife.Notallstudiesaddressthisissue.Thereis,however,agrowingawarenessofitsimportanceinclinicaloncologytrials,especiallyintherapiesforwhichcureisnottheprimarygoalandsurvivalgainsareloworunknown64.Asaconsequence,themorerecentPRRTreportshaveincludeddataontheclinicaleffectivenessoftherapy.Twostudieswith90Y-DOTATOCprovidedevidenceforafavourableclinicalresponsein60–70%ofthepatients47,65.Inpatientstreatedwith177Lu-DOTATATE,qualityoflifeassessmentshowedasignificantimprovementintheglobalhealth/qualityoflifescore(Δscore+9.2,scalerange0–100,P<0.01),especiallyinthosepatientswithproventumourregression(Δscore+10.5,P<0.05)(Figure3)66.Althoughtheassessmentmethodsforidentifyingclinicalchangesdifferinthesestudies,thecombinedresultssuggestthatpatientsmayexperienceaclinicalbenefitfromPRRT.
FUTURE DEVELOPMENTS AdirectionoffutureresearchtoimprovecurrentPRRTforGEPtumoursincludesthedevelopmentofnewstablesomatostatinanalogueswithahighaffinityforthedifferentSSTRsubtypes.Thenewanalogue[DOTA0-1-naphthyl3]octreotide(DOTANOC),forexample,isananaloguethathasahighaffinityforSSTR2,SSTR3andSSTR567.ItmightthereforebeapromisinganaloguetobeusedfortreatmentofpatientswithtumoursthatnotbearonlySSTR2,butalsoexpressSSTR3and/orSSTR5.Furthermore,combinedtreatmentwithdifferentradiolabelledsomatostatinanalogues,analogoustothefavourableresponsewithcombinationalchemotherapyinsolidtumourscomparedwithsingle-agenttherapy,isofgreatinterest.Thisapproachwillofcoursebelimitedbythecombinedtoxicityoftheradiolabelledpeptides.PreclinicalPRRTstudieswith90Y-DOTATOCand177Lu-DOTATATEindicatethatthereisanoptimaltumoursizeintermsoftheefficacyoftumourreductionforeachradionuclide.Asmostpatientshavemetastaticdiseasewithtumoursofdifferentsizes,combinationPRRTcouldachievehighercureratescomparedwithsingle-agenttherapy.HighercureratesarepossiblewhenthedensityofexpressedSSTRsisenhanced.InvitroandinvivostudiesshowthattheirradiationofneuroendocrineAR42J(ratpancreatictumour)cellscanupregulatetheexpressionofSSTR2andgastrinreceptors68.PRRTaftertheupregulatedexpressionofSSTR2mayleadtoahigheruptakeoftheradiolabelledpeptideandconsequentlyahighertherapeuticefficacy.MostresearchinPRRTisfocusedonthedifferentSSTRsubtypes.Neuroendocrinetumoursmay,however,coexpressothertumour-specificpeptides,suchasvasoactiveintestinalpeptide,cholecystokin,bombesinandGLP-1receptors69.
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Figure 3. Globalhealth/qualityoflifescalescoresofallthepatients(n=50)andthedifferentoutcomegroupsaccordingtotumourevaluationbefore(hatchedbars)and3monthsafter(greybars) 177Lu-octreotatetherapy.REGR,regression(complete,partialandminorremission);SD,stabledisease;PD,progressivedisease.Standarderrorsofthemeanareshown;*P<0.05;**P<0.01;NS,not significant (two-sidedanalysisofvariance;P<0.05was consideredsignificant).(ModifiedfromTeunissenet al.66).
TheconcomitantexpressionofthesereceptorscouldbeusedinthefutureinamultireceptorPRRT to targetmore efficientlyGEP tumours in eachpatientindividually.Thisapproachcould,especiallyintumourswithaheterogeneousorevenareciprocalreceptordistribution,beveryfavourableintermsofachievingamorehomogenousdistributionoftheabsorbedradiationdosewithinthetumourmass.ThecombinationofPRRTwithsurgeryand/orchemotherapyasamultimodalitytreatmentstrategyisofinterestandrequiresthestartofrandomisedtrialstoprovewhethercurrentresultscanbeimproved.StudiesthatcanalsobeconsideredaretheuseofPRRTcombinedwithsurgeryinanadjuvantsettingtoirradiateoccultmetastases,orPRRTasdebulkingtherapyfollowedbysurgeryinpatientswithinoperablebutlimitedlocaldisease.Externalbeamradiotherapyincombinationwithchemotherapysuchasgemcitabine,whichisaknownpotentradiationsensitiser,hasbeenshowntohavefavourableeffectsinpatientswithnon-small-celllungcancer70.Althoughthepatientsweretreatedwithexternalradiotherapy,gemcitabineandotherradiosensitisingagentswithconcurrentPRRTmightproveeffectiveinthefuture.
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SUMMARY PRRTholdsgreatpromiseforthefutureregardingthetreatmentofvariouscancers.Usingradiolabelledpeptides,whichbindwithhighaffinitytospecificreceptorsoncancercells,itispossibletotargetthecancerefficiently.InGEPtumours,radiolabelledsomatostatinanaloguetherapyhasbeenproventobeeffective.Dose-limitingorgansarethebonemarrowandthekidneys.Withthecurrentlyusedmaximumalloweddose,PRRTisrelativelysafe,andseriousside-effectsarerare.Itisimpossibletoconcludefromtheavailableliteraturewhichradiolabelledsomatostatinanaloguecanberegardedasthemosteffectivetherapy.Also,thedevelopmentoftherapystrategieswithcombinationsofdifferentradionuclides,whichisunderway,isofinterestasthesestrategiesmayinfutureprovideanincreaseintherapeuticefficacy.
Practice points
• PRRTwithβ-emittingagentssuchas90Yand177Lucaninducetumourshrinkageinpatientswithsomatostatin-positiveGEPtumours
• octreotidescintigraphyisusedtoselectcandidatesforPRRT
• ahighuptakeduringoctreotidescintigraphyiscorrelatedwithafavourableoutcomeoftherapy
• theco-administrationofaminoacidsduringPRRTisessentialtominimisetheriskofrenaltoxicity
• bloodexaminationbeforeeachcycleofPRRTisnecessaryasbonemarrowsuppressionisaknownriskofPRRT
Research Agenda
ThefollowingareasareofinterestinoptimisingPRRT:
• thedevelopmentofnewsomatostatinanalogueswithahighaffinityfordifferentSSTRsubtypes
• randomisedcontrolled(multicentre)trialstocomparethetherapeuticefficacyof90Y-and177Lu-labelledsomatostatinanalogues,andtheiruseincombination
• thedevelopmentofdifferentpeptideanalogueswithahighaffinity
• theimplementationofmultimodalitytreatmentstrategies:
– surgerywithadjuvantPRRT
– PRRTfordebulkingbeforesurgery
– chemotherapyasaradiosensitiserforPRRT
• methodstoupregulatetheexpressionofSSTRsinvivo
• thereductionofkidneyandbonemarrowuptake
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68. BéhéM,PuskenM,HenzelMetal.Upregulationofgastrinandsomatostatinreceptorafterirradiation.Eur J Nucl Med.2003;44(supplement2):S218.(abstract).
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1.2
1.3Aims and outline o�� the thesis
84
Aim
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is
The overall aims of the work presented in this thesis are:
-toevaluatetheeffectoftreatmentwith[177Lu-DOTA0,Tyr3]octreotateinthetreatmentofpatientswithinoperable,metastasisedsomatostatinreceptorpositiveendocrinegastroenteropancreatictumoursintermsof:
i. Toxicity ii. Effectsontumoursize iii. Side-effects iv. Qualityoflife
-toinvestigatethefeasibilityofpeptidereceptorradionuclidetherapyinpatientswithnon-radioiodineaviddifferentiatedthyroidcarcinoma.
In chapter 2.1 thefirstresultsof[177Lu-DOTA0,Tyr3]octreotatetherapyasanovelpeptidereceptorradionuclidetherapy(PRRT)inasmallseriesofpatientswithinop-erableendocrinegastroenteropancreatic(GEP)tumoursarepresentedwithemphasisonthefeasibilityoftherapyregardingtoxicityandside-effects.Additionally,thefirstresultsoftherapyoutcomeintermsofobjectivetumourresponseswerereported.Besidestheresultsoftherapyoutcomeinalargergroupofpatients(n=131),chapter 2.2 isfocusedonpredictivefactorsforafavourabletumourresponseortumourprogression.Furthermore,thefirstresultsonthelong-termoutcomeof [177Lu-DOTA0,Tyr3]octreotatetherapyarepresentedandacomparisonwithchemotherapyismade.Chapter 3 isfocusedonthequalityoflifeinpatientswithendocrineGEPtumourstreatedwith[177Lu-DOTA0,Tyr3]octreotate,whereas chapter 4 describeslong-termchangesinhormonalstatusaftertherapy.Thedifferentialuptakeof[177Lu-DOTA0,Tyr3]octreotateversus[177Lu-DOTA0,Tyr3]octreotideisevaluatedinchapter 5. Inchapter 6.1 thefeasibilityoftherapywith[177Lu-DOTA0,Tyr3]octreotateinpatientswithnon-radioiodine-aviddifferentiatedthyroidcarcinomaisevaluated.Chapter 6.2 reviewsboththediagnosticandtherapeuticuseofradiolabelledso-matostatinanaloguesinthemanagementofpatientswithnon-radioiodine-aviddifferentiatedthyroidcarcinoma.Asummaryandgeneraldiscussion,includingrecommendationsforfutureresearchcompletesthisthesis(chapter 7).
1.3
2Outcome o�� PRRT with [177Lu-DOTA0,Tyr3]octreotate
Treatment o�� patients with gastroenteropancreatic (GEP)�� tumours with the novel radiolabelled somatostatin analogue [177Lu-DOTA0,Tyr3]octreotate
2.1
Dik J. Kwekkeboom, Willem H. Bakker, Boen L. Kam, Jaap J.M. Teunissen, Peter P.M.
Kooij, Wouter W. de Herder, Richard A. Feelders, Casper H.J. Eijck, Marion de Jong,
Ananth Srinivasan, Jack L. Erion and Eric P. Krenning
European Journal of Nuclear Medicine and Molecular Imaging 2003; 30:417–422
AbstractMedicaltreatmentandchemotherapyareseldomsuccessfulinachievingobjectivetumourreductioninpatientswithmetastaticneuroendocrinetumours.Treatmentwiththeradiolabelledsomatostatinanalogue[90Y-DOTA0,Tyr3]octreotidemayresultinpartialremissionsin10–25%ofpatients.Theneweranalogue[DOTA0,Tyr3]octreotate(octreotate)hasaninefoldhigheraffinityforthesomatostatinreceptorsubtype2ascomparedwith[DOTA0,Tyr3]octreotide.Also,labelledwiththebeta-andgamma-emittingradionuclide 177Lu, ithasprovedverysuccessful inachievingtumourregressioninanimalmodels.Theeffectsof 177Lu-octreotatetherapywerestudiedin35patientswithneuroendocrinegastro-entero-pancreatic(GEP)tumourswhounderwentfollow-upfor3–6monthsafterreceivingtheirfinaldose.Patientsweretreatedwithdosesof100,150or200mCi177Lu-octreotate,toafinalcumulativedoseof600–800mCi,withtreatmentintervalsof6–9weeks.Nauseaandvomitingwithin the first24hafteradministrationwerepresent in30%and14%of theadministrations,respectively.WHOtoxicitygrade3anaemia,leucocytopeniaandthrombocytopeniaoccurredafter0%,1%and1%oftheadministrations,respectively.Serumcreatinineandcreatinineclearancedidnotchangesignificantly.Theeffectsofthetherapyontumoursizewereevaluablein34patients.Threemonthsafterthefinaladministration,completeremissionwasfoundinonepatient(3%),partialremissionin12(35%),stablediseasein14(41%)andprogressivediseaseinseven(21%),includingthreepatientswhodiedduringthetreatmentperiod.TumourresponsewaspositivelycorrelatedwithahighuptakeontheOctreoScan,limitedhepatictumourmassandahighKarnofskyPerformanceScore.Becauseofthelimitedefficacyofalternativetherapies,manyphysicianscurrentlyadoptanexpectantattitudewhendealingwithpatientswithmetastaticGEPtumours.However,inviewofthehighsuccessrateoftherapywith177Lu-octreotateandtheabsenceofseriousside-effects,weadvocateitsuseinpatientswithGEPtumourswithoutwaitingfortumourprogression.
Abstract �INTRODUCTIONNeuroendocrine gastro-entero-pancreatic (GEP) tumours,which comprisepancreaticisletcelltumours,non-functioningneuroendocrinepancreatictumoursandcarcinoids,areusuallyslowgrowing.Ifthetumourislocalized,thetherapyofchoiceissurgery.Whenametastatictumourcausesasyndromebyhormonaloverproduction(i.e.carcinoidsyndrome,hypergastrinaemia),treatmentwithsomatostatinanaloguesresultsinsymptomaticreliefinmostcases.Intermsofobjectivetumourreduction(completeandpartialremission),however,treatmentwithsomatostatinanaloguesisseldomsuccessful,whetherornotitisgivenincombinationwithinterferon-α1-3.
Anewdevelopment incyto-reductivetherapyforGEPtumours is theuseofradiolabelledsomatostatinanalogues. Initialstudieswithhighdosesof [111In-DTPA0]octreotide (111In-octreotide;OctreoScan) inpatientswithmetastaticneuroendocrinetumourswereencouraging,althoughpartialremissionswereexceptional4,5.However,111In-coupledpeptidesarenotidealforpeptidereceptorradionuclideradiotherapy(PRRT)becauseofthesmallparticlerangeandthereforeshorttissuepenetration.Therefore,anotherradiolabelledsomatostatinanalogue,[90Y-DOTA0,Tyr3]octreotide,wasdeveloped.Using this compound,partialremissionshavebeenreportedin10–25%ofpatientswithneuroendocrinetu-mours6-8.
Recently,itwasreportedthatthesomatostatinanalogue[DOTA0,Tyr3]octreotatehasaninefoldhigheraffinityforthesomatostatinreceptorsubtype2ascomparedwith[DOTA0,Tyr3]octreotide9.Also,labelledwiththebeta-andgamma-emittingradionuclide177Lu,thiscompoundwasshowntobeverysuccessfulinachievingtumourregressionandanimalsurvivalinaratmodel10.Inacomparisoninpatients,wefoundthattheuptakeofradioactivity,expressedasapercentageoftheinjecteddoseof[177Lu-DOTA0,Tyr3]octreotate(177Lu-octreotate),wascomparabletothatafter111In-octreotideforkidneys,spleenandliver,butwasthree-tofourfoldhigherforfouroffivetumours11.Weconcludedthat177Lu-octreotatepotentiallyrepresentsanimportantimprovementbecauseof(a)thehigherabsorbeddosesthatcanbedeliveredtomosttumourswithaboutequaldosestopotentiallydose-limitingorgansand(b)thelowertissuepenetrationrangeof 177Luascomparedwith90Y,whichmaybeespeciallyimportantforsmalltumours.
Inthisstudywepresentthefirstdataonthesideeffectsaswellastheantitumoraleffectsof 177Lu-octreotatetherapyin35patientswithGEPtumours,whohadafollow-upof3–6monthsafterreceivingtheirfinaldose.
2.1
92
�MATERIALS AND METHODS
PatientsThirty-fivepatientswithGEPtumourswerestudied.AllpatientshadtumouruptakeontheOctreoScanprecedingthetherapythatwasatleastashighastheuptakeinthenormallivertissue.Noneofthepatientshadreceivedpriortreatmentwithotherradiolabelledsomatostatinanalogues.EightpatientsusedSandostatins.c.;thismedicationwasdiscontinuedfrom1daybeforeto1dayafterthetreatment.Prerequisitesfortreatmentwere:Hb≥6mmol/l,WBC≥2×109/l,platelets≥80×109/l,creatinine≤150µmol/landKarnofskyPerformanceScore≥50.Allpatientsgavewritteninformedconsenttoparticipateinthestudy,whichwasapprovedbythemedicalethicalcommitteeofthehospital.
Methods [DOTA0,Tyr3]octreotatewasobtainedfromMallinckrodt,StLouis,Mo.,USA.177LuCl3wasobtainedfromNRG,Petten,theNetherlandsandMissouriUniversityResearchReactor(MURR),Missouri,Mo.,USA,andwasdistributedbyIDB,Baarle-Nassau,theNetherlands.177Lu-octreotatewaspreparedasdescribedpreviously11.
Granisetron3mgwasinjectedi.v.andaninfusionofaminoacids(lysine2.5%,arginine2.5%in1l0.9%NaCl;250ml/h)wasstarted30minbeforetheadministrationoftheradiopharmaceuticalandlastedupto3.5hafterwards.Theradiopharmaceuticalwasco-administeredviaasecondpumpsystem.Thetreatmentdosesof100mCiwereinjectedin20minandthoseof150and200mCiwereinjectedin30min.Theintervalbetweentreatmentswas6–9weeks.Patientsweretreateduptoacumulativedoseof750–800mCi(27.8–29.6GBq)(correspondingtoaradiationdosetothebonemarrowof2Gy)11,unlessdosimetriccalculationsindicatedthattheradiationdosetothekidneyswouldthenexceed23Gy;inthesecasesthecumulativedosewasreducedto600–700mCi.
Routinehaematology,liverandkidneyfunctiontests,hormonemeasurementsandserumtumourmarkersweremeasured1weekpriortoeachtherapy,aswellasatfollow-upvisits.EORTCqualityoflifeforms(QLQ-C30)12werefilledoutbythepatientsateachvisit.
CTorMRIscanningwasdonewithin3monthsbeforethefirsttherapy,and6–8weeks,3monthsand6monthsafterthelasttreatment.
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In vivo measurementsThetumoursontheCTorMRIscansweremeasuredandscoredaccordingtotheWHOsolidtumourresponsecriteria.TheuptakeonthepretreatmentOctreoScanswasscoredvisuallyonplanarimagesona4-pointscale:grade1,lowerthannormallivertissueuptake;grade2,equaltonormallivertissueuptake;grade3,greaterthannormallivertissueuptake;grade4,higherthannormalspleen/kidneyuptake.
StatisticsAnalysisofvariance(ANOVA),paired t testsandchi-squaretestswereused.Pvalues<0.05wereconsideredsignificant.
RESULTS
Thestudypopulationcomprised14menand21womenwithameanageof54years(range19–78years).Twelvehadcarcinoidtumour,12neuroendocrinepancreatictumour,8neuroendocrinetumourofunknownoriginand3gastrinoma.
Figure 1A–C. Planarscansof theabdomen,3daysafter the injectionof200mCi 177Lu-octreotateinapatientwithlivermetastasesofanoperatedneuroendocrinepancreatictumour.A Afterthefirsttreatment;B afterthesecondtreatment;C afterthefourthtreatment.Notethelossofintensityofuptakeintheliverlesions(arrows inA).Thissignvirtuallyalwaysindicatesatumourvolumeresponse.D, E CTscansofthesamepatient:beforetreatment(D)and3monthsafterthelasttreatment(E).Tumour(arrows inD)isnotdemonstratedonE.NeitherMRInorOctreoScancoulddemonstratedefinitetumourdepositsatthattime.
2.1
94
Twelvepatientshadbeenoperatedinthepast,1hadhadradiotherapy,3hadhadchemotherapyand14hadbeentreatedwithoctreotide(Sandostatin).
Sixteenofthe35(46%)patientshaddocumentedprogressivediseasewithin1yearbeforethestartofthetherapy.Cycledoseswere100mCiinsevenpatients,150mCiin14and200mCiintheremaining14.Higherdosageswerenotadministered,since200mCi 177LuCl3 istypicallyboundto180–300µg[DOTA0,Tyr3]octreotate,andhigherdoseswouldresultinalowerpercentagetumouruptakeowingtoreceptorsaturation.In30patients,thefinalintendedcumulativedoseof600-800mCiwasadministered.Threeofthefiveremainingpatientshadprogressivediseaseanddiedbeforecompletingtheirtreatment;theothertwopatients,whowerebothelderly,stoppedtheirtreatmentafterreachingacumulativedoseof600mCibecauseoftheburdentheyfeltthetreatmenttobe.
Table 1. Tumourresponsesin34patients,3monthsafterthefinaladministrationof 177Lu-octreotate.ThreepatientswithPDdiedbeforereachingtheirfinaldose.
RESPONSE Total
Tumourtype CR PR SD PD
Carcinoid 4(33%) 6(50%) 2(17%) 12
NEPancreas 1(8%) 1(8%) 7(58%) 3(25%) 12
NEunknownorigin 4(57%) 1(14%) 2(29%) 7
Gastrinoma 3(100%) 3
Total 1(3%) 12(35%) 14(41%) 7(21%) 34
WHOtoxicitygrade2or3anaemia(Hb4.95–6.2or4.0–4.9mmol/l,respectively),leucocytopenia(WBC2.0–2.9or1.0–1.9×109/l,respectively)andthrombocytopenia(platelets50–74.9or25.0–49.9×109/l,respectively)occurredafter8%and0%,5%and1%,and3%and1%oftheadministrations,respectively.Toxicitygrade2or3leucocytopeniaorthrombocytopeniaoccurredintwooutofthree(67%)patientswhohadhadpreviouschemotherapy,asagainstsevenoutof32(22%)patientswhohadnot.Meanhaematologicalparametersroseagainduringthefollow-upafterthefinaladministration.Serumcreatinine,creatinineclearanceandserumHbA1cdidnotchangesignificantly(datanotshown).Inpatientswithoutthyroidhormonemedication,serumTSHandfT4levelsdidnotchange.Inwomen,serumLHandFSHconcentrationsdidnotchangesignificantly;inmen,serumtestosteronedecreasedandserumLHconcentrationsincreasedsignificantly.Alsoinhibin-BconcentrationsdecreasedandserumFSHlevelsincreasedsignificantly.
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Figure 2. A, BMRIscans inawomanwithhepaticmetastasesofagastrinoma.Beforetreatment(A)shewasinoperablebecauseofthesizeandlocalizationofthemetastases.Threemonthsaftercompletionofhertreatmentwith800mCi177Lu-octreotateshehadaPR(B).Notealsothatthehypertrophyofthegastricwall(arrow inA)haddiminished.Concomitantly,serumconcentrationsofgastrin(closed dots)andchromogranin-A(open dots)haddecreasedmarkedly(C).At6monthstheMRIshowednofurtherregression.Thepatientunderwentleftpartialhepatectomyandthetworight-sidedlesionsweredrainedandinjectedwithalcohol.MRI3monthsaftersurgeryshowedfurtherregressionoftheright-sidedlesions.
Theeffectsofthetherapyontumoursizewereevaluable in34patients.Threemonthsafterthefinaladministration(onaverage9monthsfromthestartofthetreatment),acompleteremission(CR),evaluatedwithCTscanning,MRIandsomatostatinreceptorimaging,wasfoundinonepatient(3%),partialremission(PR)in12(35%),stabledisease(SD)in14(41%)andprogressivedisease(PD)in7(21%),includingthethreepatientswhodiedduringthetreatmentperiod(Table1)(Figs.1,2).Follow-upevaluation6monthsafterthefinaltherapywasavailablefor19ofthe34patients.AllsevenpatientswhohadPRafter3monthsstillhadPRafter6months;in10ofthe12patientswithSD,theevaluationwasunchanged,whereasonehadaminimalresponse(MR)andonehadPD.
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Tumourresponse(CRorPR)wassignificantlymorefrequentinpatientswhosetumourshadahighuptakeontheOctreoScan[6/7(86%)withgrade4uptakevs.7/27(26%)withgrade2or3uptake;chi-squaretest:P<0.05].Fiveoutofthesevenpatients(71%)withPDhadhepatomegalyanddiffuselivermetastasesvs6outof27(22%)withCR,PRorSD(chi-squaretest:P<0.05).TumourresponsewasmorefrequentinpatientswithdocumentedPDwithin1yearbeforethestartofthetreatment(8/15;53%)thaninthosewithout(5/19;26%),althoughthisdifferencewasnotstatisticallysignificant(P=0.11;chi-squaretest).Ofthe15patientswithdocumentedPDbeforethestartofthetreatment,3(20%)hadSDatfollow-up.PatientswhohadaKarnofskyPerformanceScoreoflessthan80beforethetreatmentmorefrequentlyhadPD(5/8;63%)thanthosewhohadhigherscores(2/26;8%)(P<0.01;chi-squaretest).
Theserumtumourmarkerchromogranin-Awaselevatedin29patients.Duringthetreatmentandfollow-up,therewasacleardecreaseinserumchromogranin-AconcentrationsinpatientswithPRorCR,whereastheseconcentrationswerevirtuallyunchangedinpatientswithSD,andinitiallyshowedanincreaseinpatientswithPD(Fig.3).
Thepatient-assessedqualityoflife,accordingtotheEORTC-QLQ30questionnaire,wasevaluatedin25patients.Tenpatientswereexcludedbecauseofprogressivedisease/death(n=5)ormissingformsduringthefollow-upperiod(n=5,foreignpatients).Scoresbeforethestartofthetreatment,afterreceiving400–600mCi177Lu-octreotateandatfollow-up3monthsafterthefinaltreatmentwereevaluated.Therewerenosignificantdifferencesforfunctionalscalesorsinglesymptomscales.Theglobalhealthscale,onwhichpatientswereaskedtoassignmarksregardingboththeirgeneralhealthandtheirqualityoflife,andwhichrangedfrom0to100,wasjudgedashigherthan70byninepatients(36%)beforethestartofthetreatment,by17(68%)patientsduringthetreatmentandby16(64%)patientsafterthetreatment(P<0.05;chi-squaretest).
DISCUSSIONTherearefewtreatmentoptionsformetastaticGEPtumours.Theuseofradiolabelledsomatostatinanaloguesfortumourregressionisapromisingnewdevelopment.With [90Y-DOTA0,Tyr3]octreotide,PR(orCR)hasbeenreported in 10–25%ofpatientswithneuroendocrinetumours6-8.Inthepresentstudywefoundobjectivetumourshrinkagein38%ofthepatients,butPDbeforethestartofthetreatmentwasdocumentedinonly46%ofthepatients.Thislastfactisimportant,becausedocumentedPDwaspresentinmorethan80%ofpatientsintwoofthereportedseries treatedwith [90Y-DOTA0,Tyr3]octreotide 6,8.Aswithchemotherapy,anobjectivetumourresponseafterPRRTismorelikelyinpatientswith(fast)growing
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tumours.Indeed,inourserieswealsofoundatrendtowardsamorefavourabletreatmentoutcomeinpatientswithdocumentedPDbeforethestartofthetreatment.ItmaythereforebeconcludedthatthepercentageofpatientswithsignificanttumourshrinkageinourstudymighthavebeenevenhigherhadthepercentageofpatientswithPDpriortotreatmentbeencomparabletothatinstudieswith[90Y-DOTA0,Tyr3]octreotide.Theside-effectsoftreatmentwith 177Lu-octreotatearefewandmostlytransient,withmildbonemarrowdepressionasthemostcommonfinding.Neitherrenalnorpituitaryfunctiondeterioratedinanyofourpatients.Otherside-effectscanbeascribedtotheradiationdosetothetestesinmen.Thisdoseleadstosignificantlylowerserumtestosteroneandinhibin-BlevelswhichinturngiverisetohigherserumLHandFSHconcentrations,therebysubstantiatingthatthepituitaryfunctionisunimpaired.
Thepatient-assessedglobalhealthscoreimprovedin30%ofpatientsduringthetreatmentandthefollow-upperiod.Thisisanimportantfindingwhichreflectstheimprovementinpatientwell-beingandstressesthescarcityofside-effectsasperceivedbypatients.Thefactthatotherscoresmainlyaddressingsymptomsdidnotchangesignificantlyislikelyduetothediversityofsymptomsbetweenpatients,theuseofSandostatinbysymptomaticpatientsandthesmallsizeofthepatientgroup.
Figure 3. Serumchromogranin-AconcentrationsduringandaftertherapyinpatientswithPR,SDorPD.Thereductioninthenumberofpatientsduringthecourseofthefollow-upwasduetodeathormissingvalues.Notethelogarithmicy-axis.
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ManyphysiciansadoptanexpectantattitudewhendealingwithpatientswithmetastaticGEPtumoursowingtothelowsuccessratesofchemotherapyprotocols.However,giventhattreatmentwith177Lu-octreotateresultedinPR(orCR)in38%ofourpatients,thisattitudemaybequestioned.Althoughtherewasa(statisticallynon-significant)tendencytowardsmorefrequenttumourregressioninpatientswhohaddocumentedPDbeforethestartofthetreatment,thoseofourpatientswhohadanobjectivetumourresponsemorefrequentlyhadalimitedtumourload.Thisimpliesthatwaitingfortumourprogressionmightplacepatientsinaworseposition,asPDduringoraftertreatmentwasmorefrequentinpatientswithanextensivetumourload,especiallyintheliver.Wethereforeadvocatetreatmentwith177Lu-octreotateatanearlierstageofmetastaticdisease,whenevenCRmaybepossible.Anotherargumentinfavourofearlytreatmentisthatneuroendocrinetumourscandedifferentiateinthecourseofthedisease,andlosetheirsomatostatinreceptors,makingtreatmentwithradiolabelledsomatostatinanaloguesimpossible.Ifseriousside-effectsoftreatmentwith177Lu-octreotateremainabsentduringlongerpatientfollow-up,suchtreatmentcouldalsobeconsideredinanadjuvantsettinginpatientswithneuroendocrinetumourswhoareoperatedonwithcurativeintent.
Lastly,asithasbeenshowninanimalexperimentsthat90Y-labelledsomatostatinanaloguesaremoreeffectivefor largertumoursand 177Lu-labelledsomatostatinanaloguesaremoreeffectiveforsmallertumours 13,14,combinationtherapywith90Y-labelledand177Lu-labelledoctreotatemaybetriedinthenearfuture.Suchtherapymightyieldevenbetterresultsthantreatmentwitheitheroftheradionuclidesalone15.
ACKNOWLEDGEMENTSTheauthorswishtothankallsupportingpersonneloftheDepartmentofNuclearMedicinefortheirexperthelpandeffort.
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2. JansonET,ObergK.Long-termmanagementofthecarcinoidsyndrome.Treatmentwithoctreotidealoneandincombinationwithalpha-interferon.Acta Oncol.1993;32:225–229.
3. DucreuxM,RuszniewskiP,ChayvialleJA,BlumbergJ,CloarecD,MichelH,RaymondJM,DupasJL,GouerouH,JianR,GenestinE,HammelP,RougierP.Theantitumoraleffectofthelong-actingsomatostatinanaloglanreotideinneuroendocrinetumors.Am J Gastroenterol.2000;95:3276–3281.
4. ValkemaR,deJongM,BakkerWH,BreemanWAP,KooijPPM,LugtenburgPJ,deJongFH,ChristiansenA,KamBLR,deHerderWW,StridsbergM,LindemansJ,EnsingG,KrenningEP.PhaseIstudyofpeptidereceptorradionuclidetherapywith[111In-DTPA0]octreotide:theRotterdamexperience.Semin Nucl Med.2002;32:110–122.
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6. WaldherrC,PlessM,MaeckeHR,HaldemannA,Mueller-BrandJ.Theclinicalvalueof[90Y-DOTA]-D-Phe1-Tyr3-octreotide(90Y-DOTATOC)inthetreatmentofneuroendocrinetumours:aclinicalphaseIIstudy.Ann Oncol.2001;12:941–945.
7. PaganelliG,ZoboliS,CremonesiM,BodeiL,FerrariM,GranaC,BartolomeiM,OrsiF,DeCiccoC,MackeHR,ChinolM,deBraudF.Receptor-mediatedradiotherapywith90Y-DOTA-D-Phe1-Tyr3-octreotide.Eur J Nucl Med.2001;28:426–434.
8. ValkemaR,JamarF,BakkerWH,NorenbergJ,SmithC,StolzB,KvolsL,PauwelsS,KrenningEP.Safetyandefficacyof [Y-90-DOTA,Tyr(3)]-octreotide (Y-90-SMT487;OctreoTher)peptidereceptorradionuclidetherapy(PRRT).Preliminaryresultsofaphase-1study.Eur J Nucl Med.2001;28:1025.
9. ReubiJC,ScharJC,WaserB,WengerS,HeppelerA,SchmittJS,MackeHR.AffinityprofilesforhumansomatostatinreceptorsubtypesSST1-SST5ofsomatostatinradiotracersselectedforscintigraphicandradiotherapeuticuse.Eur J Nucl Med.2000;27:273-282.
10. ErionJL,BugajJE,SchmidtMA,WilhelmRR,SrinivasanA.Highradiotherapeuticefficacyof[Lu-177]-DOTA-Y(3)-octreotateinarattumormodel.J Nucl Med.1999;40:223P.
11. KwekkeboomDJ,BakkerWH,KooijPP,KonijnenbergMW,SrinivasanA,ErionJL,SchmidtMA,BugajJL,deJongM,KrenningEP.[177Lu-DOTA0Tyr3]octreotate:comparisonwith[111In-DTPA0]octreotideinpatients.Eur J Nucl Med.2001;28:1319–1325.
12. AaronsonNK,AhmedzaiS,BergmanB,BullingerM,CullA,DuezA,FilibertiA,FlechtnerH,FleishmanSB,deHaesJC.TheEuropeanOrganizationforResearchandTreatmentofCancerQLQ-C30:aquality-of-lifeinstrumentforuseininternationalclinicaltrialsinoncology.J Natl Cancer Inst.1993;85:365–376.
13. deJongM,BreemanWA,BernardBF,BakkerWH,SchaarM,vanGamerenA,BugajJE,ErionJ,SchmidtM,SrinivasanA,KrenningEP.[177Lu-DOTA0,Tyr3]octreotateforsomatostatinreceptor-targetedradionuclidetherapy.Int J Cancer.2001;92:628–633.
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14. DeJongM,BreemanWA,BernardBF,BakkerWH,VisserTJ,KooijPP,vanGamerenA,KrenningEP.Tumorresponseafter[90Y-DOTA0,Tyr3]octreotideradionuclidetherapyinatransplantablerattumormodelisdependentontumorsize.J Nucl Med.2001;42:1841–1846.
15. DeJongM,ValkemaR,JamarF,KvolsLK,KwekkeboomDJ,BreemanWAP,BakkerWH,SmithC,PauwelsS,KrenningEP.Somatostatinreceptor-targetedradionuclidetherapyoftumors:preclinicalandclinicalfindings.Semin Nucl Med.2002;32:133–140.
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2.1
2.2Radiolabeled somatostatin analog [177Lu-DOTA0,Tyr3]octreotate in patients with endocrine gastroenteropancreatic tumors
Dik J. Kwekkeboom, Jaap J. Teunissen, Willem H. Bakker, Peter P. Kooij, Wouter W.
de Herder, Richard A. Feelders, Casper H. van Eijck, Jan-Paul Esser, Boen L. Kam
and Eric P. Krenning
Journal of Clinical Oncology 2005; 23:2754-2762
AbstractPurposeThereare fewtreatmentoptions forpatientswithmetastasizedor inoperableendocrinegastroenteropancreatic(GEP)tumors.Chemotherapycanbeeffective,buttheresponseisusuallylessthan1year.Here,wepresenttheresultsoftreatmentwitharadiolabeledsomatostatinanalog,[177Lu-DOTA0,Tyr3]octreotate(177Lu-octreotate).
Patients and methodsOnehundredthirty-onepatientswithsomatostatinreceptor-positive tumorsweretreatedwithuptoacumulativedoseof600to800mCi(22.2to29.6GBq)of177Lu-octreotate.
ResultsOnepatientdevelopedrenalinsufficiency,andanotherpatientdevelopedhepatorenalsyndrome.Creatinineclearancedidnotchangesignificantlyintheotherpatients.WHOhematologic toxicity grade 3 or 4 occurred after less than 2% of theadministrations.Weobservedcompleteremissioninthreepatients(2%),partial
remissionin32patients(26%),minorresponse(tumordiameterdecreaseof25%to50%)in24patients(19%),stabledisease(SD)in44patients(35%),andprogressivedisease(PD)in22patients(18%).Higherremissionrateswerepositivelycorrelated
withhighuptakeonpretherapysomatostatinreceptorimagingandalimitednumberoflivermetastases,whereasPDwassignificantlymorefrequentinpatientswithalowperformancescoreandextensivedisease.Mediantimetoprogressionin103patientswhoeitherhadSDortumorregressionwasmorethan36months.
ConclusionTreatmentwith 177Lu-octreotateresultsintumorremissioninahighpercentageofpatientswithGEPtumors.Serioussideeffectsarerare.Themediantimetoprogressioncomparesfavorablywithchemotherapy.Resultsarebetterinpatientswithalimitedtumorload.Therefore,earlytreatment,eveninpatientswhohavenoPD,maybebetter.
Abstract INTRODUCTIONEndocrinegastroenteropancreatic(GEP)tumors,whichcomprisepancreaticislet-celltumors,nonfunctioningendocrinepancreatictumors,andcarcinoids,areusuallyslowgrowing.Whenmetastasized,treatmentwithsomatostatinanalogsresultsinreducedhormonaloverproductionandsymptomaticreliefinmostcases.However,
treatmentwithsomatostatinanalogsisseldomsuccessfulintermsoftumorsizereduction1-3.
AnewtreatmentmodalityforinoperableormetastasizedendocrineGEPtumorsistheuseofradiolabeledsomatostatinanalogs.ThemajorityofendocrineGEPtumorspossesssomatostatinreceptorsandcan,therefore,bevisualizedusingtheradiolabeledsomatostatinanalog[111In-DTPA0]octreotide(OctreoScan;Mallinckrodt,StLouis,MO).Therefore,alogicalsequencetothistumorvisualizationinpatientswastoalsotrytotreatthesepatientswithradiolabeledsomatostatinanalogs.Initialstudieswithhighdosagesof[111In-DTPA0]octreotideinpatientswithmetastasizedneuroendocrinetumorswereencouraging,althoughpartialremissions(PRs)wereexceptional4,5.Thisisnotsurprisingbecause111In-coupledpeptidesarenotidealforpeptidereceptorradionuclideradiotherapy(PRRT)becauseofthesmallparticlerangeand,therefore,shorttissuepenetrationoftheAugerelectrons.
Another r ad iolabeled somatost at in analog that i s u sed for PRRT i s[90Y-DOTA0,Tyr3]octreotide.SeveralphaseIandIIPRRTtrialshavebeenperformedusingthiscompound.Completeremissions(CRs)andPRshavebeenreportedin7%to33%ofpatientswithneuroendocrinetumors6-11.
Thesomatostatinanalog[DOTA0,Tyr3]octreotatehasanine-foldhigheraffinityforthesomatostatinreceptorsubtype2comparedwith[DOTA0,Tyr3]octreotideinvitro12.Also,labeledwiththebeta-andgamma-emittingradionuclide177Lu,thiscompoundwasshowntobesuccessfulintermsoftumorregressionandanimalsurvivalinaratmodel13.Inacomparisoninpatients,wefoundthattheuptakeofradioactivity,expressed aspercentageofthe injecteddoseof [177Lu-DOTA0,Tyr3]octreotate(177Lu-octreotate),wascomparabletothatafter[111In-DTPA0]octreotideforkidneys,
spleen,andliverbutwasthree-tofour-foldhigherforfouroffivetumors 14. Inapreliminaryreportontheresultsofthistreatmentinthefirst35patientswithendocrineGEPtumors15,wefoundCRsandPRsin38%ofthepatients.Noseriousside
effectswereobserved.Here,wepresenttheresultsoftreatmentwith177Lu-octreotateinalargeseriesofpatientswithendocrineGEPtumors.Also,weanalyzedwhethercertainpatientortumor-relatedfactorspredictafavorabletreatmentresponseorpredictthedurationofsucharesponse.
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�PATIENTS AND METHODS
PatientsOnehundredthirty-onepatientswithendocrineGEPtumorswerestudied.Allpatientshad tumor tissueuptakeduring [111In-DTPA0]octreotidescintigraphyprecedingthetherapythatwasatleastashighastheuptakeinthenormallivertissue.Noneofthepatientshadreceivedpriortreatmentwithotherradiolabeledsomatostatinanalogs.Fourpatientshadpreviouslybeentreatedwithembolization,
andonepatientwastreatedwithchemoembolizationforlivermetastases.Prerequisitesfortreatmentwerehemoglobin(Hb)≥6mmol/L,WBC≥2x109/L,platelets≥80x109/L,creatinine≤150µmol/Lorcreatinineclearance≥40mL/min,andKarnofskyperformancescore(KPS)≥50.Thepreliminaryresultsin35patientswerealsoreportedpreviouslyelsewhere15.Allpatientsgavewritteninformedconsenttoparticipateinthestudy,whichwasapprovedbythemedicalethicalcommitteeofthehospital.
Methods[DOTA0,Tyr3]octreotatewasobtainedfromMallinckrodt(StLouis,MO). 177LuCl3wasobtained fromNRG (Petten, theNetherlands)andMissouriUniversityResearchReactor(Columbia,MO)andwasdistributedbyIDB(Baarle-Nassau,theNetherlands).177Lu-octreotatewaslocallypreparedasdescribedpreviously14.
Granisetron3mgwasinjectedintravenously,andaninfusionofaminoacids(lysine2.5%andarginine2.5%in1L0.9%NaCl;250mL/h)wasstarted30minutesbeforetheadministrationoftheradiopharmaceuticalandlasted4hours.Viaasecondpump
system,theradiopharmaceuticalwascoadministered.Cycledosageswere100mCi(3.7GBq)insevenpatients,150mCi(5.6GBq)in16patients,and200mCi(7.4GBq)intheremaining108patients.Thetreatmentdosesof100mCiwereinjectedin20minutes,andthedosesof150and200mCiwereinjectedin30minutes.Theintervalbetweentreatmentswas6to10weeks.Patientsweretreateduptoacumulativedoseof750to800mCi(27.8to29.6GBq;correspondingwitharadiationdosetothebonemarrowof2Gy)14,unlessdosimetriccalculationsindicatedthattheradiationdosetothekidneyswouldthenexceed23Gy;inthesecases,thecumulativedosewasreducedto600to700mCi.
Routinehematology,liverandkidneyfunctiontests,andhormonemeasurementswereperformedbeforeeach therapy,aswellasat follow-upvisits.Computedtomography(CT)ormagneticresonanceimagingwasperformedwithin3monthsbeforethefirsttherapy,and6to8weeks,3months,and6monthsafterthelasttreatment,andthereafterevery6months.
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�In Vivo MeasurementsThe tumorsonCTormagnetic resonance imagingweremeasuredandscoredaccordingtotheSouthwestOncologyGroupsolidtumorresponsecriteria 16.Theuptakeduringpretreatment[111In-DTPA0]octreotidescintigraphywasscoredvisuallyonplanarimagesusingthefollowing4-pointscale:lowerthan(grade1),equalto(grade2),orgreaterthan(grade3)normallivertissue;orhigherthannormalspleenorkidneyuptake(grade4).
StatisticsAnalysisofvariance,pairedttests,χ2tests(or,ifapplicable,Fisher’sexacttests),Pearson’scorrelationtests,andlogisticregressionwereused.Forsurvivalanalysis,log-ranktestsandCoxregressionmodelswereused.
RESULTSOnehundredthirty-onepatientswithmetastasizedorinoperableendocrineGEPtumorsweretreatedbetweenJanuary2000andSeptember2003.Twopatientswerelosttofollow-up;inalloftheother129patients,follow-updataforatleast3monthsafterthelasttherapywereavailable.Therewere66womenand65men;
themeanagewas56years(range,19to83years).Eightpatientshadgastrinoma,twohadinsulinoma,33hadnonfunctioningendocrinepancreatictumors,18hadendocrinetumorsofunknownorigin,and70hadcarcinoidtumors(onethymic,onegastric,fourbronchial,and64smallbowelcarcinoids).In18patients,theliverwastheonlyknownsiteoftumorspread;intwopatients,thiswastheskeleton;andin11otherpatients,sitessuchaslymphnodesorpancreaswerethesoleknowntumorsites.Intheremaining100patients,combinationsofthesetumorsiteswerepresent(Figure1).
Sixty-threepatientshadpreviouslybeenoperatedon,sevenhadhadexternal-beamradiation,20hadbeentreatedwithchemotherapy,and66hadusedsomatostatinanalogs(usuallySandostatin;Novartis,Basel,Switzerland).Fifty-twopatientsusedsomatostatinanalogsinbetweentreatments.Inallbutthreepatients,short-actingsomatostatinanalogswerestoppedatleast1daybeforethetreatment,andlong-actingsomatostatinanalogswerestoppedatleast6weeksbeforethetreatment.Inthreepatientswithseveresymptomsofcarcinoidsyndrome,theadministrationofsomatostatinanalogswasnotstopped;inthesethreepatients,apretreatmentOctreoScanduringcontinuedsomatostatinanalogtreatmenthadshownsufficientuptakeoftheradiolabeledanaloginthetumorsites.Fifty-five(42%)ofthe131patientshaddocumentedprogressivedisease(PD)within1yearbeforethestartofthetherapy,37patients(28%)hadstabledisease(SD),andin39patients(30%),informationondiseaseprogressionwasabsent.
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Figure 1. Thedistributionofknowntumorsitesin131patients.Venndiagramisshowninwhichcirclediametersareproportionaltototalnumbersofpatientswithcertainlocalizations.Overlappingareasrepresentpatientswithlesionsinbothcategories.
Treatmentintervalswere6to10weeks,exceptinfourpatientswhohadpersistentthrombocytopeniaandin13otherpatientsbecauseofreasonsunrelatedtothe
treatment.In116patients,thefinalintendedcumulativedoseof600to800mCiwasadministered.Tenofthe15remainingpatientsdiedofPDbeforecompletingtheirtreatment;twoelderlypatientsstoppedtreatmentafterhavingreceived600mCibecausetheyfeltthetreatmentwastootiring;onepatientstoppedearlybecauseofdevelopingkidneyfailure;onepatientstoppedearlybecauseacolorectalcarcinomawasdiagnosed;andonepatientstoppedearlybecauseofsocialreasons.
Nauseaandvomiting(WHOtoxicitygrade1to2)withinthefirst24hoursaftertheadministrationwerepresentin31%and14%oftheadministrations,respectively.Mildabdominalpainwasnoticedby12%ofthepatients,especiallythosewithliver
enlargement.Increasedhairloss(WHOtoxicitygrade1)wasnoticedby64%ofthepatients;hairregrowthoccurredwithin3monthsafterthelastadministration.
Serioussideeffectsoccurredintwopatients.Onepatientinwhom,intheyearprecedingthetherapy,serumcreatinineconcentrationshadrisenfrom60to70µmol/Lto90to 100µmol/Landwhohadaurinarycreatinineclearanceof41mL/minwhenenteringthestudyeventuallydevelopedrenalinsufficiency1.5yearsafterreceivingherlasttreatment(cumulativedose,600mCi).Akidneybiopsydemonstratedtubulardepositionsandmicroangiopathy.Eventually,thepatientrefrainedfromhemodialysisanddiedshortlythereafter.Inanotherpatientwho
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2.2
haddiffuselivermetastasesfromanendocrinepancreatictumorthathadgrownrapidlyinthemonthsprecedingthetherapy,anincreaseinupperabdominalpainandadeteriorationofliverfunctionsoccurredinthedaysandweeksafterthefirstadministration.Thepatientdevelopedhepatorenal syndromeanddiedafter5
weeks.
WHOtoxicitygrade3or4anemia(Hb,4.0to4.9or<4.0mmol/L,respectively),leukocytopenia(WBC,1.0to1.9or<1.0x109/L,respectively),andthrombocytopenia(platelets,25.0to49.9or<25x109/L,respectively)occurredafter0.4%and0.0%,1.3%and0.0%,and1.5%and0.2%oftheadministrations,respectively.Patientswhohadbeentreatedwithchemotherapyhadsignificantlymorefrequentthrombocytopeniatoxicitygrade2,whereaspatientsolderthan70yearshadasignificantlyhigherfrequencyofWHOtoxicitygrade2leukocytopenia,especiallyneutropenia(Fisher’sexacttest,P<.01).MeanHb,leukocytes,andplateletsdecreasedsignificantlyduringtreatmentbutwerenotsignificantlydifferentfrompretreatmentvalues18to24
monthsafterthelasttherapy(Figure2).
Figure 2.Mean(±SEM)serumhemoglobin(Hb;closedcircles,solidline),WBC(closedsquares,solidline),andplatelets(opencircles,dottedline)duringandaftertherapywith[177Lu-DOTA0,Tyr3]octreotate.
Serumcreatinine,creatinineclearance,andserumHbA1cdidnotchangesignificantly.Excludingfivepatientswhowerehypothyroidbeforethetreatmentandinwhom,subsequently,replacementtherapywasstartedandalsoexcludinganothersixpatients
whoalreadyusedthyroidmedication,serumthyrotropinlevelsdidnotchangesignificantlyduringoraftertreatment,whereasfreethyroxineconcentrationsweresignificantlylower(mean,18.3pmol/Lbeforetherapy;and15.5to17.5pmol/L3to24monthsaftertherapy).
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�Inwomen,serumluteinizinghormone(LH),follicle-stimulatinghormone(FSH),estradiol, and inhibin-Bconcentrationsdidnotchange significantly. Inmen,serumtestosteroneconcentrationsdecreasedsignificantlyinthefollow-upperiod(fromameanof14.4nmol/Lbeforetreatmentto10.4nmol/L24monthsafter
thelasttreatment;P< .01,analysisofvariance,Bonferronitests),whereasserumLHconcentrationsdidnotchangesignificantly.Seruminhibin-Bconcentrationsdecreasedsignificantly(fromameanof179ng/Lbeforetreatmenttoanadirof23ng/L3monthsafterthelasttreatment)accompaniedbyariseinserumFSHconcentrations,butbothreturnedtovaluesnotsignificantlydifferentfrompretreatmentlevels18to24monthsafterthelasttreatment(Figure3).
Figure 3.Mean(±SEM)seruminhibin-B(squares,dottedline)andfollicle-stimulatinghormone(FSH;circles,solidline)concentrationsinmenduringandaftertherapywith[177Lu-DOTA0,Tyr3]octreotate.
Tumorsizecouldbeevaluatedin125patients(twopatientswerelosttofollow-up,andinfourpatients,nomeasurablediseasewasdocumented).ACRwasfoundinthreepatients(2%),PRwasfoundin32patients(26%),minorresponse(MR)wasfoundin24patients(19%),SDwasfoundin44patients(35%),andPDwasfoundin22patients(18%),includingthe10patientswhodiedbeforetheintendedcumulativedosewasreached(Table1;Figure4).
Higherremissionrateswerepositivelycorrelatedwithhighuptakeduringpretherapy[111In-DTPA0]octreotidescintigraphyanda limitednumberof livermetastases,whereasPDwassignificantlymorefrequentinpatientswithalowKPSandextensivedisease(logisticregression,Table2,Figures5and6).Ahightumoruptakeduring[111In-DTPA0]octreotidescintigraphyandgastrinomatumortypeweresignificantlycorrelated;also,alowKPSandweightlossandextensiveliverinvolvementwerealsosignificantlycorrelated(Pearson’scorrelationtest,P<.05).
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Table 1. Tumor responses in 125 patients 3months after the last administration of177Lu-octreotate
CR PR MR SD PD
Tumor TypeNo. of patients
%No. of patients
%No. of patients
%No. of patients
%No. Of patients
%Total
patients (No.)
Carcinoid - - 13 20 13 20 28 42 12 18 66
NEpancreas 3 9 7 22 7 22 11 34 4 13 32
NEunknownorigin
- - 6 35 2 12 4 24 5 29 17
Gastrinoma - - 5 63 2 25 1 12 - - 8
Insulinoma - - 1 50 - - - - 1 50 2
Total 3 2 32 26 24 19 44 35 22 18 125
NOTE. Ten patients with PD died before reaching their final dose.Abbreviations: CR, complete remission; PR, partial remission; MR, minor response; SD, stable disease; PD, progressive disease; NE, neuroendocrine; 177Lu-octreotate, [177Lu-DOTA0,Tyr3]octreotate.
Figure 4. Computedtomographyscansinapatientwithametastasizednonfunctioningendocrinepancreatictumorbeforetreatment(left)and3monthsafterthelasttreatment(right).Noticethedecreaseinnumberofcysticliverlesionsandthedecreaseintotalliversize.Thepatienthadaminorresponse.
Ontheposttherapyscansafterthethirdorfourthtreatment,ifcomparedwiththescanafterthefirsttreatment,areducedtumoruptakewasfrequentlyseeninpatientswhoeventuallyexperiencedatumorregression(Figures7and8).
112
�Table 2.Resultsoftheanalysisoffactorsthatmaypredictthechancesoftumorregressionorprogression,testedwithχ2testsandlogisticregressionformultivariateanalysis
Remission PD
Factor No. Patients No. % P (χ2) P (logistic) No. % P (χ2) P (logistic)
[111In-DTPA0]octreotide scintigraphy uptake
≈Liver 4 1 25 .008 .002 0 0 NS NS
>Liver 97 40 41 21 22
>>Liver 24 18 75 1 4
Tumor type
Gastrinoma 8 7 88 .018 NS 0 0 NS NS
Other 117 52 44 22 19
Tumor mass
Limited 21 14 67 NS NS 0 0 .045 .028
Moderate 78 35 45 15 19
Extensive 26 10 38 7 27
Liver metastases
None/moderate 91 48 53 .042 .017 11 12 .008 NS
Extensive 34 11 32 11 32
Bone metastases
Absent 94 48 51 NS NS 15 16 NS NS
Present 31 11 36 7 23
Weight loss
Absent 103 50 49 NS NS 12 12 .000 NS
Present 22 9 41 10 46
KPS
>70 104 53 51 NS NS 10 10 .000 .000
≤70 21 6 29 12 57
Progressive at baseline
No 34 16 47 NS NS 4 12 NS NS
Yes 53 26 49 13 25
NOTE: Remission includes CR, PR, and MR. All tumor characteristics listed in the first column pertain to baseline observations. Tumor mass was judged on [111In-DTPA0]octreotide scintigrams, and liver involvement was judged on CT/MRI. Weight loss was scored positive if it at least amounted to 1 kg per month, existing for at least 3 months.
Abbreviations: PD, progressive disease; ≈, Liver, approximately equal to liver uptake; > Liver, more than liver uptake; >> Liver, very high uptake; KPS, Karnofsky performance score; NS, not significant; CR, complete remission; PR, partial remission; MR, minor response; CT, computed tomography; MRI, magnetic resonance imaging.
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Figure 5. Analysisoffactorsthatmaypredicttumorremission(minorresponse,partialremission,orcompleteremission).(*)P <.05;(**)P <.01,logisticregression.KPS,Karnofskyperformancescore.
Medianfollow-uptimeinthe103patientswhohadeitherSDortumorregressionwas16months(range,7to44months).Mediantimetoprogressionwasmorethan36months;intheeightpatientswhohadgastrinoma,mediantimetoprogressionwas20months(P <.01,log-ranktest;Fig9).Also,inpatientswithextensiveliverinvolvement,themediantimetoprogressionwassignificantlyshorterat26months(P < .05,log-ranktest).NeitherinitialtumorresponsenoranyotherofthefactorslistedinTable2weresignificantinpredictingthetimetoprogressionwhentestedseparately.
Figure 6. Analysisoffactorsthatmaypredicttumorprogression(progressivedisease).(*)
P <.05;(**)P <.01,logisticregression.KPS,Karnofskyperformancescore.
2.2
114
�
Figure 7. Posttherapyscansafter200mCiof[177Lu-DOTA0,Tyr3]octreotate(firsttolasttherapy,lefttoright)inapatientwithgastrinomawhoeventuallyhadpartialremission.Noticethedecreasinguptakeinthelivermetastases.
Inamultivariatemodel,however,gastrinomatumortypeandthepresenceofbonemetastaseswerethefactorsthatindicatedasignificantlyshortertimetoprogression(Coxregression,P <.004andP <.037,respectively).
Figure 8. Theuptakeintumorsitesafterthelast(thirdorfourth)therapy,expressedaspercentageoftheuptakeafterthefirsttreatment,accordingtotreatmentoutcome(x-axis).Boxesshowmediansand25thto75thpercentiles;whiskersindicateranges.PD,progressivedisease;SD,stabledisease;MR,minorresponse;PR,partialresponse.
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DISCUSSION InthisstudyinalargenumberofpatientswithendocrineGEPtumorswhoweretreatedwith177Lu-octreotate,wefoundafavorableeffectontumorsize(MR,PR,orCR) in47%ofpatients.Serioussideeffects thatwerepotentially treatmentrelatedwerefoundinonlytwopatients.Renalinsufficiencyoccurredinoneofourpatients.
Ithasalsobeenreportedinpatientswhoweretreatedwith[90Y-DOTA0,Tyr3]oct-reotide,especially ifnoaminoacidswerecoadministeredtoreducethekidneyradiationdose 7,10,17.Therefore,ourprotocol,whichusedaminoacidcoinfusionandlimitedtheestimatedcumulativedosetothekidneysto23Gyorless,seemsadequateinreducingthechancesoftherapy-relatedkidneyfailure.Onepatientwhohadextensiveanddiffuselivermetastasesdevelopedlethalhepaticfailure.Thisgravecomplication,whichwasprobablyaresultofamuchhigherradiationdosetotherelativelylimitednumberofviablehepatocytesthaninpatientswithalimitedtumorburdenintheliver,hasalsobeenreportedinthreepatientswhoweretreatedwith[111In-DTPA0]octreotide5andonepatientwhowastreatedwith[90Y-DOTA0,Tyr3]octreotide10,allofwhomalsohadextensiveliverdisease.Therefore,insuchpatients,extracaution,intermsofadditionaltestingforliver-synthesizingcapacityand,ifnecessary,loweringthecycledose,seemswelladvised.
Figure 9. Progression-freeperiodinpatientswithgastrinoma(dottedline)andpatientswithothertumors(solidline).Thetimetoprogressionwassignificantlyshorterintheeightpatientswithgastrinomas.
116
�Inpreviousstudieswith111In-and90Y-labeledsomatostatinanalogs,myelodysplasticsyndromeandleukemiahavebeenreportedasinfrequentsideeffects,especiallyinpatientstreatedwithhighcumulativedoses4,10.Inthepresentstudy,noneofthepatientshadthisgravecomplication,andthisisprobablybecauseofthefactthatwelimitedourmaximumcumulativedosetoarelativelysafeuppervalue,whichcorrespondstoabonemarrowradiationabsorbeddoseof2Gy.
Transientandrelativelymildbonemarrowsuppressionwasfoundinaminorityofpatientsandinalowerpercentagethanreportedinmoststudieswith111In-and90Y-labeledsomatostatinanalogs4,5,9,10,17.Transienthairloss,butnoturningbold,waspresentintwothirdsofthepatients;thisisprobablyaresultofthefactthat177Lu-octreotatehasaslowerurinaryexcretionratethan[111In-DTPA0]octreotide14,thuscausingalongerretentionofradioactivityinthewholebody.Todate,therearenoreportsonthepresenceofsomatostatinreceptorsin,forinstance,hairfollicles.
Thepituitaryglandpossessessomatostatinreceptors.Therefore, theoretically,treatmentwith177Lu-octreotatecouldimpairpituitaryfunction.Inourpatients,wesawnodecreaseinserumgonadotrophorthyrotrophhormoneconcentrations,soobviouslytheabsorbedradiationdosetothepituitarywaslow.Inmen,atransientsignificantdecreaseinseruminhibin-BconcentrationsandaconcomitantincreaseinserumFSHlevelswerefoundduringandaftertherapy.ThisradiationeffectonthetesticularSertolicellshasalsobeendescribedaftertherapywith131Iinpatientswiththyroidcancer18.Longerlasting,significantdecreasesoftestosteroneinmenandof free thyroxine in thewholepatientgroupwerealso found.Thesewerenotaccompaniedbysignificant increases inserumLHorTSHconcentrations,andtherefore,althoughstatisticallysignificant,thedecreaseswereclinicallynotsignificantlyrelevant.Itcanalsobehypothesizedthattheseminordecreasesintestosteroneandthyroidhormoneconcentrationswerecausedbychronicillnessaswell.
Wefoundantitumoreffects(CR,PR,orMR)in47%ofourpatients.Thereasonstocategorizetumorsizereductionsof25%to50%asMRsandtoregardtheseasfavorabletherapeuticeffectsarethatendocrineGEPtumorsusuallygrowslowlyandalsobecausemanyofthesetumorsarecystic,whichmakesitunlikelythattheirresponsetotherapyiscomparabletothatoffast-growingsolidtumors.CRandPRoccurredin28%ofthepatients.With[90Y-DOTA0,Tyr3]octreotide,remissionratesof7%to33%inGEPtumorpatientshavebeenreported6,7,9-11.Thedifferencesinremissionratesmay,inpart,bearesultofdifferencesinstudydesignanddosagesused,butthedifferencesmayalsobearesultofpatientselection.Inourpatients,wefoundthatahighuptakeduring[111In-DTPA0]octreotidescintigraphyandlimitedliverinvolvementwerepredictivefactorsforafavorabletumorresponse,whereasalow
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KPSand,toalesserextent,ahightumorloadweresignificantfactorsinpredictingtumorprogression.Inthestudiesusing[90Y-DOTA0,Tyr3]octreotide,whichwereperformedinrelativelysmallpatientgroups,insufficientdataontheseimportantfactorsareavailable.Thislackofcomparabledataunderscorestheneedforrandomizedtrialscomparing[90Y-DOTA0,Tyr3]octreotideand177Lu-octreotate.Indeed,weplantoperformsuchastudycomparing90Y-and177Lu-labeledsomatostatinanalogs.
WetreatedbothpatientswhohadPDatbaselineandthosewhowerestableorinwhomdiseaseprogressionwasnotdocumented.Thereasonforthiswasthat,inmanyofthesepatients,waitingfordiseaseprogressionwouldhaveimpliedaseriousdeteriorationoftheirclinicalcondition.Asthepresentanalysisshows,thiswouldalsohaveimplieddiminishedchancesofasuccessfultherapy.Unfortunately,wedidnothaveacontrolgroupofuntreatedpatients.However,Faisset al. 19recentlyreportedtumorremissionsinfour(5%)of80GEPtumorpatientswhohadPDatstudyentryandweretreatedwithsomatostatinanalogsand/orinterferonalfa.Bycontrast,wefoundtumorremissionsin47%ofourpatients,whetherornottheyhadPDatstudyentry.Itseemshighlyunlikelythatsuchadifferencecouldhavebeencausedbypatientselection.
Apartfromtheproportionofpatientswithatumorremission,thedurationofsucharesponseisanotherimportanttreatmentoutcomeparameter.Reportedresponseratesforsingle-agentandcombinationchemotherapyinpatientswithendocrineGEPtumorsareashighas40%to60%forwell-differentiatedpancreatictumorsandpoorlydifferentiatedtumorsofanyorigin,whereassuccessratesformidguttumorsrarelyexceed20%inrecentstudies(Table3,20-29seereviewin30).Highresponserateshavebeenreportedinolderseries20-22(Table3),butinthesestudies,theresponseevaluationalsoincludedbiochemicalresponses(changesinserumtumormarkerlevels)aswellasphysicalexaminationfortheevaluationofhepatomegaly.Indeed,muchofthediscrepancybetweenolderandmorerecentstudiescanbeascribedtodifferencesinresponsecriteria,asisillustratedinamorerecentstudybyChengandSaltz23whomaintainedthattheirpercentageofpatientswithanobjectiveresponsewouldhaveincreasedfrom6%to25%iftheyhadacceptednotonlymeasuredCTscanchangesasresponsecriteria,butalsodecreasesofhepatomegalyassessedwithphysicalexamination.Despitethevaryingpercentagesofobjectiveresponsesthathavebeenreportedforchemotherapy,themediantimetoprogressioninmostofthestudiesislessthan18months.Inthisrespect,ourtreatmentwith177Lu-octreotateperformedconsiderablybetter,withamediantimetoprogressionofmorethan36months.However,somecautionintheinterpretationofthesedataiswarrantedbecausethemedianfollow-upinthisongoingstudyis16months.Also,cardiacandrenaltoxicity,aswellasvomitingandhematologictoxicity,aremuchmorefrequentwithchemotherapythanwithtreatmentwith177Lu-octreotate(Table3).
118
�Unexpectedly,we foundthatpatientswithgastrinomashadashorter timetoprogressionthanotherpatientswhohad,forinstance,carcinoidsornonfunctioningendocrinepancreatictumors.Intheory,thiscouldbecausedbyafastergrowthpatternofgastrinomas.ThereareonlyafewreportsinrelativelysmallnumbersofneuroendocrinetumorspecimensonproliferativemarkerslikeKi-67.Todate,therearereportsthatevidencethatahighKi-67proliferativeindexcorrelateswithafasttumorgrowthandshortsurvivalinvivoforbothfunctioningandnonfunctioningendocrineGEPtumors31-33,butasfarastheauthorsareaware,thereisnodirectevidencethatproliferativeindicesdifferbetweenmetastasizedgastrinomasandotherendocrineGEPtumors.However,aninterestingdifferenceisthat,onimmunostains,gastrinomas,incontrasttootherendocrinepancreatictumors,frequentlycoexpressneuroendocrineandexocrinemarkers,suchascarcinoembryonicantigen,cytokeratin19,andepithelialmembraneantigen34.Thiscouldimplythedifferentoriginsofgastrinomasand,itcanbespeculatedthatgastrinomasalsohavedifferentbehaviorinvivo.
Tumorremissionwaspositivelycorrelatedwithahighuptakeduring[111In-DTPA0]oct-reotidescintigraphyanda limitednumberof livermetastases,whereasdiseaseprogressionwassignificantlymorefrequentinpatientswithalowperformancestatusandahightumorload.Thisimpliesthatthechancesofasuccessfultreatmentaregreaterifpatientsaretreatedinanearlystageoftheirdisease.Incontrasttowhatwereportedearlierinamuchsmallergroupofpatients 15,thepercentageofpatientswitharemissiondoesnotdiffersignificantlybetweenthosepatientswhohavediseaseprogressionatbaselineandthosewhodonot;therefore,towaitfordiseaseprogressionhasnoadvantageintermsofchancesofsuccess.However,firmconclusionsontheeffectofourtherapyonoverallsurvivalcannotbedrawnfromthisoranyotherstudywithradiolabeledsomatostatinanalogsbecauserandomizedtrialscomparingtreatmentwithradiolabeledanalogswithnoadditionaltreatmenthavenotbeenperformed.
Treatmentwiththeradiolabeledsomatostatinanalog177Lu-octreotateresultsintumorremissioninahighpercentageofpatientswithendocrineGEPtumors.Serioussideeffectsarerare.Themediantimetoprogressionismorethan36months,whichcomparesfavorablywithchemotherapy.Resultsarebetterinpatientswithalimitedtumorload.Therefore,earlytreatment,eveninpatientswhohavenoPD,maybebetter.
AcknowledgmentWethankallsupportingpersonneloftheDepartmentsofNuclearandInternalMedicine(ErasmusMedicalCenter,Rotterdam,theNetherlands)fortheirexperthelpandeffort.
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Tab
le 3
.Resultsandsideeffectsofchem
otherapyinpatientswithneuroendo
crinetumorscomparedwiththepresentstudy
Reg
imen
Tu
mo
r T
yp
esN
o. o
fP
atie
nts
PR
an
d C
R
(%)
Med
ian
Res
po
nse
Du
rati
on
(mo
nth
s)
Hem
ato
logi
c T
oxi
city
Gra
de
3 an
d 4
(%
)
Nau
sea
and
V
om
itin
g (%
)O
ther
Maj
or
Sid
e E
ffec
tsSt
ud
y
Doxorubicin
Carc
3321*
4NA
NA
—Moertel20
FUCarc
1926*
3NA
NA
—Moertel20
STZ+FU
Carc
4333*
7NA
NA
—Moertel20
STZ
NEP
4236*
170
83Ren
altoxicity,29%
;liverfailure,2%
Moertele
t al.
21
STZ+FU
NEP
4263*
1729
85Ren
altoxicity,31%
Moertele
t al.
21
STZ+FU
NEP
3345*
725
81Diarrhea,33%
;ren
alin
sufficiency,7%
Moertele
t al.
22
STZ+doxorubicin
NEP
3669
*20
580
Diarrhea,5%;ren
alin
sufficiency,4%;
heartfailure,9%
Moertele
t al.
22
STZ+doxorubicin
NEP
166
>18
19NA
Diarrhea,19%
;cardiactoxicity,19%
Chen
gandSaltz
23
DTIC
Carc
1513
4NA
NA
—VanHazele
t al.
24
DTIC
Carc
5616
329
88Diarrhea,23%
Bukowskie
t al.
25
DTIC
Carc/NEP
714
NA
NA
0—
Ritzele
t al.
26
FU+IFN
-ACarc/NEP
2421
1342
NA
Diarrhea,8%
Andreyeve
t al.
27
Mitox
antron
eCarc
359
1432
26—
Neijte
t al.
28
Paclitaxel
Carc/NEP
244
361
63Diarrhea,54%
;neurologictoxicity,61%
Anselle
t al.
29
177 Lu-octreotate
Carc/NEP
131
28>36
<2
31Ren
alin
sufficiency,1%;liverfailure,1%
Presentstudy
Abb
revi
atio
ns: P
R, p
arti
al r
emis
sion
; CR
, com
plet
e re
mis
sion
; DT
IC, d
imet
hylt
riaz
enoi
mid
azol
e ca
rbox
amid
e; F
U, fl
uoro
urac
il; S
TZ, s
trep
tozo
cin;
Car
c, c
arci
noid
s;
NEP
, neu
roen
docr
ine
panc
reat
ic t
umor
s; N
A, n
ot a
vaila
ble;
IFN
-A, i
nter
fero
n al
pha;
177 Lu
-oct
reot
ate,
[177 Lu
-DO
TA0,T
yr3 ]o
ctre
otat
e. R
espo
nse
eval
uati
on in
clud
ing
bioc
hem
ical
res
pons
es a
nd p
hysi
cal e
xam
inat
ion
for
eval
uati
on o
f hep
atom
egal
y.
120
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34. GurevichL,KazantsevaI,IsakovVA,etal.Theanalysisofimmunophenotypeofgastrinproducingtumorsofthepancreasandgastrointestinaltract.Cancer2003;98:1967-1976.
3Quality o�� Li��e in patients with gastro-enteropancreatic tumors treated with [177Lu-DOTA0,Tyr3]octreotate
Jaap J. Teunissen, Dik J. Kwekkeboom and Eric P. Krenning
Journal of Clinical Oncology 2004; 22:2724-2729
AbstractPurpose Toevaluatethequalityoflife(QoL)inpatientswithmetastaticsomatostatinreceptorpositivegastroenteropancreatictumorstreatedwith[177Lu-DOTA0,Tyr3]octreotate(177Lu-octreotate)therapy.
Patients and Methods Fiftypatientswhohadbeentreatedwith600to800mCiof177Lu-octreotateandhadafollow-upofatleast3monthswerestudied.ThepatientscompletedtheEuropeanOrganizationfortheResearchandTreatmentofCancerQualityofLifeQuestionnaireC30beforetherapyandatfollow-upvisit6weeksafterthelastcycle.OverallQoLandspecificQoLdomainsofboththetotalgroupofpatientsandsubgroupsaccordingtotreatmentoutcomewereanalyzed.Twenty-fourpatientshadregression,19hadstabledisease,sixhadprogressivedisease,andonehadnonassessablediseasestatus.Analysisofvariancewasusedforstatisticalcomparison.
Results Asignificantimprovementintheglobalhealthstatus/QoLscalewasobservedafter therapywith 177Lu-octreotate (P < .01).Thescore increasedsignificantlysixweeksaftertherapytoameanof78.2,upfrom69.0(scalerange,0to100).Furthermore,significantimprovementwasobservedintherole,emotional,andsocialfunctionscales.Thesymptomscoresforfatigue,insomnia,andpainweresignificantlydecreased.PatientswithproventumorregressionmostfrequentlyhadanimprovementofQoLdomains.Unexpectedly,patientswithprogressivediseasealsoindicatedanimprovementintheirglobalhealth/QoLscore.
Conclusion 177Lu-octreotatetherapysignificantlyimprovedtheglobalhealth/QoLandseveralfunctionandsymptomscalesinpatientswithmetastasizedgastroenteropancreatictumors,butespeciallyinthosepatientswithproventumorregression.
Abstract
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INTRODUCTIONNeuroendocrinegastroenteropancreatic(GEP)tumors,includingpancreaticislet-celltumors,nonfunctioningneuroendocrinepancreatictumors,andcarcinoids,arerelativelyrareneoplasms.Incomparisonwithothermalignancies,thesetumorsusuallygrowslowly 1.Manifestationsofdiseaseinpatientsaremainlybasedonsymptomsorsyndromescausedbytheoverproductionofbioactivesubstancesorhormonesbythetumor,likeincarcinoids,gastrinomas,andinsulinomas.Innonfunctioningtumors,diagnosisoccursatarelativelylatestageofthediseaseandtherefore,widespreadmetastaticdiseaseisoftenpresent.Insymptomaticpatients,treatmentwithsomatostatinanalogsisthetherapyofchoiceandhighlyeffectiveinthesesymptomsreduction2,3.However,somatostatinanalogtreatmentresultsintumorregressioninonly4%to10%ofthepatients4-6.
PeptidereceptorradionuclidetherapyisapromisingtreatmentmodalityinpatientswithmetastasizedGEPtumors7-9.Treatmentwith[177Lu-DOTA0,Tyr3]octreotate(177Lu-octreotate)resultedinacompleteremission(CR)in3%,partialremission(PR)in35%,stabledisease(SD)in41%,andprogressivedisease(PD)in21%ofthepatients.Also,reportedsideeffectswerefew9.Thetherapeuticeffectontumorvolumeismostfrequentlyusedastheprimaryendpointinclinicaloncologictrials.However,overthelastdecades,theeffectoftherapyontheself-reportedqualityoflife(QoL)hasalsobecomeanimportant(secondary)endpoint.TodetectsubjectivedifferencesinaspectsofQoL,manyassessmentinstrumentshavebeendeveloped.MostwidelyusedistheEuropeanOrganizationofResearchandTherapyinCancerQualityofLifeQuestionnaireC30(EORTCQLQ-C30),whichisespeciallydesignedtoassessQoLinclinicalcancertrials.ThisquestionnairehasbeenvalidatedandisacceptedasareliablemethodfortheassessmentofQoL10.Therefore,wechosethisquestionnairetoevaluatetheimpactoftreatmentwith177Lu-octreotateonQoLinpatientswithmetastasizedGEPtumors.
PATIENTS AND METHODS
Study DesignPatientswerereferredfrombothtertiarycarereferralcentersandcommunityhospitalsthroughoutthecountry.Duringthetreatmentandthereafter,thepatientscameforfollow-upinourhospital.ThemostimportantcriteriaforinclusionwerehistologicallyprovenmetastaticGEPtumor(s)andgoodtumoruptakeonsomatostatinreceptorscintigraphy.Also,patientshadtohaveaKarnofskyperformancestatusscore(KPS)≥509,11.Exclusioncriteriawere:creatininclearance>40mL/min,platelets>80x109/L,hemoglobin>9.7g/dL,andWBCcount>2.0x109/L.Atotalof66patientswithmetastaticsomatostatinreceptorpositiveGEPtumorstreatedwith600to800mCi177Lu-octreotate(threetofourcycles,6-to9-weekinterval)could
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beanalyzed.Eightpatientswereexcludedbecauseofmissingformsatthe6-weekfollow-upvisit.Inthesecases,theformsweremissingbecauseofadministrativereasons.Sevenpatientswereexcludedbecauseoffollow-upoutsidetheNetherlands,andonebecauseofprogressivedisease.Atotalof50patientswereanalyzed.
Outcome MeasuresQoLwas assessedwith theEORTCQLQ-C30 (version 3.0), apatient-basedquestionnairewhichincludesatotalof30itemsandiscomposedofscalesthatevaluatephysical(fiveitems),emotional(fouritems),role(twoitems),cognitive(twoitems),andsocial(twoitems)functioning,aswellasglobalhealthstatus(twoitems).Highermeanscoresonthesescalesrepresentbetterfunctioning.Therearealsothreesymptomscalesmeasuringnauseaandvomiting(twoitems),fatigue(threeitems),andpain(twoitems),andsixsingleitemsassessingfinancialimpactandvariousphysicalsymptoms.Ahighermeanvalueonthesymptomscales/singleitemsmeansmoresymptomatology.FollowingthescoringinstructionsgivenbytheEORTCQualityofLifeStudygroup,therawEORTCQLQ-C30scoreswerelinearlytransformedto0-100scalesbeforestatisticalanalyseswereperformed12.Ameanchangeinscorebetween0and5wasregardedasnotclinicallyimportant.Achangeinscoresbetween5and10wasregardedasa“little”subjectivechange,whereasachangebetween10and20wasregardedasa“moderate”change,andmorethan20wasregardedasan“important”change,aspreviouslydescribed13.Thedifferentoutcomegroupsweredefinedasregression(includingCR,PR,andminimalregression[MR];25%to50%reductionintumorsize),SD,andPD,andweredeterminedbymeansofcomputedtomography(CT)andmagneticresonanceimaging(MRI)measurementsfollowingtheWHOsolidtumorresponsecriteria.MRwasincludedintheregressiongroupbecauseoftheusuallyslowgrowthrateofneuroendocrinetumors,ifcomparedwithothercarcinomas,andbecauseofthecysticlesionsthatthesetumorsoftencause.
Timing and Data CollectionInaccordancewiththerequirementsfromthehospital’sEthicsCommittee,informedconsentwasobtainedfromallthepatients.Questionnaireswerefilledoutatfixedpointsinthetreatmentschemeintheweekbeforethefirsttreatmentandatthefirstfollow-upvisit6weeksafterthelasttreatment.ThetreatingphysicianscoredtheirKPS.Thepatientswerecarefullyinstructedhowtofilloutthequestionnaire,butwerenotassistedinansweringthequestions.Atthe6-weekfollow-upvisit,thepatientswereunawareoftheresponseasthequestionnaireswerefilledoutonthesamedaythefirstfollow-upCTorMRIwasperformed.Patientswereonlyinformedaboutoutcomeoftherapyatthenextfollow-upvisitwhentumorimagingwasevaluated.Thefirstquestionnairewasusedasbaseline.
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Missing DataThequestionnaireswerecollectedcarefully,butsomewerenotfilledoutadequatelyandcontainedmissingvaluesatthetimeofanalysis.ThemissingitemswerehandledwiththemethodofsimplemeanimputationasdescribedintheGuidelinesforassessingQoLinclinicaltrialsprovidedbytheEORTC12.Data AnalysisAnalysisofvariance(two-sided)wasusedtocomparethepatients’ratingsbeforeandaftertreatment.P<.05wasconsideredsignificant.ThelinearassociationsbetweenchangesinKPSscoresandpatients’globalhealth/QoLscoreswereinvestigatedusingSpearman’srankcorrelation(two-tailed).
RESULTSBaselinepatients’characteristicsare listedinTable1.Thequestionnairesof50patients(meanage,58years;range,30to78years),beforeandaftertreatment,wereavailableforanalysis.
Ofthe50patients,26patients(52%)hadcarcinoidtumor,13(26%)neuroendocrine(NE)pancreatictumor,seven(14%)hadNEtumorofunknownorigin,three(6%)hadgastrinoma,andone(2%)hadinsulinoma.Twenty-twopatients(44%)hadbeenoperatedinthepast,fivepatients(10%)hadreceivedchemotherapy,and24patients(48%)hadbeentreatedwithsomatostatinanalogsbeforethe177Lu-octreotatetherapy.Seventeenoftheincluded50patients(34%)haddocumentedprogressivediseasewithin1yearbeforethestartoftherapy.Intheotherpatients,diseasewasstableformorethan1year,orprogressionhadnotbeendocumentedwithCTorMRIwithintheprecedingyear.Treatmentwith177Lu-octreotateresultedinthefollowingresponses3monthsaftertherapy:24patients(48%)hadtumorregression(CR,PR,andMR),19patients(38%)hadSD,andsixpatients(12%)hadPD.Inonepatient,itwasnotpossibletomeasuretumorresponsebecauseevidenceofdiseasebeforeandaftertherapycouldonlybevisualizedwithsomatostatinscintigraphy.
Eightpatientswereexcludedfromtheanalysisbecauseofmissingforms.Twoofthesehadtumorregression,threehadSD,twohadPD,andinonepatientnotreatmentoutcomecouldbeestablished.Thesetreatmentoutcomeswerenotsignificantlydifferentfromthewholepatientgroup(Fisher’sexacttest[two-sided];P <.05).ThetotalamountofmissingitemsofalltheEORTCQLQ-C30questionnaireswas14of3,000,yieldingacompletionrateof99.5%.Thesemissingitemswererandomlydistributedandtherefore,simplemeanimputationwasconsideredappropriatetohandlethedatawithouttheintroductionofsignificantbias14.
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Table 1. Baselinecharacteristicsatstudyentry
selinecharacteristicsatStudyEntry No.ofpatients %
Total 50
Sex
Male 22 44
Female 28 56
Age,years
Mean 58.3
Range 30-78
KarnofskyPerformanceScore
Mean 87.2
Median 90
Range 50-100
Typeoftumor
Carcinoid 26 52
NEtumorunknownorigin 7 14
NEtumorpancreas 13 26
Gastrinoma 3 6
Insulinoma 1 2
Metastases
Liver 45 90
Bone 10 20
PriorTherapy
Surgery 22 44
Chemotherapy 5 10
Somatostatinanalogs 24 48
Abbreviation: NE, neuroendocrine.
Themeanintervalbetweenbaselineandfirstfollow-upvisit(6weeksafterthelasttherapy)wasapproximately7months(range,5to12months).Thisintervalvariedbecauseinsomepatients,treatmentshadtobepostponedasaresultofsustainedbonemarrowsuppression,andbecausethenumberoftreatmentsvariedduetopatientsreachingtheircumulativemaximumkidneyradiationdose.Thelatterwascalculatedforeachindiviualpatientseparately,andvariedconsiderably.Allpatientsreceivedbetween600and800mCiof177Lu-octreotate.
TheEORTCQLQ-C30data indicatedthatpatientsassignedhighscorestothefunctionalscalesatbaseline(Table2).
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Table 2. Patients(n=50)meanscoresonEORTCQLQ-C30scalesandsingleitems
At baseline Follow-up (6 weeks)
Mean SD Mean SD Change P*
Global quality of life †
Globalhealth-status/qualityoflife 69.0 20.8 78.2 16.9 9.2 <0.01
Functional scales †
Physical 80.8 19.3 84.6 20.4 3.8 0.07
Role 67.0 31.7 82.0 25.2 15.0 <0.01
Emotional 77.7 15.7 85.8 15.5 8.1 <0.001
Cognitive 88.7 16.0 88.3 17.3 -0.4 0.89
Social 80.7 22.7 90.3 21.3 9.6 <0.01
Symptom scales ‡
Fatigue 31.9 24.4 22.8 22.5 -9.1 <0.01
Nausea/Vomiting 6.7 16.5 5.0 11.3 -1.7 0.46
Pain 23.3 28.8 15.0 20.0 -8.3 <0.05
Single items ‡
Dyspnea 16.3 23.7 17.3 27.1 1.0 0.71
Insomnia 26.0 30.3 14.3 21.5 -11.7 <0.01
Appetiteloss 10.2 19.5 8.7 21.1 -1.5 0.70
Constipation 8.8 20.2 6.1 16.2 -2.7 0.32
Diarrhea 16.7 26.3 12.2 18.9 -4.5 0.26
Economicalimpact 5.3 14.1 5.3 15.6 0.0 1.00
Body Weight 71.3 14.5 74.0 15.5 2.7 0.01
Karnofsky Performance Status Scale
87.2 12.3 87.9 12.0 0.7 0.52
NOTE Mean scores and ± SD of the EORTC QLQ-C30 questionnaire before and after (6 weeks follow-up visit) 177Lutetium-octreotate therapy. Body weight and KPS are also shown.Abbreviations: EORTC QLQ-C30, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30; SD, standard deviation.*: P < .05 was regarded as statistical significant.†: Scores ranges from 0 to 100, with a higher score representing a higher level of function. ‡: Scores ranges from 0 to 100, with a higher score representing a higher level of symptoms.
Theroleandcognitivefunctionscalesweregivenrespectivelythelowest(67.0)andthehighest(88.7)scores.Thescorefortheglobalhealthstatus/QoLscale(69.0)wasslightlylowerthanmostofthefunctionalscales.Thehighestscoresofthesymptomsscalesandsingleitemswereassignedtofatigue(31.9),insomnia(26.0),andpain(23.3),aswellasdiarrhea(16.7)anddyspnea(16.3).
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Theglobalhealth/QoLscalescorechangedsignificantlyfrom69.0to78.2(P <.01).Moreover,significantimprovementsweredemonstratedintheemotionalfunctionscale(77.7to85.8;P <.001),therolefunctionscale(67.0to82.0;P < .01)andinthesocialfunctionscale(80.7to90.3;P < .01).Inthesymptomsscalescores,fatigueandpaindecreasedfrom31.9to22.8(P <.01)and23.3to15.0(P <.05),respectively.Onlyinsomnia,asoneofthesixsingleitems,decreased11.7pointsinscore(P <.01).Atbaseline,17(34%)of50patientshaddiarrheaaspartofasecretorysyndrome,versus16(32%)of50atthefirstfollow-upvisit(P <.05).However,patientswhoinitiallyhaddiarrheahadasignificantdecreaseindiarrheascorefrom49.0to15.7(P <.0001)aftertherapy.Onlyonepatientinthisgroupswitchedtomorphine,whichprobablyaccountedfortheobserveddecreaseofdiarrheainthispatient.Meanbodyweightincreaseduringtheaverageperiodof7monthschangedsignificantlyfrom71.3to74.0kg(P <.01).
Inthegroupwithtumorregression,theglobalhealth/QoLscalescoreincreasedsignificantlyfrom70.1to80.6(P < .05).Thephysical,role,emotional,andsocialscaleimprovedwithanincreaseinscoreof6.0,22.2,10.0,and11.1,respectively(P<.05).Thescoreofthesymptomscalefatiguedecreasedfrom30.3to19.2(P<.01)andthesingleiteminsomniadecreasedfrom23.6to8.7(P <.01)aftertherapy.Bodyweightincreasedsignificantlyfrom72.4to77.2kg(P <.01).TheKPSdidnotchangesignificantly(Figure1).
Inthegroupwithstabledisease,nosignificantchangeswerefoundinthefunctionalscales.Inpatientswithpainatbaseline(13of19patients;68%),asignificantdecreaseinscorewasfoundfrom41.0(baseline)to17.9(6weeksaftertherapy;P < .01).Inpatientswithstabledisease(n=19),nofurthersignificantchangeofanyotherscorewasfound.Inpatientswithprogressivedisease(n=6),onlytheglobalhealth/QoLscoreincreasedfrom48.6to72.2(P <.01;Fig2).
Thechangeinscoreoftheself-reportedglobalhealth/QoLscalebetweenbeforeandaftertherapywaspositivelycorrelatedwiththechangeinKPS(Pearson’srankcorrelation;ρ=0.39;P < .01).Twenty(60%)outof33patientswhohadalowerorequalKPSaftertherapyreportedanincreaseinglobalhealth/QoLscale,and12(80%)of15patientswhohadahigherKPSafterthetherapyalsohadahigherglobalhealth/QoLscalescorecomparedtobaseline(Fig3).
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Figure 1. ChangesintheEuropeanOrganizationfortheResearchandTreatmentofCancerQualityofLifeQuestionnaireC30scalesandKarnofskyperformancescore(KPS)inpatientswithtumorregressionbefore(baseline)andat6weeksfollow-up.Onlyscalesthatchangedsignificantlyareshown.SEtothemeanareshownaboveeachbar.Graybars:before[177Lu-DOTA0,Tyr3]octreotatetherapy;blackbars:aftertherapy.*P <.05;**P <.01.
Figure 2. Globalhealth/qualityoflife(QoL)scalescoresofallthepatients(N=50)andthedifferentoutcomegroupsaccordingtotumorevaluationbefore(graybars)andafter(blackbars)[177Lu-DOTA0,Tyr3]octreotatetherapy.SEtothemeanareshownaboveeachbar.REGR,regression;SD,stabledisease;PD,progressivedisease;NS,notsignificant.
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Figure 3.Changesinglobalhealth/qualityoflife(QoL)scoresperpatientversuschangesinKarnofskyperformancescore(KPS).Valuesarescoresat6weeksfollow-upminusscoresatbaseline.Theline(y=x)representsequalchanges.Notethatpositivechangesinglobalhealth/QoLscalearemorefrequentthanpositivechangesinKPS.
DISCUSSIONTreatmentwithradiolabeledsomatostatinanalogs,like177Lu-octreotate,inpatientswithmetastasizedneuroendocrineGEPtumorsmaybeveryrewardingintermsoftumorvolumereduction7-9.Here,wereporttheoutcomeofhealthrelatedquality-of-life(HRQoL)assessmentbeforeandaftertreatmentwith177Lu-octreotate.TheEORTCQLQ-C30scoresofpatientswithmetastasizedGEPtumorsatbaselineindicatedthatthepatientsmaintainarelativelygoodHRQoL.ThisisinlinewithapreviousstudybyLarssonet al.15inwhichthequestionnairewasusedtostudythegeneralHRQoLinpatientswithGEPtumors.AssessmentofHRQoLdataresultsindetailedinformationaboutmanyaspectsofthepatients’QoL,includingsymptoms,specificfunctionalscales,andtheoverallhealth/QoLscale.Thecombinedglobalhealth/QoLscaleisregardedasthemostimportantscaletoscore,asitgivesanoverallimpressionoftheexperiencedHRQoL.Furthermore,ithasbeenshowntobeagoodpredictorofsurvival16,17.
ToidentifyaspectsofHRQOLinwhichthepatientsclearlyhadgainedmeaningfulimprovement,asignificantchangeofmorethanfivepointswasconsideredtobeclinicallyimportant,accordingtothemethoddescribedbyOsobaet al.13.Thepatientsinourstudyexperiencedsuchanimprovementoftheirglobalhealth/QoLafter
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therapywith177Lu-octreotate.Inaddition,therole,emotional,andsocialfunctionscalescoreshowedaclinicallyimportantimprovement.Thesymptomscalesfatigueandpainandthesingleiteminsomniaweretheonlyscoresthatwerehighatbaselineanddecreasedsignificantly.Fatigueisthemostfrequentlyreportedsymptomincancerpatients,anditsreasonisoftenobscure18-20.Also,insomniaisreportedin30%to50%ofpatientswithcancer21.ProfounddiarrheaisacommonsymptominpatientswithGEPtumors.However,wefoundnosignificantchangeindiarrhea,mostprobablybecausemostpatientswithseverediarrheausedsomatostatinanalogsthatresultedinanadequatesymptomcontrol.However,patientswhostillsufferedfromdiarrheabeforethestartof177Lu-octreotatetherapydidnoticeanimprovementofthissymptom.
Thechangeinself-reportedglobalhealth/QoLwaspositivelycorrelatedwiththechangeinKPSasjudgedbythephysician.CorrelationbetweenKPSscoresandthedifferentdomainsofQoLhavebeenreportedinotherstudies22,23.Inthesestudies,however,itwasconcludedthat,althoughassociated,bothmeasuresarenotassessingthesameconstruct.Schaafsmaet al. 22statedthattheEORTCQLQ-C30isamorecomprehensivemeasureofQoLthantheKPS.Thisisinlinewiththegreaternumberofpositivechangeswefoundintheglobalhealth/QoLscaleasreportedbythepatient,ascomparedwiththechangesinthephysician-basedKPS.Larssonet al.24statedthatpatientswithGEPtumorsratedthephysicalaspectsoflifeasthemostimportantaspectforexperiencingagoodHRQoL.Incontrast,wefoundnoevidenceofsignificantchangeinthephysicalfunctionscale,whereasotherscales,includingtheglobalhealth/QoL,didincreasesignificantly.Thus,althoughreportedasthemostimportantaspectofQoL,itappearsthat,whenthelevelofphysicalfunctioningisrelativelyhighasinourpatients,aspectsofQoLotherthanphysicalfunctioningbecomeimportanttodeterminethepatients’overallQoL.
InthegroupwithSD,noworseningofsymptomsordecreaseinfunctioningscaleswasfound.However,consideringthefive(26%)of19patientswhohaddocumentedPDintheyearbeforetherapy,astabilizationofanyaspectofQoLsuggestsapositiveeffectof177Lu-octreotatetherapy.Furthermore,patientswithpainatbaselinehadasignificantdecreaseinscorewithmorethan20points.Waldherret al. 25reportedsimilarfindingsofclinicalbenefitinagroupof21patientswithNEtumorstreatedwiththeradiolabeledsomatostatinanalog90Y-DOTATOC.However,theyusedaphysician-basedmethod,whereaswepreferred touseamorepatient-basedmethodwiththeEORTCQLQ-C30.IncontrasttothegroupofpatientswithSD,asignificantimprovementoftheglobalhealth/QoLscalewasfoundinpatientswithPD.Thedifferencebetweenthelowscoreatbaselineinthelattergroup,comparedwiththerelativelyhighscoreinpatientswithSD,couldexplainthiscontradictingobservation.Incombinationwiththeabsenceofanysignificantchangeinanyother
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scale,itsuggeststhat,inpatientswithPD,evenasmallchangeinanyotherscalecouldhavehadalargeimpactontheiroverallhealth/QoL.BecauseourgroupwithPDrepresentedasmallnumberofpatientsand,moreover,onepatientwaslosttofollow-up,theaccuracyoftheseobservationsremainsquestionable.Also,aplaceboeffectcannotberuledoutcompletely.
Inconclusion,wefoundthat177Lu-octreotatetherapyimprovedtheQoLinpatientswithmetastasizedGEPtumors,especiallyinthepatientswithprovenregression.
ACKNOWLEDGMENTWewishtothankallthepatientswhoparticipatedinthisstudyandthesupportingpersonneloftheDepartmentofNuclearMedicinefortheirexperthelpandeffort.
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4E����ects o�� therapy with [177Lu-DOTA0,Tyr3]octreotate on endocrine ��unction
Jaap J. M. Teunissen, Eric P. Krenning, Frank H. de Jong, Yolanda B. de Rijke, Richard A.
Feelders, Maarten O. van Aken, Wouter W. de Herder and Dik J. Kwekkeboom
Submitted
AbstractPurpose Peptidereceptorradionuclidetherapy(PRRT)withradiolabelledsomatostatinanalogues is anovel therapy forpatientswithsomatostatin receptor-positivetumours.WedeterminedtheeffectsofPRRTwith[177Lu-DOTA0,Tyr3]octreotate(177Lu–octreotate)onglucose-homeostasisandthepituitary-gonadal,-thyroidaland-adrenalaxes.
Methods Hormonelevelsweremeasuredandadrenalfunctionassessedatbaselineandupto24monthsoffollow-up.
Results In35men,meanseruminhibinBlevelsweredecreasedat3monthsposttherapy(205±16to25±4pg/ml; P<0.05)andFSHlevelsincreased(5.9±0.5to22.7±1.4IU/L; P<0.05).Theselevelsreturnedtonearbaselinelevels.TotaltestosteronandSHBGlevelsdecreased(15.0±0.9to10.6±1.0nmol/Land61.8±8.7to33.2±3.7nmol/L; P<0.05),respectively,whereasnon-SHBG-bound-Tdidnotchange.Anincrease(5.2±0.6to7.7±0.7IIU/L; P<0.05)ofLHlevelswasfound3monthsoffollow-upreturningtobaselinelevelsthereafter.In21postmenopausalwomen,decreaseinFSH(74.4±5.6to62.4±7.7IU/L; P<0.05)andLHlevels(26.8±2.1to21.1±3.0IU/L; P<0.05)werefound.
Twooutof66patientsdevelopedpersistentprimaryhypothyroidism.FT4levelsdecreased(17.7±0.4to15.6±0.6pmol/L; P<0.05),whereasTSHandT3levelsdidnotchange.rT3levelsdecreased(0.38±0.03to0.30±0.01nmol/L; P<0.05).BeforeandaftertherapyACTH-stimulationtestsshowedanadequateresponse(>550nmol/L;n=18).FivepatientsdevelopedelevatedHbA1clevels(>6.5%).
Conclusion In men 17 7Lu–octreotate therapy induced transient inhibitory effects onspermatogenesis,but,non-SHBG-bound-Tlevelsremainedunaffected.Inthelong-term,gonadotropinlevelsdecreasedsignificantlyinpostmenopausalwomen.OnlyfewpatientsdevelopedhypothyroidismorelevatedlevelsofHbA1c.Therefore,PRRTwith177Lu–octreotatecanberegardedasasafetreatmentmodalitywithrespecttoshort-andlong-termendocrinefunction.
Abstract
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INTRODUCTIONTreatmentwith radiolabelled somatostatin analogues, or peptide receptorradionuclide therapy (PRRT), is a new treatmentmodality inpatientswithmetastasisedorinoperablesomatostatinreceptor-positivetumours.RecentreportsontheeffectivenessofPRRTwiththeradioligands[90Y-DOTA0,Tyr3]octreotide(90Y-octreotide)or[177Lu-DOTA0,Tyr3]octreotate(177Lu–octreotate)inpatientswithneuroendocrinetumours,report20-30%partialremissions1-3.Short-termside-effectsincludedmildnausea,vomitingandabdominalpain4,5.Seriousside-effectsarerelatedtotissuespecificradiationexposureandradiationsensitivity.Radiationabsorbeddosestobonemarrowandkidneysaredoselimiting.Sofar,reportedseriouscomplicationsinclude2casesofmyelodysplasticsyndrome5andseveralcasesofradiation-inducedrenalfailure6-8,especiallyinpatientswhodidnotreceiveamino-acidco-infusion,whichiscurrentlyusedtoreducerenalabsorbedradiationdose9.
Additionalnon-intendedtargetsofPRRTareendocrineorgans.Manyofthese,suchastheanteriorpituitarygland,endocrinepancreas,adrenalmedullaandthyroidareknowntoexpresssomatostainreceptors(SSTRs),especificallySSTRsubtype210-13.TheradiopharmaceuticalscurrentlyusedinPRRTtargetespeciallythisSSTRsubtype,followedbysubtype5and314.
Untilrecently,limiteddataregardingtheeffectofPRRTonendocrinefunctionwasavailable.Inapreviousreportonthetherapeuticeffectof177Lu-octreotateinalargegroupofpatientswithgastroenteropancreaticneuroendocrinetumours,webrieflyreportedontheshort-termeffectsofPRRTonendocrinefunction5.Inthepresentstudy,wefocusedonboththeshort-andlong-termeffectsofPRRTontheanteriorpituitary,gonadal,thyroid,endocrinepancreasandadrenalfunction.
SUBjECTS AND METHODS
Patients and study designSeventy-ninepatientswhoweretreatedwith600-800mCi177Lu-octreotate(threetofourcycleswith6to9-weekinterval)betweenJanuary2000andDecember2004andwithafollow-upperiodof12-24months,wereselectedforanalysis.Onlylocal(Dutch)residentswereanalysed,becausethesehadtheirfollow-upatourinstitution.AllpatientshadtumouruptakeonSSTRscintigraphythatwasatleastashighasthephysiologicaluptakeinnormallivertissueonplanarimagingprecedingtherapy.Hormonemeasurements,routinehaematology,liverandkidneyfunctiontestswereperformedbeforeeachadministrationof177Lu-octreotateandateachfollow-upvisit.Outcomeoftherapywasassessedbycomputedtomographyormagneticresonance
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imagingandperformedwithin3monthsbeforethefirsttherapy,at6to8weeks,at3and6monthsafterthelasttreatment,andthereafterevery6months.
Inclusioncriteriawere:Karnofskyperformancescore≥50,creatininclearance≥40ml/min,haemoglobin>9.7g/dL,plateletcount>75x109/LandWBC>2.0x109/L.Allpatientsgavewritteninformedconsentbeforeinclusioninthestudy,whichwasapprovedbythemedicalethicscommitteeofthehospital. 177Lu-octreotatepreparationandadministrationoftherapywereperformedasdescribedearlier5.
Hormone measurementsBloodsampleswereprocessedwithin2hoursafterwithdrawal.Serumwasstoredat–20°Cuntilassayed.
Gonadotropins, gonadal hormones and cortisolSerumlevelsofLH,FSH,SHBGandcortisolweremeasuredusingluminescence-basedimmunometricassays(Immulite2000,DiagnosticProductsCorp.,LosAngeles,
CA,USA)Serumestradiol(E2),andtotaltestosterone(TT)levelsweremeasuredusingnonextractioncoated-tuberadioimmunassay(Coat-a-Count,DiagnosticProductsCorp.,LosAngeles,CA,USA).Sensitivitiesoftheassayswere0.1IU/LforFSHandLH,10pmol/LforE2and0.1nmol/LforTT.InterassaycoefficientsofvariationforLHandFSH,were<7%,<5%forSHBG,5%forcortisol,<10%forE2and<9%forTT.Non-SHBG-bound-TlevelswerecalculatedbyusingthemassactionequationasdescribedbySödergard15usingavariablealbuminconcentration.TheaffinityconstantsusedforthebindingoftestosteronetoSHBGoralbuminwere5.97x108L/moland4.06x104L/mol,respectively.DimericinhibinBlevelswereassessedusinganimmunoenzymometricassayOxfordBioInnovation,(Oxford,UK),Thedetectionlimitoftheassaywas10ng/L.Interassaycoefficientsofvariationwere<15%and21%atconcentrationsof215and19ng/L,respectively.
Thyroid hormonesSerumFT4andT3weremeasuredbychemoluminescenceassays (VitrosECiImmunodiagnosticSystem;Ortho-Clinical-DiagnosticsInc.,Rochester,NY,USA).SerumlevelsofTSHweremeasuredusingtheImmulite2000system.ReverseT3(rT3)wasmeasuredbyRIAaspreviouslydescribed16.Interassaycoefficientsofvariationamountedto4%forTSH,5%forFT4,3.3%forT3,and10%forrT3.
HbA1c
Percentage of glycolysated hemoglobin (HbA1c)was determined byHPLCmeasurement.
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Hypothalamo-pituitary-adrenal (HPA)-axis assessmentThe1µg(low-dose)ACTHstimulationtest(LDST)wasusedtotesttheintegrityoftheHPAaxis.TheLDSTwasperformedinthirty-ninepatientsbeforetherapy.EighteenpatientsalsohadanLDST12-18monthsaftertherapy.Cortisolwasmeasured0,20,30and60minutesaftertheinjectionof1µgtetracosactrin(Synacthen,NovartisPharma)intravenously.Thesolutionof1µgACTH/mlwasusedimmediatelyafterpreparation.Theintravenouslineusedwasflushedwithsalineaftertheadministrationandaftereachtimeabloodsamplewastaken.Astimulatedpeakcortisolconcentrationofatleast550nmol/Lwasconsideredtobeanadequateresponse.
Statistical Analyses All resultsareexpressedasmeanconcentrations±standarderrorof themean(SEM).Hormoneswereanalysedusingrepeated-measuresanalysisofvariance(ANOVA)withBonferroni’scorrectionformultiplecomparisons.FortheHPA-axisanalysispairedstudentt-testswasused.P-values<0.05(2-tailed)wereconsideredsignificant.
RESULTSPatients’characteristicsarelistedinTable1.Datafromthirty-fivemenwereavailableforanalysis.Threewereexcludedatbaseline:onehadseverechemotherapy-inducedhypogonadism,onehadtesticularatrophyandonehadhighlevelsofFSHandLHsuggestiveofaco-existinggonadotropin-secretingpituitaryadenoma,whichwasnotfurtheranalysed.
Atbaseline,onepatienthadcombinedlowTT(<8.1nmol/L)andinhibinB(<150pg/ml)levels,2patientshadisolatedlowTTlevels,2otherpatientshadlownon-SHBG-bound-T(<5.9nmol/L)andanother10patientshadisolatedlowinhibinBlevels.
MeaninhibinBleveldecreasedsignificantlyfrom205±16pg/mltoanadirlevelof25±4pg/mlat3monthsafter177Lu-octreotatetherapy(P<0.05)andreturnedtonearpre-treatmentlevelsinthefollow-upperiodthereafter.At24monthsposttherapy,althoughmarginal,theinhibineBlevelwassignificantlydecreased(Figure1a).MeanFSHlevelshadamirroredcoursewithatransientincreasefrom5.9±0.5IU/Ltoamaximumof22.7±1.4IU/L3monthsafterthelasttherapy.Twenty-fourmonthsafterthelasttherapy,themeanFSHlevelwasnotsignificantlydifferentfrombaseline.
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Table 1. Baselinepatientcharacteristics
No. of Patients Mean (range) %
Total 79
Gender
Male 38 48
Age 58.4(30-83)
Female 41 52
Age 54.8(20-74)
Ageatdiagnosis(yr) 56.7(20–83)
Weight(kg) 74.3(43–142)
BMI(kg/m2) 25.0(15.6-45.1)
Height(cm) 172(152-196)
KarnofskyPerformanceScore 89.4(50-100)
Diagnosis
Carcinoid 49 62
NEofunknownorigin 8 10
NEpancreas 15 20
Gastrinoma 1 1
Insulinoma 1 1
HürthlecellThyroidCarcinoma 3 4
MedullaryThyroidCarcinoma 1 1
Paraganglioma 1 1
Metastases
Liver 66 84
Bone 18 23
Priortherapy
Surgery 36 46
Chemotherapy 6 8
ExternalRadiotherapy 3 4
Somatostatinanalogtherapy 36 46
Abbreviations: BMI, body mass index; NE, neuroendocrine
MeanTTleveldecreasedsignificantlyfrom15.0±0.9nmol/Latbaselineto12.3±0.7nmol/Lat3months(P<0.05)withafurtherdeclineto10.6±1.0nmol/Lat24monthsaftertherapy(Figure1b).MeanLHlevelfrom5.2±0.6IU/Lto7.7±0.7IU/Lat3
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monthsoffollow-upandreturnedtolevelsnotsignificantlydifferentfrombaselineat6months.
ConcomitantwiththedecreaseofTT,themeanSHBGleveldecreasedsignificantlyfrombaselinelevelof61.8±8.7nmol/Ltoanadirof33.2±3.7nmol/Lat24monthsafterthelasttherapy(P<0.05).Thecalculatedlevelsofnon-SHBG-Tdidnotchangesignificantly(Figure1c).
BasedonthelevelsofFSH,LH,inhibinBandE2,andagebeforetherapy,threegroupsofwomen(41patientsintotal)couldbedistinguished.Eightwomenhadhormonalchangesduringfollow-upwhichweresuggestiveformenopausaltransitionandwerethereforeexcluded.Sincenomenstrualdatawasavailablefromsixpremenopausalwomen,thesewomenwerealsoexcludedfromanalysis.
Gonadotropinanalysiswasperformedin21postmenopausalwomen.Fivewomenwereexcludedbecauseofhormonalchangesduetoconcomitantdisease(n=3),previouscranialexternalbeamradiationbecauseofmeningeoma(n=1)andtemporaryuseofhighdoseopioidmedication(n=1).One39-year-oldwomanwasexcludedbecauseofbilateraloophorectomy,followedbyhormonereplacementtherapy.
Inthepostmenopausalwomen,bothmeaninhibinBandE2wereatlowlevels,<10ng/Land<50pmol/L,respectively,atbaselineanddidnotchangesignificantlythereafter.Beforetherapy,themeanFSHconcentrationwas74.4±5.6IU/L.Duringfollow-upitdecreasedsignificantlyto62.4±7.7IU/L,at24monthsoffollow-up.ThemeanLHconcentration,whichwas26.8±2.1IU/Lbeforetherapy,decreasedsignificantlyto21.1±3.0IU/Lat24months(P<0.05).(Figure2).
Sixty-sixpatientswereincludedforanalysisofthyroidhormonestatus.Excludedweretenpatientswiththyroidassociatedconditionsbeforetherapyincludingprimaryhypothyroidism(n=4),TSHsuppressivetherapyfor thyroidcarcinoma(n=4),hyperthyroidism(n=1)andcombinednecksurgeryandexternalbeamradiotherapy(n=1).Furthermore,3patientswereexcludedbecausetheyhadeitherundetectedhypothyroidism(n=1)orsubclinicalhypothyroidism(n=2)before177Lu-octreotatetherapyandweresubsequentlystartedonthyroxinetherapy.Afterthethirdcycleoftherapyonepatientdevelopedanti-TPOantibody-positivehypothyroidism.Anotherpatientgraduallydevelopedprimaryhypothyroidismaftertherapyandwaseventuallystartedonsubstitutiontherapy3.5yearsafter177Lu-octreotatetherapy.Thyroidhormonelevelsfromthesepatientswereincludedintheanalysesuntilhypothyroidismwasevident.
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Figure 1. Longitudinalanalysesofmean(±SEM)serumlevelsof(A)FSH(dottedlinewithopensquares),InhibinB(blacklinewithopencircles),(B,C)LH(dottedlinewithfilledsquares)totaltestosterone(TT;blacklinewithfilledcircles),sexhormonebindingglobuline(SHBG;dottedlinewithfilledtriangles),andnon-SHBG-boundtestosterone(n-SHBG-boundT;blacklinewithfilleddiamonds)in35menwithSSTRpositivetumorsbefore,duringandupto24monthsafter600-800mCi177Lu-octreotatetherapy.Barsalongbothy-axesrepresentthereferencerange(4SD)values;*, P<0.05.
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ThecourseofthemeanthyroidhormonelevelsoftheincludedpatientsisshowninFigure3. MeanFT4decreasedsignificantly from17.7±0.4 to 15.6±0.6 IU/Lpmol/L(referencerange11-25pmol/L; P<0.05);TSHandT3levelsdidnotchangesignificantly.MeanrT3concentrationof0.38±0.03nmol/Lwasabovethereferencerange(0.14-0.34nmol/L)beforetherapy.Duringtherapyasignificant18%decreaseofmeanrT3levelwithanadirof0.30±0.01nmol/Lafteracumulativedoseof400mCiwasfound(P<0.05).ThereafterthemeanrT3levelincreasedslowlyto0.32±0.03nmol/L,24monthsaftertherapy.TheratioofT3overrT3(T3/rT3),withaT3/rT3of6.24±0.03atbaselinewassignificantlyelevatedwithamaximumof7.54±0.33afteracumulativedoseof400mCi(P<0.05)afterwhichitreturnedtolevelsnotsignificantlydifferentfrombaseline.
Figure 2.Longitudinalanalysisofmean(±SEM)serumlevelsofFSH(dottedlinewithopensquares)andLH(dottedlinewithfilledsquares)in21postmenopausalwomenwithSSTRpositivetumorsbefore,duringandupto24monthsafter600-800mCi 177Lu-octreotatetherapy.MeaninhibinBandE2levelnotshownasthesewereatnormallowpostmenopausallevels(<10ng/Land<50pmol/L,respectively).Barsalongbothy-axesrepresentthereferencerange(4SD)values;*, P<0.05
Inasubanalysis, inwhich3groupsofpatientswereanalysedaccordingtotheiroutcomeoftumourassessmentat3monthsoffollow-up(progressivedisease,PD;stabledisease,SD;.minororpartialremission,MRorPR)asignificantdecreaseofmeanrT3(P<0.05)levelduringtherapywasdemonstratedinthegroupswithSDandMRorPRwhereasinthePDgroupnosignificantchangewasobserved(Figure4).
AnLDSTwasperformedbeforetherapyin39patients,whichshowedstimulatedcortisolvalueshigherthanthecut-offvalueof550nmol/Linallpatients.Themean
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peaklevelafterLDSTwas822±28nmol/L.TheLDSTwasrepeated12-18monthsafterthelasttherapyin18patients(8men,10women).Allpatientsagainhadstimulatedcortisolvalueshigherthan550nmol/Lafter177Lu-octreotatetherapy.Themeanpeakcortisolresponsebeforetherapywassignificanthigherthanaftertherapy(909±57nmol/Lvs.822±35nmol/L; P<0.001,n=18)(Figure5).
Figure 3a-c. Longitudinalanalysisofmean(±SEM)serumlevelsofTSH(dottedlinewithfilledtriangles),FT4(blacklinewithfilledcirlces),T3(blacklinewithfilleddiamonds),rT3(dottedlinewithopentriangles),andT3/rT3ratio(linewithopencircles),of66patientswithSSTRpositivetumorsbefore,duringandupto24monthsafter600-800mCi177Lu-octreotatetherapy.Barsalongy-axesrepresentthereferencerange(4SD)values;*, P <0.05.
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Nineoutof79patientshaddiabetesmellitusdiagnosedbeforetreatmentandwereeitheronsubcutanous insulin therapy(n=4)ororalantihyperglycemicagents(n=5).Furthermore,onepatienthadaninsulinomaandanotherpatienthadanabnormalhemoglobinpatternandthereforeserumunfitforHbA1cmeasurement.FivepatientshadelevatedHbA1c(>6.5%)before177Lu-octreotatetherapyofwhom3werestartedonoralantihyperglycemicdrugsduringorafter177Lu-octreotatetherapy.SixpatientsdevelopedhighlevelsofHbA1cafterPRRT.Inonepatientthisoccurredafterpancreaticsurgery.Intheother5patients,elevatedHbA1clevelsoccurredafter2-30monthsfromstudyinclusion(Table2).Analysisin69patientsdemonstratedadecreaseofHbA1cfrom5.7±0.1to5.5±0.1%(P<0.05)duringtherapy,butanincreaseto6.0±0.1%(P<0.05)thereafter.
Figure 4.Longitudinalanalysisofmean(±SEM)serumlevelsofrT3inpatientswithSSTRpositive tumorsbefore,duringandat3monthsof follow-upafter600-800mCi 177Lu-octreotatetherapygroupedaccordingtotheirtherapyoutcome(partialremissionandminorremission,PR/MR;filledcircles;stabledisease,SD,filleddiamonds;progressivedisease,PD,filledtriangles)at3monthsoffollow-up.Baralongthey-axisrepresentthereferencerangevalues.*, P<0.05.
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Figure 5. Meanpeakcortisolresponsewiththelowdose(1µg)ACTHstimulationtestin18patientsbeforeand12-18monthsafter177Lu-octreotatetherapyareshown.Eachdottedlineconnectsoneindividualpatient.
Table 2.Numberofpatients(n)whowereevaluableforHbA1cpercentagesbasedontheirHbA1cpercentageatbaselineandafter177Lu-octreotatetherapy.Patientsexcludedatbaselineweremedicallytreatedpatientswithdiabetes(n=9),onepatientwhohadaninsulinomaandonepatienthadwithanabnormalhemoglobinpattern.
Posttherapy
HbA1c(in%) n≤6.5 n>6.5 Total
Baseline
n>6.5 0(0%) 5(100%) 5
n≤6.5 57(90%) 6*(10%) 63
Total 57 11 68
*, one patient developed elevated levels of HbA1c after Whipple surgery
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DISCUSSIONBesidesthecurrentlyknowncomplicationsandadverseeffectsduetothenon-specificradiationabsorbeddosestothebonemarrowandkidneys,specificreceptor-relatedeffectsonnon-tumouroustissuebyPRRThavenotbeenstudiedindetail.SSTRsareexpressedinmosthormonesecretingorgans,suchaspituitarygland,pancreas,thyroidandadrenals,asevidencedbyin vitrostudiesaswellasbythephysiologicaluptakein vivoduringsomatostatinreceptorscintigraphy10,17-20.AlthoughthereceptordensityofSSTRsinnormal,non-pathologichormonesecretingorgansisnotashighasobservedinneuroendocrinetumours,thepresenceofSSTRsimplicatesthepossibilityofspecificreceptor-mediatedtargetingbyradiolabelledsomatostatinanalogues.Furthermore,astheradiopharmaceuticalsusedinPRRTaresystemicallyadministered,allorganswillreceiveanadditionalnon-specificdose,includingthoseorgansthatareknowntoberadiosensitive(e.g.thegonads).
Fifteenoutof35(43%)ofourmalepatientshadevidenceofhypogonadismpriortoPRRT.Gonadaldysfunction inpatientswithdisseminatedcancerprior tochemotherapeutictreatmenthasbeenreportedbyChlebowskiet al.21.Arelationshipbetweenmarkedlydecreasedgonadalfunctionandweightlosswasalsoobserved.Furthermore,otherfactors,includingage,historyofalcoholintake,andliverdiseasehavebeenreportedtohaveeffectsontheTTlevelsinmalepatients22.AstherearemanyfactorsthatmaycausedecreasedTTlevels,aspecificorcommoncauseofthehighpercentageofhypogonadismwithinourgroupofpatientsbeforePRRTisdifficulttopointout.BecauseoftheverysimilarpatternsofhormonalchangesobservedafterPRRTinmenwithnormalorlowlevelsofTTbeforetherapy(datanotshown),itislikelythattheseadditionalfactorsdidnotcontributetotheobservedchangeinhormonelevelsinourstudy.
DecreaseofmeanTTlevelcoincidedwithadecreaseofSHBGlevel,whereasthemeannon-SHBG-bound-TremainedstableafterPRRT.TheseobservationsareinlinewithfindingsofdeRondeet al.23whodemonstratedastrongpositiverelationshipbetweenSHBGandTTlevelsandnooronlyaweakpositiveassociationbetweenSHBGandcirculatingnon-SHBG-bound-Tlevels.BecauseSHBGcorrelatesnegativelywithBMI24,apossibleexplanationforthedecreaseofSHBGisthesignificantincreaseofbodymassindex(BMI)inourpatientsfrom24.0±0.7kg.m-2toamaximumof25.3±0.8kg.m-2at12monthsoffollow-up.Furthermore,wefoundaweakpositive,butsignificantcorrelation(Spearman’srho=0.29,p=0.01)betweenFT4andSHBG(datanotshown).CorrelationbetweenFT4andSHBGwasdemonstratedduringthyroidhormonereplacementtherapyinhypothyroidmenbyCavaliereet al. 25.However,whethertherelativelysmallincreaseofmeanBMIorthelimiteddeclineinmeanFT4levelobservedinourstudyisresponsibleforthemarkeddeclineofSHBGisquestionable.Intheory,impairedliverfunctionaftertherapycanalsocause
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decreasedSHBGlevels.Thisisunlikely,however,becauseofunchangedalbuminlevelsandstableordecreasedserumlevelsofgamma-GT,alkalinefosfatase,ASATandALATthroughoutthewholestudyperiod(datanotshown).
OurdataindicatethattransientimpairmentofspermatogenesisoccursfollowingPRRT.AsignificantdecreaseofmeanseruminhibinBlevelswithaconcomitantincreaseinFSHlevelswasobserved,withrecoverytoalmostpretreatmentlevelsafter24months.Thisisinlinewithseveralstudiesinpatientswithdifferentiatedthyroidcarcinomawhoreceivedradioiodinetherapy26-29. InhibinBisproducedintheSertolicellsofthetestisandisthemajorfeedbackregulatorofFSH30,31.IthasbeendemonstratedthatseruminhibinBlevelsarepositivelycorrelatedwithspermatogenicstatusandspermcount32,33.Therefore,althoughwedidnotperformsemenanalyses,ourresultslikelyindicatetemporarilyimpairedspermatogenesis.BoththegonadalandpituitaryglandfunctionarepotentiallyatriskafterPRRT.Effectsongonadotrophlevelsafter 177Lu-octreotatetherapywasdemonstratedinpostmenopausalwomen.AsignificantdecreaseinbothFSHandLHwasfound.TheobserveddecreaseinmeanFSHandLHlevelofapproximately12.5%and8.2%peryear,respectively,washigherthancouldbeexpectedbecauseofageingassuch.Inastudyof680postmenopausalwomen,thedecreaseofgonadtropinlevelsbetweentheagesof55and75yearswaslessthan1%peryear34.
Twooutof66(3%)patientsdevelopedprimaryhypothyroidismaftertreatment.Onepatienthadhypothyroidismwiththedevelopmentofanti-TPOantibodiessuggestingautoimmuneinducedhypothyroidism.Theotherpatienthadslowlyprogressiveprimaryhypothyroidismandwasputon substitution therapy3.5years after177Lu-octreotatetherapy.ThyroidhormoneanalysesofthetotalgroupdemonstratedasignificantdecreaseofFT4attheendofthestudyperiod.Thisis inlinewithasignificantdecreaseofFT4levelswereportedearlier5.ThedeclineofFT4wasnotaccompaniedbyasignificantincreaseofTSHorT3,thoughtrendstowardsanincreaseanddecrease,respectively,werenoticed.Ofinterest,analysisexcludingthetwohypothyroidpatientsrevealednosignificantchangeinFT4,TSHorT3.Sincechronicityandseverityofdiseasemighthaveanimpactonthethyroidhormonestatusandevencaninducenon-thyroidalillness(NTI),theobservedchangesofthyroidhormonesinthelong-termcouldreflectthedevelopmentofNTIratherthantheeffectofPRRT.SignsofNTIwereobservedatbaselinewithanincreasedmeanlevelofrT3.Specificchangesinthyroidhormonelevelswerereportedtocorrelatewiththeseverityofillnessoreventobeprognosticforsurvivalincriticallyillpatients35.DirectlyafterthefirstcycleofPRRT,rT3returnedtoreferencerangevalues.Thereafter,rT3slowlyincreasedbutremainedwithinthenormalreferencerange.Theactiveoverinactivethyroidhormone(T3/rT3)ratiohadasimilar,butinversepattern.Thesechangessuggestarapidchangetoamorefavorabledisease
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statedirectlyafterinitiationofPRRTandwhichpersistsduringfollow-up.Asub-analysisofpatientsaccordingtotherapyoutcomeindicatedthatpatientswhohadPDhadanosignificantchangeinrT3level,whereastheotherpatientshadasignificantdecrease,returningtothenormalrangeduringtherapy.Therefore,inourgroupofpatients,thechangeinrT3andT3/rT3ratioprobablyreflectedchangesinthediseasestatus.
Thehypothalamo-pituitary-adrenal(HPA)axisisnotaffectedbyPRRTintermsof intact adrenal reserve.Allpatientshadadequate responseswith theLDSTbeforetherapy.Additionally,adequateresponsesineighteenpatientsaftertherapyindicatednoapparentprimaryorsecondaryadrenal insufficiency.TheLDSTisavalidreplacementforthecommonlyusedshortsynacthentestandtheinsulintolerancetest(ITT),ofwhichthelatteriswidelyregardedasthegoldstandardtestfortheintegrityoftheHPAaxis36.Unfortunately,theITTisnotcompletelysafe,costlyanddifficulttoperforminanoutpatientsetting,thushamperingitsclinicaluse.AnLDSTpeakcortisolresponsehigherthan550nmol/LwasobservedinallpatientsandwasregardedasasufficientresponseindicatingsustainedintegrityoftheHPA-axis.Inarecentmeta-analysisonthediagnosisofadrenalinsufficiency,itwasconcludedthatacut-offvaluebetween500and600nmol/Lcortisolisnecessarytoachievereasonablesensitivityforthedetectionofbothprimaryandsecondaryadrenalinsufficiency37.
Interestingly,meanpeakcortisollevelafterPRRTwassignificantlylowerthanbeforetherapy.WhetherthissubtledifferenceinLDSTresponseaftertherapyreflectsradiation-inducedmildpartialadrenalinsufficiencyorsimplyalessstressfulstateofthepatientsisnotclear.However,Schmiegelowet al.,reportedsimilarfindingsin73patientstreatedwithradiotherapyandchemotherapyforchildhoodbraintumourswithameanfollow-upof15years38.NineteenpercentofthepatientshadinsufficiencyoftheHPAaxis,whereastheremainderofpatients,eventhoughanadequateresponsetoanACTHtestorITT,hadlowerpeakcortisollevelscomparedwithcontrols.Theexternalbeamradiotherapy,notchemotherapy,wasregardedasthemainfactorthathadcontributedtotheobservedadrenalinsufficiency.ItwasconcludedthatthislattergroupmightbepotentiallyatriskofbecomingHPAaxisinsufficientinthefuture.Life-longfollow-upwasrecommendedinthesepatients.Althoughit isdifficulttocompare 177Lu-octreotatetherapywithexternalbeamradiationtherapyintermsofdose-tempo,exposureareaandperiodoffollow-up,thesestudiesindicatethatdespitetheadequateLDSTresponsesfoundinourpatients,awarenessofaradiation-induceddisturbanceoftheHPA-axisisimportantinthelong-termfollow-up.
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Fivepatientsoutof62(8%)developedincreasedlevelsofHbA1cafter177Lu-octreotatetherapywithoutanyobviouscause,suchassubsequentpancreaticsurgery.Pancreaticisletsexpresssomatostatinreceptors,especiallythesubtypeSSTR2a39.However,46%ofourpatientsusedsomatostatinanalogues,suchasoctreotide,duringand/oraftertherapy.Therefore,besidesthepossibilityofadirectradiationeffectasthecauseoftheobservedsubtle,butsignificantincreaseofmeanHbA1caftertherapy,long-termtreatmentwithsomatostatinanalogues,couldhavecontributedaswell.
Inconclusion,inmen177Lu–octreotatetherapyinducedtransientinhibitoryeffectsonspermatogenesis,but,non-SHBG-bound-Tlevelsremainedunaffected.Inthelong-term,gonadotropinlevelsdecreasedsignificantlyinpostmenopausalwomen.OnlyfewpatientsdevelopedhypothyroidismorelevatedlevelsofHbA1c.Noclinicallyapparentrelevanteffectswasobservedonpituitary-adrenal function.Despitetemporaryandminorhormonalchanges,PRRTwith177Lu–octreotatecanberegardedasasafetreatmentmodalitywithrespecttotheshortandlong-termendocrinefunction.
Weconcludethatpatientswhoaretreatedwith177Lu-octreotatetherapymaydevelopradiation-inducedhormonedisturbances,someofwhichhavebeenproventobetemporary,andwhichareingeneralmild.Noseverehormoneinbalancewasobservedand,therefore,177Lu-octreotatetherapy,intermsofendocrinesequelae,canberegardedassafe.However,awarenessofthepossibilityofchangesin,andtherebysurveillanceof,theendocrinestatus,isimportantandimplicatesthenecessityoffuturestudies.
ACKNOWLEDGEMENTWewishtothankallthepatientswhoparticipatedinthisstudyandthesupportingpersonneloftheDepartmentofNuclearMedicinefortheirexperthelpandeffort.
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5 Comparison o�� [177Lu-DOTA0,Tyr3]octreotate and [177Lu-DOTA0,Tyr3]octreotide: which peptide is pre��erable ��or PRRT?
Jan-Paul Esser, Eric P. Krenning, Jaap J.M. Teunissen, Peter P. M. Kooij, Arthur L.H. van
Gameren, Willem H. Bakker and Dik J. Kwekkboom
European Journal of Nuclear Medicine and Molecular Imaging 2006; 33:1346–1351
AbstractPurpose Patientswithsomatostatinreceptorsubtype2-positivemetastasisedneuroendocrinetumourscanbetreatedwith[177Lu-DOTA0,Tyr3]octreotate.Someuseoctreotideasthepeptideforpeptidereceptorradionuclidetherapy(PRRT).Wecomparedin seven patients [ 17 7Lu-DOTA0,Tyr3]octreotide ( 17 7Lu-DOTATOC) and[177Lu-DOTA0,Tyr3]octreotate(177Lu-DOTATATE),toseewhichpeptideshouldbepreferredforPRRTwith177Lu.
Methods Inthesamepatients,3,700MBq177Lu-DOTATOCand3,700MBq177Lu-DOTATATEwasadministeredinseparatetherapysessions.Aminoacidswereco-administered.Whole-bodyscanningwasperformedondays1,4and7posttherapy.Bloodandurinesampleswerecollected.Wecalculatedresidencetimesfortumours,spleenandkidneys.
ResultsAllpatientshadlongerresidencetimesinspleen,kidneysandtumoursafteruseof 177Lu-DOTATATE(p=0.016ineachcase).Comparing 177Lu-DOTATATEwith177Lu-DOTATOC,themeanresidencetimeratiowas2.1fortumour,1.5forspleenand1.4forkidneys.DoselimitingfactorsforPRRTarebonemarrowand/orkidneydose.Althoughtheresidencetimeforkidneyswaslongerwhenusing177Lu-DOTATATE,themeanadministereddosetotumourswouldstillbeadvantageousbyafactorof1.5,assumingafixedmaximumkidneydoseisreached.Plasmaradioactivityafter177Lu-DOTATATEwascomparabletothatafter177Lu-DOTATOC.Urinaryexcretionofradioactivitywascomparableduringthefirst6h;thereaftertherewasasignificantadvantagefor177Lu-DOTATOC.
Conclusion 177Lu-DOTATATEhadalongertumourresidencetimethan177Lu-DOTATOC.Despitealongerresidencetimeinkidneysafter177Lu-DOTATATE,tumourdosewillalwaysbehigher.Therefore,weconcludethatthebetterpeptideforPRRTisoctreotate.
Abstract
5
INTRODUCTIONOneofthenewtreatmentmodalitiesformetastasisedneuroendocrinegastro-entero-pancreatic(GEP)tumours—takingitsplacealongsidesurgery,(chemo)embolisation,chemotherapyandtreatmentwithsomatostatinanalogues—ispeptidereceptorradionuclidetherapy(PRRT).Since2000wehavetreatedpatientswithsomatostatinreceptorpositivepathologywith[177Lu-DOTA0,Tyr3]octreotate;inmostcasesthesepatientshavehadmetastasisedneuroendocrinetumours(NETs).Ananalysisof131ofthemorethan400treatedpatientswithso-calledGEPtumourswasperformedafterobtainingallresultsfollowingcompletionoftreatment.Adecreaseintumoursizewasfoundin47%,stablediseasein35%andtumourprogressiondespitetreatmentin18%1.Asignificantimprovementinqualityoflifeinthosepatientswithtumourregressionwasalsonoted2.Theaveragedurationoftheeffectoftherapywasmorethan36months,calculatedfromthestartoftherapy.FromthesefiguresitseemsthatPRRTisapromisingchoiceoftreatmentformetastasisedneuroendocrineGEPtumours.SomeresearchgroupsuseradiolabelledoctreotideforPRRT3,4whereasweuseradiolabelledoctreotateasthepeptide,thisapproachbeingsupportedbyevidencefromdifferentsources.Reubiet al.reportedthatoctreotatehasahigheraffinitythanoctreotideforsomatostatinreceptorsubtypesst25.DeJonget al.comparedinvitroandinvivo111In-labelledsomatostatinanaloguesfortumourscintigraphyandradionuclidetherapyinthesamesomatostatinreceptor-positiveratCA20948pancreatictumour.DTPA-chelatedoctreotatehadthehighestuptakeinthetargetorgans6.Further,thesameauthorsinvestigated[177Lu-DOTA0,Tyr3]octreotateinbiodistributionandradionuclidetherapyexperimentsusingLewisratsbearingtheCA20948tumourandreportedexcellentresultsofradionuclidetherapy,especiallyinanimalsbearingsmallertumours 7.Capelloandco-workersevaluatedthetherapeuticeffectsofsomatostatinanalogueschelatedwithDOTAandlabelledwith90Yor177Luinaninvitrocolony-formingassayusingtheratpancreatictumourcelllineCA20948.Theyconcludedthat[DOTA0,Tyr3]octreotatelabelledwith177Luor90YisthemostpromisinganalogueforPRRT8.Nilssonet al.studiedthebiokineticsandtherapeuticeffectofradiolabelledsomatostatinanaloguesonamidgutcarcinoid(GOT1)graftedtonudemice.Theytested[111In-DTPA-D-Phe1]octreotideand[177Lu-DOTA0,Tyr3]octreotate,andconcludedthatoctreotateisthemostpromisingpeptideforuseintreatment9.Schmittet al. comparedthebiodistributionof [177Lu-DOTA0,Tyr3]octreotate,[111In-DTPA]octreotideand99mTc-depreotideinnudemicebearingtumoursfromthehumanSCLCcelllineNCI-H69.[177Lu-DOTA0,Tyr3]octreotategavethehighesttumouractivityconcentration10.Kwekkeboomet al.foundinacomparisonwith[111In-DTPA0]octreotideinpatientsathree-tofourfoldhighertumouruptakewith[177Lu-DOTA0,Tyr3]octreotate11.Insummary,allthesestudiesshowedthatoctreotatemightbethebettercandidateforPRRT.However,recentlyForreret al.couldnotfindasignificantdifferencewhencomparing111In-DOTATOCand111In-DOTATATEinfivepatientswithmetastasisedNETs12.Sofar,however,nocomparisonbetween
162
[177Lu-DOTA0,Tyr3]octreotide(177Lu-DOTATOC)and[177Lu-DOTA0,Tyr3]octreotate(177Lu-DOTATATE)hasbeenpublished.ThereforewedecidedtocompareoctreotidewithoctreotateintherapeuticdosesinthesamepatientstoinvestigatewhichisthepreferablepeptideforPRRT.Randomly,weselectedpatientswhocameforPRRTanddividedtheusualfirsttherapeuticdoseof7,400MBq(200mCi)intotwoseparatedoses/treatments,eachof3,700MBq(100mCi)177Lu.Inordertoexcludepossibletherapeuticeffects,onegroupstartedwithoctreotideasthepeptideandonegroupwithoctreotate,thenswitchingtotheotherpeptideforthesecondtherapy.
MATERIAL AND METHODS
PatientsFourmalepatients(age44–64,mean59years)andthreefemalepatients(age43–67,mean56years)withknownNETswereinjectedwith3,700MBq177Lu-DOTATATEor177Lu-DOTATOC.Fourpatientsreceived177Lu-DOTATOCforthefirsttreatmentandthree,177Lu-DOTATATE;asalreadymentioned,thesecondtreatmentwaswiththeotherpeptide.ThreepatientshadNETsofthepancreas,twoamidgutcarcinoid,oneacarcinoidofunknownprimaryandoneacarcinoidofthelung.AllexceptonepatientwithaNETofthepancreashadmetastases.Theintervalbetweenthetwotherapieswas8weeks.Long-actingsomatostatinanalogueswerestoppedatleast6weeksbeforetreatmentandshort-actinganalogueswerestoppedatleast24hoursbeforetreatment.AllpatientshadahistologicallyprovenNETandhadneverpreviouslyhadPRRT.TumoursiteswereconfirmedbyCTorMRItogetherwithapositiveOctreoScan.Allpatientsgaveinformedconsenttoparticipationinthestudy,whichwasapprovedbythehospital’sethicscommittee.
RadiopharmaceuticalsBoth somatostatin analogues, [DOTA0,Tyr3]octreotide (DOTATOC) and[DOTA0,Tyr3]octreotate(DOTATATE),weresynthesisedaccordingtopreviouslypublishedprocedures 11andlabelledwith 177Lu(obtainedfromNRG,Petten,theNetherlandsanddistributedbyIDB-Holland,BaarleNassau,theNetherlands).
InfusionTopreventnausea,firstgranisetron3mgwasinjectedi.v.;thereafteraninfusionofaminoacids(lysine2.5%,arginine2.5%in1l0.9%NaCl:250ml/h)wasstarted30minbeforetheadministrationoftheradiopharmaceuticalandlastedintotalfor4h.Theradiopharmaceuticalwasco-administeredin30minviaasecondpumpsystem.
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Imaging AllimagingwasdoneonaPickerPrism2000XPdual-headgammacamera.Countsfrombothgammapeaksof177Lu(208and113keV)werecollectedinseparatewindows(width20%).Parallel-hole,medium-energygeneral-purposecollimatorswereused.Whole-bodyscansof40minwereobtained24hand4and7daysposttherapy.Aknownaliquotofradioactivitywasplacedbetweenthepatients’kneestoenablecalculationoftheuptakeinspleen,kidneysandtumours.
Measurement of radioactivity in blood and urineBloodsamplesweretaken10minaftertheinfusionoftheradiopharmaceuticalhadbeencompletedand30min,60min,4h,24h,4daysand7daysthereafter.Urinewascollectedinfourintervals:0–3,3–6,6–12and12–24hafterinfusion.Radioactivityinthesesampleswasmeasuredwithagammacounter(LKB-Wallac1282Compugamma,Turku,Finland)andadosecalibrator(VDC-202,VeenstrainstrumentenB.V.,Joure,theNetherlands).
MethodsRegionsofinterest(ROIs)weredrawnmanuallyonthewhole-bodyscansoverkidneys,spleenandtumours.RegionswereplacedclosetotheROIsforbackgroundcorrection.Organsshowingsuperimpositionoftumourwereexcludedforevaluationoforganresidencetime.Noattenuationcorrectionwasperformedbecauseeverypatientwashis/herowncontrol.Instead,theratioofresidencetimeintheorgansandtumoursbetweenthetwotherapieswasconsideredmostimportant.Thedosemeasuredbeforeinfusionminustheresidualradioactivityintheinfusionsystemafteradministrationwasdefinedas100%.Alldatawereexpressedaspercentageofthis100%.
StatisticsAnalysisofvariance(ANOVA)andSigntestswereusedforstatisticalanalysis.P values<0.05wereconsideredsignificant.
RESULTSAscanbeseeninFigure1,forbothpeptidestherewasfastclearancefromthebloodexpressedaspercentageofinjectedactivity(%IA),resultinginadecreasetolessthan10%withinthefirst3h.Duringthefirstdaythebloodclearanceof177Lu-DOTATOCwasslightlyfasterthanthatof177Lu-DOTATATE,butthedifferencedidnotreachsignificance(ANOVAtestP>0.05).Thereafterthebloodclearanceforbothpeptideswasnearlythesame.
164
Figure 1.Serumradioactivityexpressedasmeanpercentageinjectedactivity(%IA)
Thecumulativeexcretedactivityintheurinewashigherfor177Lu-DOTATOCthanfor177Lu-DOTATATE,at81%versus71%(Figure2).Thiswassignificantforthetimeperiods0–12h(ANOVAP=0.045)and0–24h(ANOVAP=0.026).
Thebiodistributionpatternforthetwopeptideswasnearlythesame.However,theresidencetimeofradioactivityinthetumourswassignificantlylongerinallpatientsafter177Lu-DOTATATE(Table1;Signtest,P=0.016).Comparing177Lu-DOTATATEwith177Lu-DOTATOC,themeanratioofthetumourresidencetimewas2.1(Figure3).Similarly,theresidencetimesinthespleenandthekidneysweresignificantlylongerafter177Lu-DOTATATE(Signtest,P=0.016forbothspleenandkidneys).Comparing177Lu-DOTATATEwith177Lu-DOTATOC,themeanratiooftheresidencetimewas1.5forspleenand1.4forkidneys.
DISCUSSIONTreatmentoptionsforinoperable,metastasisedNETsarelimited.Usually,treatmentwithsomatostatinanaloguesisstartedifpatientssufferfromsyndromescausedbyhormonaloverproductionbythetumours.Althoughusuallyveryrewardingintermsofsymptomcontrol,suchtreatmentseldomresultsintumourgrowthremission.Ifthetumourisprogressive,chemo-embolisationorembolisationoflivermetastasesmaybeeffectiveifthebulkofthetumourissituatedwithintheliver13,14.Radiologicalexpertiseinthisprocedurehastobeavailable,however.
Com
pari
son
o�� [17
7 Lu-D
OTA
0 ,Tyr
3 ]oct
reot
ate
and
[177 Lu
-DO
TA0 ,T
yr3 ]o
ctre
otid
e: w
hich
pep
tide
is p
re��e
rabl
e ��o
r PR
RT?
5
Figure 2. Cumulativeradioactivityexcretedinurine,expressedasmean(±SEM)percentage
injectedactivity(%IA)
Anotheroptionischemotherapy.O’Tooleet al.reviewedtheuseofchemotherapyforGEPtumoursandfoundthatthepublishedseriesevaluatingchemotherapyformidgutendocrinetumourswereoutdatedandhadyieldeddisappointingresults.Thustheobjectiveresponserateswithcombinationchemotherapy(including5-fluorouraciland/orstreptozotocin)rarelyexceeded20%.TheseauthorsreportedthatonlyfortherelativelyrarepoorlydifferentiatedGEPtumoursischemotherapy,usingcisplatinandetoposide,thereferencetreatment:objectiveresponseratesof>50%wereachievedinsuchpatients,butdespitethechemosensitivityofthesetumours,diseasecontrolwaslimited(8–10months)15.Öbergalsoreviewedchemo-therapyandbiotherapyinthetreatmentofNETs.Hereportedthatstreptozotocin-basedcombinationsincluding5-fluorouracilanddoxorubicinresultedinpartialremissionsin40–60%ofthepatients,withamediansurvivalofabout2yearsinpatientswithadvanceddisease.Cisplatinplusetoposidedemonstratedsignificantanti-tumoureffectsinanaplasticendocrinepancreatictumoursandlungcarcinoids.However,forclassicalmidgutcarcinoids,thesamecombinationofcytotoxicagentsresultedinshort-lastingresponsesinonly10%ofpatients 16.Summarising,theresultsofchemotherapyaredisappointinginthemostcommonNETs,themidgutcarcinoids.AlthoughresultsaresomewhatbetterforpancreaticNETs,thereportedtimetoprogressionandthedurationofsurvivalarerelativelyshort.Therefore,chemotherapyisbestreservedforpatientswithrelativelyrareundifferentiatedoranaplasticNETs.
166
Arelativelynewtreatmentmodalityisradiolabelledsomatostatinanalogues.Variouspeptidesandradionuclideshavebeenused.Themostcommonlyusedpeptidesare[DOTA0,Tyr3]octreotide(DOTATOC)and[DOTA0,Tyr3]octreotate(DOTATATE),labelledwitheither90Yor177Lu.Wecompared177Lu-DOTATOCand177Lu-DOTATATEinatherapeuticsettingandwithinthesamepatients.
Ourassumptionthatoctreotateisthepreferablepeptidewhenlabellingitwith177Luwasconfirmed.Wefoundalongerresidencetimeinthetumoursinallourpatientsafter177Lu-DOTATATEtreatmentcomparedwith177Lu-DOTATOC,leadingtoahigherabsorbedtumourdose.Themeandifferencewasstatisticallysignificant(P=0.016).Alongerresidencetimeisespeciallyofinterestwhenusingradionuclideswithalongerhalf-life(6.7daysfor177Lucomparedwith2.7daysfor90Y).
Reubiet al.evaluatedtheinvitrobindingcharacteristicsofdifferentsomatostatinradiotracers,amongwhichwerelabelledandunlabelledDOTATOCandDOTATATE.Theyshowedahigherbindingaffinitytosomatostatinreceptorsubtype2(sst2)for90Y-DOTATATEthanfor90Y-DOTATOC5.OurfindingsareinconcordancewiththoseofReubiet al.:wefoundasignificantlylongerresidencetimeinthetumoursandinthespleenusingDOTATATE.Wealsofoundthat177Lu-DOTATATEshowshigheraffinityforsst2comparedwith177Lu-DOTATOC.
Forreret al. 12compared111In-DOTATOCand111In-DOTATATE.Theyused111Inasasurrogatefor90Yandfoundcomparabledataforthetwopeptideswithregardtotumour-to-kidneyratios.Thereforetheyconcludedthattheywouldcontinuewiththerapyusing90Y-DOTATOC.
Theassumptionthat 111In iscomparable to 90Y isdisputable. In2000,Reubiet al.testedtheaffinityofdifferentsomatostatinradiotracers.Therewasamarkeddifferenceinaffinityaftersmallstructuralchangesintheradioligandmolecule,theintroductionofametal,thereplacementofonemetalbyanotherorthereplacementofonechelatorbyanother5.
Forreret al.alsoassumedthatadiagnosticinvestigationwith222MBq111Incouldbetranslatedtoatherapeuticsession12.Theyusedonly10µgpeptidetopredicttheoutcomeofatherapeuticdosewithasignificantlyhigherpeptideconcentration.Forourevaluationweused200µgofpeptidewith3,700MBqofactivity.Theamountofpeptidethatwetypicallyusewhenadministering177Lu-DOTATATEis130–210µg,dependingonthespecificactivityoftheradionuclide;therefore,wethinkthatoursetupisfarmorecomparabletotheusualtherapeuticconditions.
Com
pari
son
o�� [17
7 Lu-D
OTA
0 ,Tyr
3 ]oct
reot
ate
and
[177 Lu
-DO
TA0 ,T
yr3 ]o
ctre
otid
e: w
hich
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tide
is p
re��e
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e ��o
r PR
RT?
5
Tab
le 1
. Residencetim
e(h)andratiobetw
eenbothpeptides,notcorrectedforattenuation
Tu
mo
ur
Kid
ney
Sple
en
Pat
ien
tD
OT
AT
OC
DO
TA
TA
TE
TA
TE
:TO
CD
OT
AT
OC
DO
TA
TA
TE
TA
TE
:TO
CD
OT
AT
OC
DO
TA
TA
TE
TA
TE
:TO
C
10.53
0.57
1.1
0.37
0.56
1.5
0.81
1.16
1.4
20.05
0.11
2.2
0.42
0.56
1.3
0.78
1.05
1.3
31.21
1.81
1.5
0.34
0.45
1.3
0.25
0.31
1.2
40.03
0.07
2.3
0.47
0.61
1.3
0.85
1.28
1.5
50.11
0.26
2.4
0.46
0.72
1.6
2.1
3.17
1.5
60.55
1.2
2.2
0.34
0.41
1.2
0.97
1.32
1.4
70.07
0.22
3.1
0.21
0.28
1.3
0.45
0.89
2.0
Mean±SE
M±SE
MSEM
0.36±0.16
±0.16
0.16
0.60±0.25
±0.25
0.25
2.1
0.37±0.03
±0.03
0.03
0.51±
0.06
±0.06
0.06
1.4
0.89±0.22
±0.22
0.22
1.31±0.34
1.5
Pvalue
0.016
0.016
0.016
168
Figure 3.Planaranteriorwhole-bodyscans1dayposttherapy,after177Lu-DOTATOC(left)
andafter177Lu-DOTATATE(right).PatientnumberscorrespondtothoseinTable1.
Com
pari
son
o�� [17
7 Lu-D
OTA
0 ,Tyr
3 ]oct
reot
ate
and
[177 Lu
-DO
TA0 ,T
yr3 ]o
ctre
otid
e: w
hich
pep
tide
is p
re��e
rabl
e ��o
r PR
RT?
5
Thepharmacokineticsof177Lu-DOTATOCand177Lu-DOTATATEinourstudy,suchasurinaryexcretionandbloodclearance,werenearlythesamecomparedtotheresultsofForreret al.Oneofthedose-limitingfactorsforPRRTcanbethetotalkidneydose.Comparing177Lu-DOTATATEwith177Lu-DOTATOC,wefounda2.1timeslongertumourresidencetimeoftheradioactivityafter 177Lu-DOTATATE,leadingtoahigherabsorbedtumourdose.Theresidencetimeratioforthekidneys(1.4)waslowerthanthatfortumours.Consequently,ingeneralonecansaythattumourstreatedwith177Lu-DOTATATEwillalwaysreceiveahighertotaldoseofradioactivitythanthosetreatedwith177Lu-DOTATOC.Evenifoneassumesthatacertainmaximumtotaldosecanbegiventhatisdeterminedbythemaximumradiationabsorbeddosetothekidneys,therewillstillbeahigherradiationabsorbeddosetothetumourafter177Lu-DOTATATE,giventhatdivisionofthemeantumourresidencetimeratio(2.1)bythemeankidneyresidencetimeratio(1.4)yieldsafactorof1.5infavourof 177Lu-DOTATATE.Furthermore,weknowfromourownunpublisheddata,obtainedinmorethan400patients,thatin70%ofpatientstreatedwith177Lu-DOTATATE,themaximumdoseallowedforapresumedbonemarrowabsorbeddoseof2Gy,i.e.29,600MBqor800mCi,determinestreatmentcessation,andnotthemaximumallowedkidneydoseof23Gy.Therefore,inmostpatients,themeantumourresidencetimeratioof2.1infavourof177Lu-DOTATATEwillapply.
Inconclusion,[177Lu-DOTA0,Tyr3]octreotatedemonstratedasignificantlylongertumourresidencetimethan[177Lu-DOTA0,Tyr3]octreotide inpatientswithsst2receptor-positivemetastasisedNETs.Therefore,whenlabelledwith177Lu,octreotateisthepreferredpeptideforPRRT.
ACKNOWLEDGEMENTSTheauthorswishtothankallsupportingpersonneloftheDepartmentofNuclearMedicine,ErasmusMC,fortheirhelpandeffort.Also,gratitudeisexpressedtoProf.H.R.Maecke,UniversityHospitalBasel,forthesupplyof[DOTA0,Tyr3]octreotide.
170
REFERENCES
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2. Teunissen JJ,KwekkeboomDJ,KrenningEP.Qualityof life inpatientswithgastroenteropancreatictumorstreatedwith[177Lu-DOTA0,Tyr3]octreotate.J Clin Oncol.2004;22:2724–2729
3. BodeiL,CremonesiM,ZoboliS,GranaC,BartolomeiM,RoccaP,etal.Receptor-mediatedradionuclidetherapywith90Y-DOTATOCinassociationwithaminoacidinfusion:aphaseIstudy.Eur J Nucl Med Mol Imaging.2003;30:207–216.
4. KwekkeboomDJ,Mueller-BrandJ,PaganelliG,AnthonyLB,PauwelsS,KvolsLK,etal.Overviewofresultsofpeptidereceptorradionuclidetherapywith3radiolabeledsomatostatinanalogs.J Nucl Med.2005;46Suppl1:62–66.
5. ReubiJC,ScharJC,WaserB,WengerS,HeppelerA,SchmittJS,etal.AffinityprofilesforhumansomatostatinreceptorsubtypesSST1–SST5ofsomatostatinradiotracersselectedforscintigraphicandradiotherapeuticuse.Eur J Nucl Med.2000;27:273–282.
6. DeJongM,BreemanWA,BakkerWH,KooijPP,BernardBF,HoflandLJ,etal.Comparisonof111In-labeledsomatostatinanaloguesfortumorscintigraphyandradionuclidetherapy.Cancer Res.1998;58:437–441.
7. DeJongM,BreemanWA,BernardBF,BakkerWH,SchaarM,vanGamerenA,etal.[177Lu-DOTA0,Tyr3]octreotateforsomatostatinreceptor-targetedradionuclidetherapy.Int J Cancer.2001;92:628–633
8. CapelloA,KrenningEP,BreemanWA,BernardBF,KonijnenbergMW,deJongM.Tyr3-octreotideandTyr3-octreotateradiolabeledwith177Luor90Y:peptidereceptorradionuclidetherapyresultsinvitro.Cancer Biother Radiopharm.2003;18:761–768.
9. NilssonO,KolbyL,BernhardtP,Forssell-AronssonE,JohansonV,AhlmanH.GOT1xenograftedtonudemice:auniquemodelforinvivostudiesonSSTR-mediatedradiationtherapyofcarcinoidtumors. Ann N Y Acad Sci.2004;1014:275–279.
10. SchmittA,BernhardtP,NilssonO,AhlmanH,KolbyL,Forssell-AronssonE.Differencesinbiodistributionbetween99mTc-depreotide,111In-DTPA-octreotide,and177Lu-DOTA-Tyr3-octreotateinasmallcelllungcanceranimalmodel.Cancer Biother Radiopharm.2005;20:231–236.
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12. ForrerF,UusijarviH,WaldherrC,CremonesiM,BernhardtP,Mueller-BrandJ,etal.Acomparisonof111In-DOTATOCand111In-DOTATATE:biodistributionanddosimetryinthesamepatientswithmetastaticneuroendocrinetumours.Eur J Nucl Med Mol Imaging.2004;31:1257–1262.
13. DominguezS,DenysA,MenuY,RuszniewskiP.Hepaticarterialchemoembolizationinthemanagementofadvanceddigestiveendocrinetumours.Ital J Gastroenterol Hepatol.1999;31Suppl2:213–215.
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15. O’TooleD,HenticO,CorcosO,Ruszniewski P. Chemotherapy for gastro-enteropancreaticendocrinetumours.Neuroendocrinology.2004;80Suppl1:79–84.
16. ÖbergK.Chemotherapyandbiotherapyinthetreatmentofneuroendocrinetumours.Ann Oncol2001;12Suppl2:111–114.
Com
pari
son
o�� [17
7 Lu-D
OTA
0 ,Tyr
3 ]oct
reot
ate
and
[177 Lu
-DO
TA0 ,T
yr3 ]o
ctre
otid
e: w
hich
pep
tide
is p
re��e
rabl
e ��o
r PR
RT?
5
���� �� �� �� ��
6 Radiolabelled somatostatin analogues and di����erentiated thyroid carcinoma
6.1Peptide receptor radionuclide therapy ��or non–radioiodine-avid di����erentiated thyroid carcinoma
Jaap J.M. Teunissen, Dik J. Kwekkeboom, Peter P.M. Kooij, Willem H. Bakker
and Eric P. Krenning
Journal of Nuclear Medicine 2006; 46:107S–114S
AbstractInpatientswithprogressivemetastatic (or recurrent)differentiated thyroidcarcinoma(DTC)whodonotrespondtoradioiodinetherapyordonotshowuptakeonradioiodinescintigraphy,treatmentoptionsarefew.Becausethesetumorsmayexpresssomatostatinreceptors,peptidereceptorradionuclidetherapymightbeeffective.Weevaluatedthetherapeuticefficacyoftheradiolabeledsomatostatinanalog177Lu-1,4,7,10-tetraazacyclododecane-N,N ‘,N”,N’’’-tetraaceticacid0(DOTA),Tyr3-octreotate(177Lu-DOTATATE)inpatientswithDTC.Theuptakeofradioactivityintumorswasalsostudiedinrelationtotreatmentoutcome.
Methods
FivepatientswithDTC(3withHürthlecellthyroidcarcinoma[HCTC],1withpapillarythyroidcarcinoma[PTC],and1withfollicularthyroidcarcinoma[FTC])weretreatedwith22.4–30.1GBqof 177Lu-DOTATATE.ResponsetotherapywasevaluatedwithCT.Uptakeon177Lu-DOTATATEscintigraphy(24haftertreatment),expressedaspercentageofinjecteddose,wascomparedwithuptakeonpretherapy111In-octreotidescintigraphy(24hafterinjection).
Results Afterthelasttreatmentwith177Lu-DOTATATE,1patientwithHCTChadstabledisease as amaximum response, 1 patientwithHCTChadminor remission(tumorshrinkagebetween25%and50%),and1patientwithHCTChadpartialremission(shrinkage>50%).TheresponsesinPTCandFTCwerestablediseaseandprogressivedisease,respectively.AdecreaseinserumthyroglobulinlevelwasfoundinpatientswithHCTC.Patientswithminorandpartialremissionshadthehighest177Lu-DOTATATE–to–111In-diethylenetriaminepentaaceticacid0-octreotide(111In-octreotide)uptakeratios(3.2and2.4,respectively)whereastheotherpatientshaduptakeratiossmallerthan1.5.
Conclusion 177Lu-DOTATATEtherapycanbeeffectiveinpatientswithprogressiveDTCwhohavenotherapeuticoptionsandsufficientuptakeof111In-octreotideintumorlesionsasshownon111In-octreotidescintigraphy.ThisfindingisespeciallyimportantinpatientswithHCTC,becausetheycannotbenefitfromradioiodinetherapybecauseofnon–iodine-avidlesionsatdiagnosis.
Abstract
6.1
INTRODUCTIONStandardtherapyinpatientswithdifferentiated(follicularandpapillary)thyroidcarcinoma(DTC)involvestotalornear-totalthyroidectomy,followedbyablationofthethyroidremnantwith131I.Althoughlong-termprognosiswiththiscombinationofsurgeryandradioiodinetherapyisgenerallyquitegood,tumorrecurrencesoccurinabout20%ofpatients,sometimesdecadesafterinitialtherapy1,2.Follow-upinthesepatientsisbasedonacombinationofserumthyroglobulin(Tg)monitoringandradioiodinewhole-bodyscans(WBSs).WheneverrecurrenceormetastaticdiseaseisevidentontheWBS,patientsareretreatedwithradioiodine.However,in20%–30%ofthesepatients,additional131Itherapyisnoteffectivebecauseofthelackofradioiodineuptakeintumors3,4.Inaddition,Hürthlecellthyroidcarcinomas(HCTCs),whichareassignedtothegroupoffollicularthyroidcarcinoma(FTC),areknowntorarelytakeupiodine,evenatthetimeofdiagnosis5.
Alternative treatments in patientswith no uptake of radioiodine are few.Dedifferentiationisassociatedwithaworseprognosis,whichislargelybecausethesepatientscannotbetreatedwithradioiodine6.Patientswithiodine-concentratingpulmonarymetastaseshavea5-yrsurvivalrateof60%comparedwith30%forpatientswithtumorsthatdonotconcentrateradioiodine4,7.Therefore,anyeffectivetherapywouldbewelcome.Asmostofthesepatientshavewidespreadmetastaticdisease,surgeryisnotanoption.Externalbeamradiotherapycanprovideonlyregionalcontroloflocalizedrecurrences.Studiesontheeffectivenessofchemotherapyhavebeendisappointing8,9.
In patientswith elevated serum thyroglobulin levelswith no evidence ofdiseaseonradioiodinescintigraphy,scintigraphywiththesomatostatinanalog111In-diethylenetriaminepentaaceticacid0 (DTPA0)-octreotide (111In-octreotide,OctreoScan;Mallinckrodt)canbeanalternativeimagingmodality.Severalreportshavedemonstrateduptakeof111In-octreotideinmetastaticorrecurrentdiseaseinthemajorityofthesepatients10–13.Asaconsequence,theuseofhighdosesofradiolabeledsomatostatinanalogsastargetedtherapyinpeptidereceptorradionuclidetherapy(PRRT)hasbecomethefocusofmajorinterestasanalternativetherapy.PatientswithprogressiveDTCandtumoruptakeon111In-octreotidescintigraphyhavebeentreatedwithvariousradiolabeledsomatostatinanalogs,including111In-octreotide,90Y-1,4,7,10-tetraazacyclododecane-N,N’,N”,N’’’-tetraacetic acid0 (DOTA)-D-Phe1,Tyr3-octreotide(90Y-DOTATOC),and90Y-DOTA-lanreotide14–17.Inthisstudy,wereporttheresultsoftreatmentwiththenovelradiolabeledsomatostatinanalog177Lu-DOTA0,Tyr3-octreotate(177Lu-DOTATATE)in5patientswithDTC.
178
�MATERIALS AND METHODS
PatientsFivepatientswithrecurrentormetastaticdifferentiatedthyroidcarcinomaweretreatedwith177Lu-DOTATATE.PatientcharacteristicsaresummarizedinTable1.Allpatientshadvisibletumoruptakeon111In-octreotidescintigraphybeforetherapy.Noneofthepatientshadbeentreatedwithotherradiolabeledsomatostatinanalogsinthepast.Allpatientswereonthyroid-stimulatinghormone(TSH)suppressivethyroxintherapy.Prerequisitesfortreatmentwere:hemoglobin>5.5mmol/L;whitebloodcellcount>2x109/L;platelets>75x109/L;creatinine<150µmol/L;Karnofskyperformancestatus>50.Allpatientsgavewritteninformedconsenttoparticipateinthestudy,whichwasapprovedbythemedicalethicalcommitteeofthehospital.
Imaging111In-octreotide. Planarspotimagingwasperformedwithadouble-headγ-camera(Prism2000XP;PhilipsMedicalSystems).Windowswitha20%widthwerecenteredovereachofthe2111Inphotonpeaks(245and172keV).Fifteen-minutespotimageswereobtained24hafterinjectionof222MBqof111In-octreotide.Astandardwithaknownaliquotoftheinjecteddosewasmeasuredfordosimetry.
177Lu-DOTATATE. Planarspotimagesofthechest,neck,andupperabdomenwereobtained24hafterinjectionofthetherapeuticdoseof177Lu-DOTATATE.Upperabdomenimageswerealsoobtainedon2occasionsinthefollowingdaysforkidneydosimetry.Counts(20%windowwidth)fromthe208keVγ-peakwerecollected.Theacquisitiontimewas15or7.5min/view.Fordosimetry,astandardwithaknownaliquotoftheinjecteddosewasalsomeasured.
TherapyDOTATATEwasobtainedfromMallinckrodt.177LuCl3wasobtainedfromNRGandtheMissouriUniversityResearchReactor,distributedbyIDB.177Lu-DOTATATEwaspreparedasdescribedinapreviouspublication18.Threemilligramsofgranisetronwereinjectedintravenouslyandaninfusionofaminoacids(2.5%lysineand2.5%argininein1L0.9%NaClat250mL/h)wasstarted30minbeforeadministrationoftheradiopharmaceuticalandlastingupto3.5hafterwards.Theradiopharmaceuticalwascoadministeredthroughasecondpumpsystem.Treatmentdosesof1.9and3.7GBqwereinjectedover20minandthoseof5.6GBqand7.4GBqwereinjectedover30min.Theintervalbetweentreatmentsvariedfrom6to15wk.Thenumberoftreatmentsvariedfrom3to8.Somepatientswereincludedintheearlyphaseoftherapywith177Lu-DOTATATE,whendoseescalationwasamongtheobjectives.
Pept
ide
rece
ptor
radi
onuc
lide
ther
apy
��or n
on–r
adio
iodi
ne-a
vid
di����e
rent
iate
d th
yroi
d ca
rcin
oma
6.1
Tab
le 1
. Patientcharacteristics
Pre
177 L
u-o
ctre
ota
te T
her
apy
177 L
u-o
ctre
ota
te T
her
apy
Pat
ien
tG
end
erA
ge(y
rs)
Tu
mo
r C
lass
ifica
tio
n *
Pri
or
Th
erap
y †
Tg
(µg/
ml)
‡T
SH
(mU
/l)
§13
1 I /
123 I
scan
||11
1 In-o
ctre
oti
de
**P
D”
Cu
mu
lati
ve d
ose
(G
Bq
)N
o. o
f T
reat
men
ts
1M
52PT
CTT,N
D,R
IT(16.7GBq)¶,R
49.1
0.168
-2
Yes
25.7
8
2F
73FTC
TT,R
IT(10.6GBq),R
,C5665
<0.01
-2
Yes
22.4
3
3F
52HCTC
TT,N
D,R
IT(1.9GBq)
1110
0.02
-3
Yes
27.4
8
4F
74HCTC
TT,R
IT(12.9GBq)
126
N/A
+2
No
30.1
4
5F
52HCTC
TT,R
IT(13,0GBq),R
237
0.24
+/-
1No
22.7
3
* PT
C, p
apill
ary
thyr
oid
carc
inom
a; F
TC
, fol
licul
ar th
yroi
d ca
rcin
oma;
HC
TC
, Hür
thle
cel
l thy
roid
car
cino
ma;
† T
T, to
tal t
hyro
idec
tom
y; N
D, n
eck
diss
ecti
on; ¶
RIT
, 131 I
ther
apy
(cum
ulat
ive
dose
); C
, che
mot
hera
py; R
, ext
erna
l rad
iati
on; ‡
seru
m th
yrog
lobu
line
(Tg)
leve
l dur
ing
levo
thyr
oxin
e tr
eatm
ent p
rior
to 17
7 Lu-o
ctre
otat
e th
erap
y;
§ T
SH, t
hyro
id s
tim
ulat
ing
horm
one
duri
ng le
voth
yrox
ine
trea
tmen
t; ||
out
com
e of
rad
ioio
dine
sca
n; +
/-, m
ixed
131 I
posi
tive
and
neg
ativ
e le
sion
s; N
/A, n
ot a
vaila
ble,
**
tum
or u
ptak
e sc
ore
on 11
1 In-o
ctre
otid
e sc
inti
grap
hy: 1
; upt
ake
in le
sion
less
than
the
liver
, 2; e
qual
to th
e liv
er, 3
; hig
her
than
the
liver
as
desc
ribe
d pr
evio
usl
y 19
; ” P
D,
docu
men
ted
prog
ress
ive
dise
ase
wit
hin
one
year
bef
ore
ther
apy
180
�Asaresultofthetimeschedule,completionofalltreatmentsvariedfrom3to12monthsforanyindividual.Allpatientswereallowedtoreceiveuptoacumulativedoseof30GBq,whichcorrespondedtoacalculatedbonemarrowdoseof2Gy,exceptinthoseindividualcasesinwhichkidneydosimetryindicatedless(maximumallowedkidneydosewas23Gy).Routinehematology,liverandkidneyfunctiontests,hormonemeasurements,andserumtumormarkersweremeasured1wkbeforeeachtherapy,aswellasatfollow-upvisits.CTorMRimagingwasperformedwithin3monthsbeforethefirsttherapy,and6–8weeks,3months,and6monthsafterthelasttreatment.Thereafterfollow-upcontinuedevery6months.
In Vivo MeasurementsCT-orMRI-assessedtumormeasurementswerescoredaccordingtothefollowingcriteria:progressivedisease(PD),increaseinmeasurabletumormassvolume≥25%;stabledisease(SD),tumormassvolumeincreaseordecrease≤25%;minorremission(MR),decreaseoftumormassvolumebetween25%and50%;andpartialremission(PR),decreaseoftumormassvolume≥50%.Timetoprogression(TTP)wasdefinedasthetimeintervalbetweenthefirsttreatmentandtheearliestdateofdiseaseprogressionbasedonCTorMRimagingmeasurements.Theamountofuptakeonpretherapy111In-octreotideandposttherapy177Lu-DOTATATEscintigraphywasscoredvisuallyonplanarimagesona4-pointscaleaccordingtocriteriapreviouslydescribedbyKrenninget al. 19: lowerthan(grade1),equalto(grade2),orgreaterthan(grade3)normallivertissue;andgrade4,higherthannormalspleen/kidneyuptake.
RESULTSFivepatientswithmetastaticDTC(3withHCTC,1withpapillarythyroidcarcinoma[PTC],and1withFTC)weretreatedwith22.4–30.1GBqof177Lu-DOTATATE.Thepatientswereeithernegativeon131Iscintigraphyaftertherapyorprovenunresponsiveto131Itherapy.Metastaticdiseasewaspresentinallpatientsbasedonconventionalimaging(CT/MRimagingorsonography),pathologicuptakeof111In-octreotide,andelevatedserumTglevels.TumorresponseaftertherapywasmonitoredbyCT/MRimagingandserumTglevels(Table2).
Patient1wasdiagnosedin1995withPTCwithsupraclavicularmetastases.Initialtreatmentconsistedoftotalthyroidectomyfollowedbyradioiodineablation.InApril1996,thepatientwastreatedwithradioiodineforrecurrentdisease.Becauseofanewlydevelopedsarcomatoidcarcinomaofthevocalchord,atotallaryngectomyandbilateralnodalneckdissectionwasperformedlaterthatyear.LymphnodeswerepositiveforDTC,andathirddoseof131Iwasgiven.In1998,afourthtreatmentof131Iwasgivenbecauseofathirdrecurrence.However,nouptakeof 131Iwasvisibleonposttherapyscintigraphy.Incontrast, 111In-octreotidescintigraphyshoweduptake
Pept
ide
rece
ptor
radi
onuc
lide
ther
apy
��or n
on–r
adio
iodi
ne-a
vid
di����e
rent
iate
d th
yroi
d ca
rcin
oma
6.1
inthemediastinum.Subsequently, 177Lu-DOTATATEtherapywasinitiated.Eighttreatmentsweregivenwithacumulativetreatmentdoseof25.7GBq,whichresultedinSD.TTPwasdocumented18monthsafterthefirsttreatment,withgraduallyincreasingserumTglevels.Thereafter,CTmeasurementsshowedPD.Fouryearsafterthefirsttreatment,thepatientdiedofthedisease.
Patient2wasdiagnosedin1990withFTC.Within1yraftertotalthyroidectomyandablation,CTassessmentshowedlungmetastases,whichweretreatedwithatherapeuticdoseof131I.However,posttherapy131Iscintigraphydidnotrevealanyuptakeintumor.Therefore,additionaltreatmentconsistedoflocalexternalradiotherapyandchemotherapywithadriamycine.However,thepatienthadPD,andherclinicalconditionworsened.In2000,tumorprogressionledtoairwayobstruction,whichwascomplicatedwithpneumoniaandseverestridor,necessitatingemergencytracheostomy.Atthattime,111In-octreotidescintigraphyrevealednumerouslesionsinthechest,and,subsequently,177Lu-DOTATATEtherapywasstarted.Threetreatmentsof177Lu-DOTATATEwithatotaldoseof22.4GBqcouldnotstoptumorprogression,whichwasobviousfrombothsymptomatologyandincreasedserumTglevels.Twoweeksafterthelasttherapy,thepatientdiedoftumorprogression.
Patient3wasdiagnosedwithHCTCandhadundergone total thyroidectomycombinedwithaneckdissection.However,completeremovalofthetumormasswasnotpossiblebecauseofintraoperativeidentificationoftumorgrowthintothetrachea.Surgerywasfollowedbyradioiodinetherapy.Eighteenmonthslater,anultrasoundoftheneckrevealedcontinuedgrowthofthe(para)trachealmass,whichdidnotaccumulateany123I. 111In-octreotidescintigraphy,however,showeduptakeinthelowerneckregion.177Lu-DOTATATEtherapywasinitiated,andthepatientreceived8treatmentswithacumulativedoseof27.4GBq.Sixmonthsafterthelasttherapy,thepatientwasfoundtobeinMR.Twoyearslaterprogressionwasdemonstrated.AfteraninitialriseinserumTglevelaftertreatment,thisdecreasedtoanadirof46.6µg/L,whichreflecteddecreaseoftumormassvolume(Figure1a).
Patient4initiallyhadaleft-sidedhemithyroidectomyforHCTC.Sixteenyearslater,3 lungmetastasesweredetected,andshehadaright-sidedhemithyroidectomyfollowedby 131Itherapywith3.7GBq,afterwhichtheserumTglevelsdecreasedfrom150to18µg/L.However,nochangeintumorsizewasfound.Oneyearlaternoaccumulationduring123Iscintigraphywasfound.Despitetheabsenceofradioiodineuptake,shewasretreatedwith3.7GBqof131I,withnoeffectontumormassorserumTglevels.In1999,theserumTglevelincreasedto507µg/Land5.5GBqof131Iwasadministered.Despiteapositivelesionintherightupperlobeofthelungon131Iscintigraphyaftertherapy,againnoeffectwasfound.
182
�
Tab
le 2
. Resultsof17
7 Lu-D
OTATATEtherapy
Tu
mo
r u
pta
ke s
core
*B
est R
esp
on
se a
fter
Th
erap
y †
Pat
ien
tP
re-T
her
apy
111 In
-oct
reo
tid
eP
ost
177 L
u-o
ctre
ota
te T
her
apy
Tu
mo
r vo
lum
eT
gT
TP
(m
on
ths)
‡
12
1SD
increase
18
22
3PD
increase
4
33
3MR
decrease
43
42
2SD
decrease
24+
51
3PR
decrease
22+
* tu
mor
upt
ake
scor
e ac
cord
ing
to so
mat
osta
tin
rece
ptor
scin
tigr
aphy
vis
ual s
cori
ng s
yste
m a
s des
crib
ed p
revi
ousl
y 19
; † S
D (
stab
le d
isea
se),
< 2
5% r
educ
tion
or
incr
ease
of
tum
or s
ize;
PD
(pr
ogre
ssiv
e di
seas
e), >
25%
incr
ease
of
tum
or s
ize;
MR
(m
inor
rem
issi
on),
bet
wee
n 25
% a
nd 5
0%
red
ucti
on o
f tu
mor
siz
e; P
R (
part
ial r
emis
sion
), >
50
% r
educ
tion
of t
umor
siz
e; T
g =
thyr
oglo
bulin
; ‡ T
TP=t
ime
to p
rogr
essi
on in
mon
ths
sinc
e st
art
of t
hera
py.
Pept
ide
rece
ptor
radi
onuc
lide
ther
apy
��or n
on–r
adio
iodi
ne-a
vid
di����e
rent
iate
d th
yroi
d ca
rcin
oma
6.1
Becauseofpositivelesionsdetectedon 111In-octreotidescintigraphy,thepatientreceived4treatmentswithatotaldoseof30.1GBq177Lu-DOTATATE.TheserumTglevels,whichweremeasuredbeforeeachtreatment,increaseduptoamaximumof1,730µg/L.Afterthelasttreatment,theserumTglevelsdecreased,withanadirof746µg/L14monthslater(Figure1b).OnCT,nodifferenceintumorsizewasfound.However,theradiologyreportmentionedaninhomogeneousaspectthatsuggestedtumornecrosis.
Figure 1a-c. TimecourseofserumTgandTSHlevelsinpatient3,4,and5treatedwith177Lu-DOTATATE.Brokenlinesrepresentpretherapylevels.
184
�Patient5withanHCTCwasdiagnosedin1997andsubsequentlyunderwentatotalthyroidectomyfollowedbyradioiodineablationtherapy.Becauseoflocalrecurrencesinthesurgicalbedandlowcervicalregion,shewasretreatedwithradioiodinein2000and2001.Persistentuptakenearthejugulumwasseenon131Iscintigraphyaftertherapy.In2001,additionalimagingwasperformedbecauseofpersistentelevatedserumTglevelsandprogressivepainintheleftleg.Inadditiontothenecklesionseenon131Iscintigraphy,both18F-FDG-PETandMRIshowedlesionsinthespine(L3andL5-S1).Lackofradioiodineaccumulationinthelatter lesionssuggesteddedifferentiation,and,therefore,externalradiationwasgiven.Becauseofthegrowthofthenecklesion,whichcompressedthetrachea,thepatientdevelopedastridor.111In-octreotidescintigraphyshoweduptakeinalltumorlesionsaspreviouslyseenon18F-FDG-PETandMRI.Thepatientreceived3treatmentswithacumulativedoseof22.7GBqof177Lu-DOTATATE.Afterthesecondtreatment,serumTglevelsbegantodecrease(Figure1c).Atthesametime,theCTscanshowedregressionofthetracheallesionwithashrinkageof50%12monthsafterthelasttherapy.
Acomparisonbetweenpretherapy111In-octreotideandposttherapy177Lu-DOTATATEscintigraphyinpatients1and3isshowninFigure2.
Figure 2. Imagescomparingpretherapy111In-octreotidescintigraphy(A)andposttherapy177Lu-DOTATATEscintigraphyat24h(B).Toprowshowscorrespondingimagesoftumorsitesinpatient1withmetastaticPTC.Bottomrowshowscorrespondingimagesofpatient3withHCTC.
Pept
ide
rece
ptor
radi
onuc
lide
ther
apy
��or n
on–r
adio
iodi
ne-a
vid
di����e
rent
iate
d th
yroi
d ca
rcin
oma
6.1
Inpatient1,theuptakeofbothsomatostatinanalogswasaboutthesame.Incontrast,moreuptakewasshowninthetracheallesionofpatient3on 177Lu-DOTATATEscintigraphythanon111In-octreotidescintigraphy.Calculated177Lu-DOTATATE/111In-octreotidetumoruptakeratiosinthetumorlesionsofallpatientsvariedfrom1.1to3.2.TwopatientswithHCTC,inwhomtumorshrinkagewasdemonstrated,hadthehighestratios(Figure3).
Figure 3. Ratiosof177Lu-DOTATATEand111In-octreotideuptakeintumorsites.Uptakewasexpressedaspercentageofadministereddose.NotedifferencesinuptakebetweenpatientswithHCTCwhorespondedwithMRandPRandthosewhodidnotrespondwithtumorshrinkage.
DISCUSSIONTherapeuticoptions inpatientswithrecurrentormetastaticDTCthatcannotconcentrateradioiodinearelimited.Also,thelossofiodine-trappingability,ordedifferentiation,isassociatedwithamoreaggressivebehavior6.
Inthispaperwedescribetheresultsoftherapywith177Lu-DOTATATEin5patientswithDTC,whohadnoothertreatmentavailable.CT-assessedtumorshrinkagewasfoundin2patientswithHCTC.Concomitantly,adecreaseinserumTglevelswasobservedinbothpatients.IntheotherpatientwithHCTCtheserumTglevelsdecreasedsignificantly,whereasCT-assessedtumorvolumedidnotchange.However,theaspectofthelesionschanged,whichsuggestednecrosis.DiseasestabilizationwasachievedinonepatientwithclearlyprogressivePTCbeforetherapy,whereasthepatientwithFTCprogresseddespitetreatment.TheseresultssuggestthatinsomepatientswithDTC,whohavenotreatmentoptionsleft, 177Lu-DOTATATEtherapycanbeeffective.
186
�Thereasontotreatthesepatientswith177Lu-DOTATATE,wasfoundinthesuccessfultreatmentwiththiscompoundinpatientswithsomatostatinreceptor–positivegastroenteropancreatic(GEP)tumors.Objectivetumorshrinkagewasdemonstratedinupto38%ofpatients20.Inaddition,reportsinwhichothersomatostatinanalogswere labeledwithdifferent radionuclides, suchas 111Inor 90Y, showedsimilartherapeuticbenefitinpatientswithGEPtumors16,17,21,22.ApartfromGEPtumors,otherresultsoftherapyinpatientswithDTCwerereported(Table3).PatientswithDTCweretreatedbecausetheyhadprogressivedisease,somatostatinreceptor–positivelesionson111In-octreotidescintigraphy,andnoothertreatmentoptionavailable.
Krenninget al. 19 reported the first 2DTCpatients treatedwith radiolabeledsomatostatinanalogs.BothhadPTCandweretreatedwith111In-octreotide,whichwasavailablefortherapy.Onepatient,whohadatotalcumulativedoseofatleast20GBq,showeddiseasestabilization,whereastheotherpatient,whohadreceived<20GBq,waslosttofollow-up.Inareviewthatsummarizedtheuseof111In-octreotidetherapyinatotalof50patientsinasingleinstitution,40patientswereevaluatedaftercumulativedosesofat least20GBqupto160GBq.Withinthisgroup,5patientshadDTC,including4patientswithPTCand1withFTC17.Fourpatientswereprogressivedespitetreatment,whereas1patient,whowasreportedearliertohaveSDforsometime,ultimatelyprogressed.Inarecentreport,11patientswithprogressiveiodinenonresponsivethyroidcarcinomaweretreatedwithhigh,fixeddosesof 111In-octreotide23.Ninepatientswereevaluable,because2patientsdiedduringfollow-upofcausesunrelatedtotheirdisease.Sixmonthsafterthelasttherapy,4patientshadSDand5patientshadPD.StablilizationofdiseasewasaccompaniedwithastableTglevel,whereas3outofagroupof5patientswithradiologicprogressionhadincreasinglevelsofTg.Interestingly,themeanTgvalueinthelattergroupwashigherthaninthegroupwithstabilizationofdisease(meanTgvalue180,432vs.275µg/L).ItwassuggestedthatlowTgvaluescouldbeusedasselectioncriteriafor111In-octreotidetherapy.
Waldherret al. 15treated8DTCpatients(3FTC,4PTC,and1anaplasticthyroidcarcinoma)with90Y-DOTATOC.Twopatients,whoweretreatedwith9.1and14.8GBq,hadSDanddocumentedTTPof8months,whereastheotherpatientshadPD.Chinolet al.21alsoused90Y-DOTATOCtotreat2patientswithPTC.Unfortunately,theefficacyoftherapyinthese2patientswasdifficulttodeterminefromthisstudy,becauseresultswerepresentedastheeffectoftreatmentinthewholegroupofsomatostatinreceptor(SSTR)positivetumors.Threepatientshadregressivedisease(>25%reductionoftumorsize),11hadSD,and11hadPD.Inaveryrecentreport,5patientswithDTCweretreatedwith90Y-DOTATOCwithadoserangeof5.6GBqto7.4GBq24.
Pept
ide
rece
ptor
radi
onuc
lide
ther
apy
��or n
on–r
adio
iodi
ne-a
vid
di����e
rent
iate
d th
yroi
d ca
rcin
oma
6.1
Tab
le 3
. Peptidereceptorradionuclidetherapyinpatientswithdifferentiatedthyroidcarcinom
a
Rad
iop
har
mac
euti
cal
Cu
mu
lati
ve D
ose
Res
po
nse
/ (
TT
P[m
o])
†C
rite
ria
‡
Ref
eren
ces
Tu
mo
r cl
assi
fica
tio
n*
Rad
ion
ucl
ide
Ch
elat
or
Pep
tid
e
Gorgesetal.20
01(14)
3xHCTC
90Y
DOTA
TOC
1.7-9.6GBq
1xSD(21);2xPD
N/A
Waldh
erretal.20
01(15)
3xFTC;4
xPT
C;1xATC
90Y
DOTA
TOC
1.7-14.8GBq
2xSD(8,8);6xPD
W
HO
Virgolinietal.2002(16)
25xTC
90Y
DOTA
Lanreotide
0.9-7.0GBq
3xRD(N/A);11xSD(N
/A);
11xPD
W
HO
Valkemaetal.20
02(17)
1xFTC;4
xPT
C
111 In
DTPA
TOC
3.0-8.3GBq
4xPD;1xSD
(N/A)
SW
OG
Chinoletal.2002(21)
2xPTC
90Y
DOTA
TOC
>7.4GBq
N/A
SW
OG
Christianetal.2003(12)
1xHCTC
90Y
DOTA
TOC
N/A
N/A
N/A
Gabrieletal.2004(24)
4xFTC;1xPT
C
90Y
DOTA
TOC
5.6-7.4GBq
5xSD(5)
N/A
Stok
keletal.2004(23)
4xFTC;5xPT
C
111 In
DTPA
TOC
14.3-33.1GBq
4xSD(N/A);5xPD
N/A
‡ W
HO
, Wor
ld H
ealt
h O
rgan
izat
ion
Cri
teri
a: R
D (
regr
essi
ve d
isea
se)=
>25
% r
educ
tion
of t
umor
siz
e; S
D (
stab
le d
isea
se)=
<25
% r
educ
tion
or
incr
ease
of t
umor
siz
e; P
D
(pro
gres
sive
dis
ease
)= >
25%
incr
ease
of t
umor
siz
e.
SWO
G, S
outh
wes
t Onc
olog
y gr
oup
crit
eria
: PR
(pa
rtia
l rem
issi
on)=
>50
% r
educ
tion
of t
umor
siz
e; S
D (
stab
le d
isea
se)=
<50
% r
educ
tion
or
<25%
incr
ease
of t
umor
siz
e;
PD (
prog
ress
ive
dise
ase)
= >2
5% in
crea
se o
f tum
or s
ize
* T
C, u
ndefi
ned
thyr
oid
carc
inom
a; P
TC
, pap
illar
y th
yroi
d ca
rcin
oma;
FT
C, f
ollic
ular
thy
roid
car
cino
ma;
HC
TC
, Hür
thle
cel
l thy
roid
car
cino
ma;
AT
C, a
napl
asti
c th
yroi
d ca
rcin
oma;
†, T
TP=t
ime
to p
rogr
essi
on (
mon
ths)
; N/A
, not
ava
ilabl
e
188
�TheauthorsreportedthatpatientswhorespondedunderthistherapyregimenhadSDforatleast5months.EspeciallyinterestingincomparisonwithourresultsisthereportbyGorgeset al.14,whodescribedthecoursesofdiseaseofthefirst3patientswithHCTCtreatedwith90Y-DOTATOC(totaldose,1.7–9.6GBq).ThepatientwiththehighestdoserespondedwithaperiodofSDof9months,whereastheother2patientshadprogressivediseasedespitetreatment.Theyconcludedthattheprotocolwasnotideal,becausetumorradiationdosewassuboptimal.
TodrawconclusionsfromallthestudiesconcerningthetherapeuticefficacyofPRRTinpatientswithnon–radioiodine-avidorunresponsivethyroidcancerisdifficult.Thenumberof treatedpatients inthereportedstudieswas low.Furthermore,differentradiolabeledsomatostatinanalogswereusedwithindividuallyvariableadministereddoses.Clearly,PRRTinDTCseemstobelesseffectivethaninGEPneuroendocrinetumors.
OnereasonforthisdifferenceinefficacymightbetheexpressionprofileofSSTRsubtypesbytumors.Reubiet al. 25,whointensivelystudiedtheSSTRsubtypeprofileofnumeroushumantumors,reportedapredominanceofSSTR2orSSTR1inGEPtumors.Incontrast,invitrostudieswiththyroidcancercelllinemonolayersandxenograftsshowedapredominantexpressionofSSTR3andSSTR5,whereasSSTR2mRNAwasonlyfaintlydetectable26.Inanotherreport,inwhichthereceptorsubtypeexpressioninbiopsiedDTCtumortissuewasinvestigatedbyNorthernBlotanalyses,SSTR1,SSTR3,SSTR4,andSSTR5wereexpressedinalltumors,whereasSSTR2wasnotdetectedinanyFTCorPTCtumors.Inlinewiththeseobservations,Forssell-Aronssonet al.27alsodemonstratedthatthehighesttumor-to-backgroundratioandexpressionofhigh-affinitySSTR2,wasfoundinmedullarythyroidcarcinomaandHürthlecellneoplasia.Inthelatter,theexpressionofSSTR2wasirregular.ThesefindingssuggestthattheSSTRsubtypeexpressionprofilefoundinDTCcellsisdifferentandmorevariablethanthatinGEPtumors.
MostradiolabeledsomatostatinanalogsavailablefortherapysharethehighbindingaffinityfortheSSTR2receptor.Itwasreportedthat,incomparisonwithDTPA0,Tyr3-octreotide,DTPA0,Tyr3-octreotateshowedimprovedbindingtoSSTRpositivetissuesinanimalexperiments28.Furthermore,thesomatostatinanalogDOTATATEhasa9-foldhigheraffinityfortheSSTR2thandoesDOTATOC,whereastheaffinitytoSSTR3andSSTR5werefoundtobelower29.InlinewiththehigheraffinityfortheSSTR2,ourbiodistributionstudieson111In-octreotideand177Lu-DOTATATEscintigraphy,reportedpreviously,showeda3-to4-foldhighertumoruptakein4outof5patients18.ThepresenceofSSTRsubtypesotherthanSSTR2wassuggestedasanexplanationforequivalenttumoruptakeofbothsomatostatinanalogsin1patientwithPTC,whoisalsodescribedinthisarticle(patient1).Interestingly,the
Pept
ide
rece
ptor
radi
onuc
lide
ther
apy
��or n
on–r
adio
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ne-a
vid
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rent
iate
d th
yroi
d ca
rcin
oma
6.1
17 7Lu-DOTATATE/111In-octreotide uptake ratios calculated in the 5 patientsdemonstratedthatthe2HCTCpatientswiththehighestuptakeratiosrespondedwithtumorshrinkage,whereastheothershadratios<1.5.Thus,inpatientswithPTCorFTCwithtumorsthatprobablyexhibitadifferentandvariableSSTRexpressionprofilewithpredominantlySSTR5andSSTR3insteadofSSTR2,thereisnoclearadvantageofTyr3-octreotateoverTyr3-octreotide.
ForthebettertumortargetingandincreaseinuptakerequiredforbettertherapeuticefficacyofPRRTinDTC,SSTRsubtype-specificanalogswithhigheraffinityforSSTR3andSSTR5arenecessary.Mostpromising is the recentstudybyWildet al. 30,whoreportedthefirstpreclinicaldataon111In-and90Y-labeledDOTA-1-Nal3-octreotide(DOTA-NOC),whichhas,apartfromhighaffinitytoSSTR2,afavorableaffinityforSSTR3andSSTR5.Inaddition,theybrieflymentionedexcellentimagesofthyroidcancerpatientsinclinicalstudieswith[111In]DOTA-NOC.ItwasassumedthatDOTA-NOClabeledwitheither90Yor177Luwillhavesimilarfavorableproperties,sothatitmightbecomeavailablefortherapyinpatientswithDTCinthenearfuture.Inouropinion,thebestcandidatesforPRRTwith177Lu-DOTATATEinnon–iodine-avidmetastaticandradioiodineunresponsiveDTCarepatientswithHCTC.Thecombinationof a largepercentageofHCTCpatientswithpositive lesionson111In-octreotidescintigraphy,relativelyhightumoruptakeof 177Lu-DOTATATEcomparedwithPTCorFTC,andthefavorableoutcomesobservedinourpatientssuggest thatespecially in thesepatients 177Lu-DOTATATEmay induce tumorshrinkageorprolongeddiseasestabilization.
ACKNOWLEDGMENTSTheauthorswishtothankallsupportingpersonnelintheDepartmentofNuclearMedicineattheErasmusMedicalCenter(Rotterdam,TheNetherlands)fortheirexperthelpandeffort.
190
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12. ChristianJA,CookGJ,HarmerC.Indium-111-labelledoctreotidescintigraphyinthediagnosisandmanagementofnon-iodineavidmetastaticcarcinomaofthethyroid.Br J Cancer. 2003;89:258–261.
13. StokkelMP,ReigmanHI,VerkooijenRB,SmitJW.Indium-111-octreotidescintigraphyindifferentiatedthyroidcarcinomametastasesthatdonotrespondtotreatmentwithhigh-doseI-131.J Cancer Res Clin Oncol. 2003;129:287–294.
14. GorgesR,KahalyG,Muller-BrandJ,MackeH,RoserHW,BockischA.Radionuclide-labeled somatostatin analogues for diagnostic and therapeutic purposes innonmedullarythyroidcancer.Thyroid. 2001;11:647–659.
15. WaldherrC,SchumacherT,PlessM,et al.Radiopeptide transmitted internalirradiationofnon-iodophilthyroidcancerandconventionallyuntreatablemedullarythyroidcancerusing[90Y]-DOTA-D-Phe1-Tyr3-octreotide:apilotstudy.Nucl Med Commun. 2001;22:673–678.
16. VirgoliniI,BrittonK,BuscombeJ,MoncayoR,PaganelliG,RivaP.In-andY-DOTA-lanreotide:resultsandimplicationsoftheMAURITIUStrial.Semin Nucl Med. 2002;32:148–155.
17. ValkemaR,De JongM,BakkerWH, et al. Phase I studyofpeptide receptorradionuclidetherapywith[In-DTPA]octreotide:theRotterdamexperience.Semin Nucl Med. 2002;32:110–122.
18. KwekkeboomDJ,BakkerWH,Kooij PP, et al. [17 7Lu-DOTA0Tyr3]octreotate:comparisonwith[111In-DTPA0]octreotideinpatients.2001;28:1319–1325.
19. KrenningEP,deJongM,KooijPP,etal.Radiolabelledsomatostatinanalogue(s)forpeptidereceptorscintigraphyandradionuclidetherapy.Ann Oncol. 1999;10(suppl2):S23–S29.
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20. KwekkeboomDJ,BakkerWH,KamBL,etal.Treatmentofpatientswithgastro-entero-pancreatic(GEP)tumourswiththenovelradiolabelledsomatostatinanalogue[177Lu-DOTA0,Tyr3]octreotate.Eur J Nucl Med Mol Imaging. 2003;30:417–422.
21. ChinolM,BodeiL,CremonesiM,PaganelliG.Receptor-mediatedradiotherapywithY-DOTA-D-Phe-Tyr-octreotide:theexperienceoftheEuropeanInstituteofOncologyGroup.Semin Nucl Med. 2002;32:141–147.
22. WaldherrC,PlessM,MaeckeHR,etal.Tumorresponseandclinicalbenefit inneuroendocrinetumorsafter7.4GBq90Y-DOTATOC.J Nucl Med. 2002;43:610–616.
23. StokkelMP,VerkooijenRB,BouwsmaH,SmitJW.Sixmonthfollow-upafter111In-DTPA-octreotidetherapyinpatientswithprogressiveradioiodinenonresponsivethyroidcancer:apilotstudy.Nucl Med Commun. 2004;25:683–690.
24. GabrielM,FroehlichF,DecristoforoC,etal.99mTc-EDDA/HYNIC-TOCand18F-FDGinthyroidcancerpatientswithnegative131Iwhole-bodyscans.Eur J Nucl Med Mol Imaging. 2004;31:330–341.
25. ReubiJC,WaserB,SchaerJC,LaissueJA.Somatostatinreceptorsst1–sst5expressioninnormalandneoplastichumantissuesusingreceptorautoradiographywithsubtype-selectiveligands.Eur J Nucl Med. 2001;28:836–846.
26. AinKB,TaylorKD,TofiqS,VenkataramanG.Somatostatin receptor subtypeexpressioninhumanthyroidandthyroidcarcinomacell lines.J Clin Endocrinol Metab. 1997;82:1857–1862.
27. Forssell-AronssonEB,NilssonO,BejegardSA,etal.111In-DTPA-D-Phe1-octreotidebindingandsomatostatinreceptorsubtypesinthyroidtumors.J Nucl Med. 2000;41:636–642.
28. deJongM,BreemanWA,BakkerWH,etal.Comparisonof111In-labeledsomatostatinanaloguesfortumorscintigraphyandradionuclidetherapy.Cancer Res. 1998;58:437–441.
29. ReubiJC,ScharJC,WaserB,etal.AffinityprofilesforhumansomatostatinreceptorsubtypesSST1–SST5ofsomatostatinradiotracersselectedforscintigraphicandradiotherapeuticuse.Eur J Nucl Med. 2000;27;273–282.
30. WildD,SchmittJS,GinjM,etal.DOTA-NOC,ahigh-affinityligandofsomatostatinreceptorsubtypes2,3and5forlabellingwithvariousradiometals.Eur J Nucl Med Mol Imaging. 2003;30:1338–1347.
�
6.2 Staging and treatment o�� di����erentiated thyroid carcinoma with radiolabeled somatostatin analogs
Jaap J.M. Teunissen, Dik J. Kwekkeboom and Eric P. Krenning
Trends in Endocrinology & Metabolism 2006; 17:19-25
AbstractInpatientswithprogressivemetastatic (or recurrent)differentiated thyroidcarcinomathateitherdonottakeupradioioidineorareunresponsivetocontinuedradioiodinetherapy,stagingisdifficultandtreatmentoptionsarefew.However,inmostofthesepatientsuptakeofradiolabeledsomatostatinanalogsisevidentonsomatostatin-receptorscintigraphy(SRS).UsingSRS,patientswithsufficientuptakeofradiolabeledsomatostatinanalogscanbeselectedforhigh-dosepeptidereceptorradionuclidetherapy(PRRT)asanalternativetargeted-treatmentoption.PRRTwiththeβ-particle-emittingradionuclides90Yttrium(90Y)and177Lutetium(177Lu)givesthebestresultsintermsofobjectivetumorresponse.Promising,novel,radiolabeledsomatostatinanalogsthathaveabroaderreceptoraffinityprofileand,thus,apotentiallywidertherapeuticrangearebeingtestedclinically.
Abstract
6.2
INTRODUCTIONStandardtherapyinmostpatientswithnon-medullarydifferentiated(papillary,follicularandHürthlecell)thyroidcarcinoma(DTC)involveseithertotalornear-totalthyroidectomyfollowedbyablationofthethyroidremnantwithradioiodine.Withareportedoverall 10-year-survivalrateof75–95%,DTCisregardedasamalignancywitharelativelygoodprognosis 1-3.However,tumorsrecurin~20%ofpatients2,3.Long-termfollow-upafterinitialtherapy,whichisbasedprimarilyonmeasurementsofserumthyroglobulin(Tg)incombinationwithradioiodinewhole-bodyscans(WBSs), is, therefore,obligatory.Additionaltreatmentwithradioiodinecanbeinitiatedwhenrecurrenceand/ormetastasesareevidentandimagedbyradioiodineWBS.However,radioiodinetherapyisnolongeranoptioninthe20–30%ofpatientswhohaverecurrencesand/orpersistentmetastasescausedbydedifferentiationwithalackofradioiodineuptake(non-radioiodine-avid)withinthetumors(4–6%ofpatientsdiagnosedwithDTC)4,5.
PatientswithdedifferentiatedDTChaveaworseprognosis,largelybecausetheycannotbetreatedwithradioiodine2,5,6.Therefore,alternative,accurateimagingmethodsfordiagnosis,andtherapeuticmodalitiesareofinterest.Hürthlecellthyroidcarcinoma(HCTC),anuncommonformofthyroidcancerthatisusuallyclassifiedasavariantoffollicularthyroidcarcinoma(FTC), isofspecial interestbecausethesecarcinomasrarelytakeupradioiodine,evenatthetimeofdiagnosis7.Inthisreview,wefocusonboththestagingandthetherapeuticpotentialofradiolabeledsomatostatinanalogsinpatientswithnon-radioiodine-avidDTC.
SOMATOSTATIN RECEPTOR SCINTIGRAPHY Overtenyearsago,wepublishedthefirstresultsofpatientswithDTCwhowereimagedbysomatostatinreceptorscintigraphy(SRS)8,9.ThepotentialvalueofSRSinpatientswithnon-radioiodine-avidDTCwasclearbecause,insomepatients,eithernewormoretumorlocalizationsweredetectedcomparedwithradioiodineWBS.Furthermore,insomepatientswithanegativeradioiodineWBS,SRSshowedtumoruptakeoftheradiolabeledsomatostatinanalog111Indium-diethylenetriaminepentaaceticacid(DTPA)octreotide(111In-octreotide).ThefindingthatSRSvisualizestumorsinpatientswithDTCwhosetumorsdonottakeupradioiodinehasgreatpotentialforstagingthediseaseandtreatingitwithsomatostatinanalogs.
The value of SRS in clinical practice MostreportedstudiesonSRSfocusontheclinicalvalueofthisimagemodalityinpatientswithnon-radioiodine-avidDTCwithprogressivedisease.Tenenbaumet al.10studiedfourpatientswithDTCofwhomthreeshowednouptakeonradioiodineWBS.Twopatients,onewithpapillarythyroidcarcinoma(PTC)andonewith
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poorlydifferentiatedthyroidcarcinoma(insular;PDTC),showed111In-octreotideuptakeonSRS.Inalargerstudyof25DTCpatients(16withradioiodine-negativetumorsandninewithradioiodine-positivetumors),20outof25(80%)showeduptakeduringSRSwith111In-octreotide11.Inthepatientswithradioiodine-negativetumors,12outof16(75%)showeduptakeonSRS.AllpatientshadelevatedserumlevelsofTg,whichreflectedthepresenceofdisease.ItwasconcludedthatSRSisauseful,additionalimageandstagingmodalityforfollow-upinpatientswithelevatedserumTg levelsandnegative radioiodineWBS.Several studieshaveconfirmedthesefindingsandreporteduptakeof 111In-octreotideineithernon-radioiodine-avidmetastaticorrecurrentdiseasein74–100%ofpatients(Table1)12-15.Bycontrast,Garinet al.16reportedapositive111In-octreotidescaninonlythreeoutof16patients(19%)inwhomnoradioiodineuptakecouldbedemonstrated.Valliet al.17reportedsimilarresultsandconcludedthatoctreotidescintigraphyhasalowerdiagnosticaccuracythanconventionalimagingmodalities,includingchestx-ray,ultrasound(US)oftheneck,spiralcomputedtomography(CT),magneticresonanceimaging(MRI)andbonescintigraphy.However,theadministrationofalowdoseof111In-octreotideandashortacquisitiontimecomparedwiththeotherstudiesmightaccountforthediscrepancyinsensitivityobserved.Giammarileet al.18,whoperformed111In-octreotidescintigraphywiththelargestgroupofpatientswithnodetectableradioiodineuptakeandelevatedserumTglevels,reportedanoverallsensitivityof51%whichwasclearlylowerthanthatofbothconventionalimaging,suchasUSoftheneckandabdomen,CTand/orMRI,andbonescintigraphy,andtherelativelynewtechniqueofpositronemissiontomography(PET)using18F-fluorodeoxyglucose(18F-FDG).Withthelargenumberofpatientsstudied,factorsthatmightinfluencediagnosticaccuracyofSRS,werediscussed.Thefirstoftheseistheanatomicallocalizationofthetumors.ThesensitivityofSRSwashighforthedetectionofmediastinallesions(93%),whereasmostfalse-negativeresultswereobservedinpatientswho,atfollow-up,wereprovedtohavehadundetectable,small,neckandlungmetastasesatthetimeofSRS.
Inadditiontoanatomicallocation,ahighserumTglevel(>50ngml-1)inpatientswhohadthyroxinesubstitutiontherapy(Tg-on)wasassociatedwithsignificantlyincreasedsensitivity.Furthermore,Görgeset al.19reportedacleardistinctionbetweenthedetectedlesionswithinthegroupofpatientswithlowserumTg-onlevels(<10ngml-1,n=11) and those from the groupwithhigh serumTg-on levels(>10ngml-1,n=39).Inthelattergroup,85%ofpatientshadapositiveSRSwhereasinthegroupwithlowserumTg-onlevelsonly27%ofpatientshadapositiveSRS.Garinet al. 16 reportedthatall theirstudiedpatientswithapositiveSRShadaserumTg-onlevel>5ngml-1.PatientswithoutuptakehadlowserumTg-onlevels(<5ngml-1).TheseresultsindicateapositivecorrelationbetweentheserumTgleveland/orthyroid-stimulatinghormone(TSH)andvisualizationonSRS.
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Table 1.111In-octreotidescintigraphyinnon-radioiodine-aviddifferentiatedthyroidcarcinomaa
Study year
Number of
patients
Tumor classification Serum Tg level range (ng ml-1) Imaging Refs
Tg-onb
(numberofpatients)
Tg-offb
(numberofpatients)
NumberofpatientswithradioiodinenegativebutSRSpositivescans
1995 3 2PTC;1insularTC 120-60000(3) 2outof3(67%) [10]
1996 16 11FTC;5PDTC 2-42500(16) 12outof15(75%) [11]
1996 6 5FTC;1PTC NA NA 6outof6(100%) [12]
1998 16 15PTC;1vesicularTC <0.2-1440(11) 3outof16(19%) [16]
1999 15 14PTC;1HCTC 10-65000(15) 1670/2030(2) 7outof15(49%) [17]
2001 293FTC;4PTC;21HCTC;1insularTC
0.48-48300(27) 19outof29(66%) [19]
2001 25 9FTC;16PTC <1.5-14910(25) 6outof8(75%) [13]
2003 17 1FTC;4PTC;12HCTC NA NA 14outof17(82%) [14]
2004 23 8FTC;13PTC;2HCTC 16.6-586000(22)c 17outof23(74%) [15]
2004 439FTC;20PTC;8HCTC;6insularTC
0.7-5250(40) 171-5850(3) 22outof43(51%) [18]
a Abbreviations: FTC, follicular thyroid carcinoma; HCTC, Hürthle cell thyroid carcinoma; NA, not available; PTC, papillary thyroid carcinoma; SRS, somatostatin receptor scintigraphy; TC, thyroid carcinoma; Tg, thyroglobulinb Tg-off, thyroglobulin levels without TSH suppressive treatment (L-thyroxine); Tg-on, thyroglobulin levels under TSH suppressive treatmentc excluding one patient with serum Tg of 0.8 ng ml-1 who was Tg antibody positive
TotestthishypothesisHaslinghuiset al.13studiedwhetherwithdrawalofthyroxinetherapyandthesubsequentincreaseinTSHandserumTglevelsmightoptimizetheinformationobtainedwithSRS.DirectcomparisonofSRSbeforeandafterwithdrawalofthyroxinetherapywasperformedinsixpatients.Essentially,thesameclinicalinformationwasobtainedafterwithdrawalofthyroxine,anditwasconcludedthatthereisnoneedtowithdrawpatientsfromthyroxinetoperformSRS.InthecaseofSRSforpurelydiagnosticpurposes,thisconclusionisfairandthebenefitforpatientsisthattheydonothavetosuffertheburdenofthyroxinewithdrawalbeforeSRS.However,althoughthesameinformationwasobtained,higherpathologicaluptakewasobservedinatleasttwopatientsinwhomthyroxin-substitutiontherapy
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�waswithdrawntemporarily13.Inviewoftherapywithradiolabeledsomatostatinanalogs(seelater),increaseduptakeinthetumorsafterthyroxinewithdrawalmightbebeneficialintermsoftumorshrinkage.SuchacorrelationbetweenuptakeonpretherapySRSandfavorableoutcomeoftherapywithradiolabeledsomatostatinanalogswasreportedinpatientswithneuroendocrinegastroenteropancreatic(GEP)tumors20.Furtherquantitiveimagingstudiesintotheeffectofthyroxinewithdrawalontumoruptakeofradiolabeledsomatosatinanalogsarewarrantedtoaddressthisissue.InviewofapossiblecorrelationofelevatedserumTglevel,tumorsizeandSRSsensitivity,thereportbyBachelotet al.21isofinterest.ThisstudydemonstratedacloserelationshipbetweentheserumTglevelafterwithdrawalofthyroid-hormonetreatmentandtumormass/extentofdisease.Thus,thereportedincreasedSRSsensitivityinpatientswithelevatedserumTglevels16,18,19mightreflectanincreaseinSRSsensitivityinlargertumors,ratherthantheelevatedserumTglevel.
In summary, these studies indicate that anatomical localization and tumorsize/extentofdiseaseareimportantindeterminingtheoutcomeofSRSinpatientswithnon-radioiodine-avidDTC.
Somatostatin receptor subtypes AnotherimportantfactorintheobserveddifferencesinuptakeduringSRSmightbetherelativeexpressionofsomatostatinreceptorsubtypes(sstr1–sstr5)andtheirdensityonthetumorcellsurface.Johnet al.demonstratedthatpositive111In-octreotidescintigraphyiscausedmainlybysstr2,whereassstr1,sstr3,sstr4andsstr5arelessimportant.Therefore,thepresenceofsstr2isessentialforimagingtumorswithSRS22.Reubiet al. 23,whousedautoradiographytostudythesstrprofileofnumeroushumantumors,reportedapredominanceofsstr2and/orsstr1inneuroendocrineGEPtumors.NoDTCtissuewasstudied.Incontrasttothehighconcentrationofsstr1andsstr2inGEPtumors,invitrostudieswithmonolayersofthyroidcancercelllinesandxenograftsshowedpredominantexpressionofsstr3andsstr5,withsstr2mRNAdetectedonlyfaintly24.Inanotherreport,whichinvestigatedsstrexpressioninbiopsiesofDTCtumortissuebynorthern-blotanalyses,sstr1,sstr3,sstr4andsstr5wereexpressedinalltumors,butsstr2wasnotdetectedineitherFTCorPTCtumors25.Thesamereportdemonstratedthehighesttumor:backgroundratioandexpressionofhigh-affinitysstr2inmedullarythyroidcarcinomaandHürthlecellneoplasia, includingHürthlecelladenenoma,ratherthanintheclinicallymorecommon,invitrostudiedPTCandFTC.InHürthlecellneoplasia,theexpressionofsstr2isirregular,andtumorswithhigh,intermediateandlowexpressionofsstr2weredemonstrated.ThesefindingsindicatethatthesstrexpressionprofileinDTCcellsisdifferentandmorevariablethaninneuroendocrineGEPtumors,whichmightexplainthevariationofuptakeobservedduringSRS(Figure1).
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Figure 1. SomatostatinanalogscintigraphyimagesfromthreepatientsthatillustratethevariableuptakeofsomatostatinanalogsinDTC.15-minplanarspotimageswereobtained24hafterinjectionof222MBq111In-octreotide.Chestandupperabdomenareshown.Allpatientshadpathologicaluptakeof111In-octreotideinthechest(darkgray–blackareas).Normal,physiologicaluptakeof111In-octreotidebytheliver(apparentasthegrayorganintheleftcornerofeachimage)isusedasreferencetosemi-quantifyuptakebychesttumors.(a)PatienthasPTCmetastatictothelungs(blackarrow)withuptakeof111In-octreotidelowerthannormalliveruptake.(b)PatienthasFTCwithwidespreadmetastaticdiseaseinthelungs(blackarrows)withuptakeof111In-octreotidesimilartoliveruptake.(c)PatienthasrecurrenceofHCTC(blackarrow)andmetastaticlesionsinbone(notshown)withuptakeof111In-octreotidehigherthanliveruptake.
Differences in SRS protocols Inadditiontotheseclinicalfactors,differencesinSRSimagingprotocolsmustalsobetakenintoaccount.Differencesintheamountofinjecteddoseand/orimagingacquisitioncharacteristicscanhaveasignificantimpactontheinterpretationofscintigraphy.Themethodologyusedis,therefore,importantbecausethismightleadtodifferencesinthesensitivityofSRS.Foroptimalandstandardizedimaging,guidelinesforSRSwith111In-octreotidewerepublishedin200126,butonlythreeofthe10studiesinTable2havebeenperformedinaccordancewiththese.Insomeclinicalcenters,onlyhalfoftherecommendeddoseof222MBqwasused.Furthermore,high-speedwhole-bodyscanning(>3cmmin-1)wasperformedfrequently,ratherthantherecommended≥10minplanar-spotimaging,whichindicatessuboptimalimaging.However,addingsingle-photonemissioncomputedtomography(SPECT)imaging,whichallowsamorepreciseanatomicdelineationthanplanarimaging,resultedinsimilarsensitivitytotheSRSstudiesthatfollowedtheguidelines.ThisunderlinestheimportanceofSPECTandtheinjectionofsufficientradioactivedoseinSRStoobtainthebestpossibleimagingwiththelowestnumberoffalse-negativecases.
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�Table 2. Differencesintheused111In-octreotidescintigraphyprotocolsa
Study year
Diagnostic 111In-octreotide scintigraphy protocol Guidelines b Refs
Dose(MBq)
Images Acquisition (Y/N)
Scanduration Timeafterinjectionc
1995 110 WBS NA 4h,24hand48h N [10]
1996 120-200 WBS;SPECT 10cm/min 4h,24hand48h N [11]
1996 220 Planarspotimages 15min 24hand48h Y [12]
1998 137-200 Planarspotimages 5minand10min 1h,4hand24h Y [16]
1999 111 WBS;SPECT 8cm/min 24hand48h N [17]
2001 110-170 WBS;SPECT 10cm/min 4hand24h N [19]
2001 222 Planarspotimages;SPECT 15min 24hand48h Y [13]
2003 111 WBS;SPECT NA 24hand48h N [14]
2004 200 WBS;SPECT 10cm/min 4hand24h N [15]
2004 110WBS;PlanarspotImages;SPECT
10cm/min(WBS);10min(planarspotimages)
4h,24hand48h N [18]
a Abbreviations: MBq, megabecquerel; NA, not available; SPEC T, single-photon emission computed tomography; WBS, whole-body scan; b Y = 111In-octreotide scintigraphy following the procedure guidelines for somatostatin receptor scintigraphy as described before [26]; N = different protocol c the 48h post injection scan was only performed when high background uptake was present on the 24h post injection scan to increase the sensitivity
NOVEL RADIOLABELED SOMATOSTATIN ANALOGS IN DTC Alternative radiolabeled somatostatin analogs are under investigation forSRS27,28.Gabrieletal.29studiedtheuseofanewradiolabeledsomatostatinanalog99mTc-EDDA/HYNIC-TOC [99mTc- labeledhydrazinonicotinyl (HYNIC)-Tyr3-octreotide(TOC)coupledwithethylenediaminediaceticacid(EDDA)asaco-ligand] in 54patientswith thyroid cancer andno radioiodineuptakeduringWBS.Therationaleforconductingthisstudywerethefavorablecharacteristicsof99mTc-EDDA/HYNIC-TOCscintigraphycomparedwith111In-octreotidescintigraphy,suchaswideravailabilityoftheradionuclide,shorteracquisitiontimeandhigher
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spatialresolution30.Asensitivityof66%for99mTc-EDDA/HYNIC-TOCscintigraphyinpatientswithDTCwas reported.Furthermore, itdemonstratedapositivecorrelationbetweentrue-positivefindingsandelevatedserumTglevels.Inaddition,directcomparisonofbothSRSmodalitieswasperformedineightpatients.Onediscordantfindinginfavorof99mTc-EDDA/HYNIC-TOCscintigraphywasreported.Althoughtheseresultsindicatethatbothradiopharmaceuticalshaveasimilaraffinityprofileforthedifferentsomatostatinreceptorsubtypes,thisremainstobeproven.Furtherstudiesarenecessarytoassesstheaffinityprofileof99mTc-EDDA/HYNIC-TOCandthevalueof99mTc-EDDA/HYNIC-TOCscintigraphyinclinicalpractice.
Recently,Rodrigues et al. 31 reported results of in vitrobinding studies andSRSof twoother radiolabeledsomatostatinanalogs; 111In-coupled to 1,4,7,10-tetraazacyclododecane(DOTA)-lanreotide(111In-DOTA-LAN)andDOTA-D-Phe1-Tyr3-octreotide (111In-DOTA-TOC).SRSwithbothradioligandsdemonstratedtumor-relateduptakein17outof18patients(94%).Eachradioliganddemonstratedanequalnumberoflesionsinradioiodine-negativeandinradioiodine-positivepatients. 18F-FDGPETimaginginthesamepatientsdetectedfewertumorlesionsin15outof18(83%)patients.
Inaddition,thenovelradiolabeledsomatostatinanalog,[111In]DOTA-1-Nal3-octreotide(111In-DOTANOC),whichbesideshighaffinityforsstr2,alsohashighaffinityforsstr3andsstr5,isofinterest28.Becauseofthisaffinityprofile,whichclearlydiffersfromthatof111In-octreotide,thisanalogholdspromiseforbettertumorimaginginpatientswithnon-radioiodine-avidDTC.
THERAPY WITH RADIOLABELED SOMATOSTATIN ANALOGS Despitethedifferencesinsensitivity,andvariationsintheexpressionofsomatostatinreceptorsubtypesanduptakeduring111In-octreotidescintigraphy,SRShasadditionaldiagnosticvalueindeterminingeithertheextentofmetastaticdiseaseorrecurrencesinDTC.Furthermore, theuptakeof 111In-octreotide in tumorsites, imagedbySRS,indicatessomatostatinreceptorsonthetumor-cellsurface,whichmightbeapotentialtherapeutictargetforsomatostatinanalogssuchasoctreotideinpatientswithDTCforwhomthereisnoalternativetreatment.However,reportsontheuseofthesenon-radioactivesomatostatinanalogstotreatpatientswithnon-radioiodine-avidDTCtumorsarescarceandevidenceoftherapeuticbenefitislimited(Box1).AnothertherapeuticapproachinpatientswithuptakeonSRSistumor-targetedtherapywithradiolabeledanalogsofsomatostatin.Thisapproach,calledpeptidereceptorradionuclidetherapy(PRRT),isknowntobeeffectiveinneuroendocrineGEPtumorswithseveralradiolabeledsomatostatinanalogs(Reviewedin20).
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InthefirstclinicalPRRTstudy,patientswithSRSpositivetumors,fiveofwhomhadDTC,weretreatedwithhighdosesof111In-octreotide35.PRRTresultedinstablediseaseinonepatientwhereastheotherfourhadprogressivedisease.InpatientswithneuroendocrineGEPtumors,2–17%hadapartialremissiondeterminedbyclinical imagingand/orbiochemicalparameters 35-37.Althoughtheresultswerepromising,mostPRRTstudiesthatfollowedusedβ-particle-emittingradionuclidessuchas90Yand177LuinsteadoftheAugerelectronemitting111In.β-particle-emittingradionuclideshavegreatertherapeuticpotentialbecausetheemittedparticlerangeexceedsthecelldiameter 38-40.Furthermore,theabilitytoirradiateneighboringcellsisanadvantageintumors,whicharecharacterizedbyaheterogeneoustissuedistributionofsomatostatinreceptors,withregionsofhighdensitynexttoregionsthatdonotexpressthereceptor41.
Inadditiontotheintroductionofβ-particle-emittingradionuclides,structuralchangesintheanalog,suchasinsertionoftyrosine(Tyr3-OCorTOC)andreplacementoftheC-terminalthreoninolwiththreonine(TATE), increasedtheaffinityforthesstr242.Asexpected,clinicalandpre-clinicalstudiesinwhichsomatostatinanalogswerecoupledtoeither90Yor177Luweremoresuccessfulintermsoftumorshrinkagethansomatostatinanalogscoupledto111In43-46.Theresultsoftreatmentwiththeβ-particle-emittingradiolabeledsomatostatinanalogs90Y-DOTA-TOCand
Box 1.TreatmentofDTCwithnon-radioactivesomatostatinanalogs
Zlocketal.32treatedfourpatientswithDTCwithrelativelyhighdoses(4mgdaily)ofnon-radioactiveoctreotidesubcutaneouslyforupto12months:eachshowedprogressivediseaseundertherapy.However, theexpressionof thesomatostatinreceptor inbiopsied tumor tissueanduptakeof111In-octreotideduringSRSwasnotevaluated,whichmakesitdifficulttoevaluatetheeffectofoctreotidetreatmentinthisstudy.Inamorerecentreport,Robbinsetal.describedtwopatientswithwidelymetastaticPTCwho,becauseoffailureofconventionaltreatment,weretreatedwithmonthlyinjectionsofaslow-releaseformofoctreotide(SandostatinLARdepot®)33BothpatientshadvisibleuptakeinthelungsonSRS.18F-FDGPETscansbeforetherapyand3–4monthsafterthestartofthemonthlyinjectionsofsandostatinLARshowedareductionofstandarduptakevaluesinbothpatients,whichsuggestedoctreotide-inducedreductionofmetabolicactivityinthetumors.However,noeffectontumorsizeand/orserumTglevelswasreported.Despitetheabsenceofanobjectiveresponse,onepatientshowedclearclinicalimprovementwhereastheotherexperiencednochangeinclinicalsignsandsymptoms.Alternativeexplanationsfortheobservedreducedmetabolicactivity,suchasinhibitionofinflammatorycellsandinhibitionofrevascularizationorangiogenesis,weresuggested.Theseearly,limitedstudiesindicatethatoctreotideislikelytobeoflimitedvalueinthemanagementofpatientswithDTC,andnofurtherstudieshavebeenpublishedsince2000.Recently,anovelsomatostatinanalog,SOM230,hasbeenintroduced34.Comparedwithoctreotide,thebindingaffinityofSOM230forsstr1,sstr3andsstr5is30x,5xand40xhigher,respectively,and2.5xlowerforsstr234.Inaddition,thefavorableeliminationhalf-lifeofSOM230(23h),makesitsuitableforclinicalapplication.Therefore,it isofinteresttostudytheanti-tumoreffectsofthissomatostatinanalogwithabroadersomatostatinreceptorprofilethanthesomatostatinanalogsthatarecurrentlyavailable.
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177Lu-DOTATATE inpatientswithneuroendocrineGEP tumors are themostencouraging,with24–33%ofpatientsexperiencingeithercompleteorpartialremission20.
Inadditiontotheuseof90Y-and 177Lu-labeledsomatostatinanalogsfortreatingpatientswithneuroendocrineGEP tumors, patientswithnon-radioiodine-avidDTChave also been treated.Recently,wehave reported the results ofthefirstpatientswithDTCtreatedwith 177Lu-DOTATATE47andreviewedtheavailableclinicalPRRTstudiesthatreporttheoutcomeofPRRTinpatientswithDTC14,19,29,35,44,48,49.Additionally,Stokkelet al.50reportedtheirresultsofhigh-dose(~15–30GBq)therapywith111In-octreotideinpatientswithprogressiveradioiodine-non-responsivethyroidcancer.Table3summarizestheavailablereportsofPRRTon62patientswithDTC.Inthisgroup,fivepatients(8%), includingtwowithHCTC(Box2),hadanobjectivetumorresponseand26patients(42%)hadstabledisease.Time-to-progressiondatawereeithernotavailableorreportedfor<1year.Comparingthesestudies,someofwhichincludeonlyafewpatients,isdifficultbecauseofdifferencesintheradionuclides,somatostatinanalogsandmaximumdosesadministered.Nevertheless,itisclearthattheradiolabeledanalogsthathavebeenevaluated,PRRTislesseffectiveinDTCthaninneuroendocrineGEPtumors.
THE FUTURE OF PRRT IN DTC Mostof theradiolabeledsomatostatinanalogsthatareusedfordiagnosticandtherapeuticpurposesbindwithhighaffinitytosstr2andwithloweraffinityfortheotherreceptorsubtypes.InDTC,studiesindicatethattheexpressionofthedifferentsomatostatinreceptorsubtypesismorevariablethaninneuroendocrineGEPtumorsinwhichsstr2isexpressedpredominantly.Theongoingdevelopmentofsomatostatin-basedradioligandswithabroaderreceptorsubtypeprofile is,therefore,ofinterest51.Wildet al.28reportedthefirstpreclinicaldataonthenovelradiolabeled(111Inand90Y)somatostatinanalogDOTANOCthathashighaffinityforsstr2,sstr3andsstr5.Theybrieflymentionedexcellentimagequalityinthefirstscintigraphystudieswith 111In-DOTANOCinpatientswiththyroidcancer.It isassumedthatDOTANOClabeledwitheither90Yor177Luwillhavesimilarfavorablebindingpropertiesand,therefore,mightbecomeavailabletotreatpatientswithDTC.PreliminaryresultsofSRSandPRRTwith111Inand177Lu-DOTANOC,respectively,areencouraging52.
204
�
Tab
le 3
.Peptidereceptorradionuclidetherapyin62patientswithdifferentiatedthyroidcarcinom
aa
Stu
dy
year
nT
um
or
clas
sifi
cati
on
PD
bef
ore
PR
RT
Rad
iop
har
mac
euti
cal
Cu
mu
lati
ve d
ose
Res
po
nse
b (T
TP
in m
on
ths)
Ref
s
(Num
bero
fpatients
outo
ftotal)
Radionu
clide
Chelator
Peptide
(GBq)
2001
33H
CTC
3/3
90Y
DOTA
TOC
1.7-9.6
1SD(21);2PD
[19]
2001
73FTC;4PTC
7/7
90Y
DOTA
TOC
1.7-14.8
2SD
(8,8);5PD
[48]
2002
22PT
CNA
90Y
DOTA
TOC
>7.4
NA
[49]
2002
51F
TC;4PTC
4/5
111 In
DTPA
Octreotide
29.5-83.2
4PD
;1SDc (N
A)
[35]
2002
2525unclassifiedTC
25/25
90Y
DOTA
LAN
0.9-7.0
3MR(N
A);11SD(N
A)
[44]
2003
11H
CTC
NA
90Y
DOTA
TOC
NA
NA
[14]
2003
53FTC;2PTC
NA
90Y
DOTA
TOC
5.6-7.6
5SD
(5)
[29]
2004
94FTC;5PTC
9/9
111 In
DTPA
Octreotide
14.3-33.1
4SD
(NA);5PD
[50]
2005
51F
TC;1PTC;3HCTC
3/5
177 Lu
DOTA
TATE
22.4-39.1
1PR(22+);1MR(4
3);
2SD
d(18,24
+);1PD(4
)[47]
a A
bbre
viat
ions
: 111 In
, 111 In
dium
; 90Y,
90Yt
triu
m; 17
7 Lu, 17
7 Lute
tium
; DO
TA, 1
,4,7
,10
-tet
raaz
acyc
lodo
deca
ne-1
,4,7
,10
-tet
raac
etic
aci
d; D
TPA
, die
thyl
enet
riam
ine
pent
aace
tic
acid
; FT
C, f
ollic
ular
thy
roid
car
cino
ma;
GB
q, g
igab
ecqu
erel
; HC
TC
, Hür
thle
cel
l thy
roid
car
cino
ma;
LAN
, lan
reot
ide;
n, n
umbe
r of
pat
ient
s; N
A, n
ot a
vaila
ble;
PT
C,
papi
llary
thy
roid
car
cino
ma;
TA
TE, T
yr3 -T
hr8 -o
ctre
otid
e; T
C, u
ncla
ssifi
ed t
hyro
id c
arci
nom
a; T
OC
, Tyr
3 -oct
reot
ide;
TTP
, tim
e to
pro
gres
sion
; b
MR
, min
or r
emis
sion
: bet
wee
n 25
% a
nd 5
0%
red
ucti
on in
tum
or si
ze; S
D, s
tabl
e di
seas
e: <
25%
red
ucti
on o
r in
crea
se in
tum
or si
ze; P
D, p
rogr
essi
ve d
isea
se: >
25%
incr
ease
in
tum
or s
ize;
PR
, par
tial
rem
issi
on: >
50
% r
educ
tion
in t
umor
siz
e;
c pa
tien
t ha
d pr
ogre
ssiv
e di
seas
e be
fore
the
rapy
d one
pat
ient
had
pro
gres
sive
dis
ease
bef
ore
ther
apy
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alog
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6.2
CONCLUDING REMARKS Inpatientswithrecurrentand/ormetastaticnon-radioiodine-avidDTC,SRScandemonstratetumorsitesinasubstantialpercentageofpatients.Therefore,SRSisusefulfor imagingandtolocalizetumorsites inpatients inwhomdiseaseissuspectedbecauseofelevatedserumTglevelbutwhoarewithoutapparentuptakeduringpostradioiodinetherapyWBS.LocalizationwithSRSmightbehelpfulinthefurthermanagementofthesepatients.ThesensitivityofSRSislikelytodependonthetumorsize,theextentofdiseaseandtheexpressionofthedifferentsomatostatinreceptorsubtypes.
InpatientswithuptakeonSRSwhohavenoalternativetherapeuticoptions,SRScanselectpotentialcandidatesforPRRT.WhenconventionaltreatmentisnolongeranoptionandSRSshowssufficientuptakeof 111In-octreotide,PRRTshouldbeconsideredasanalternativetherapy.
Researchintoradiolabeledsomatostatinanalogsthathavehighbindingaffinitytothedifferentsstrsubtypesisunderway.Thismightintroducemorereceptorsubtype-specificSRSand,thereby,moreeffectivePRRTforpatientswithDTCinthefuture.
Box 2.PRRTinpatientswithHCTC
InviewoftheirtherapeuticoptionspatientswithHCTCareofspecialinterest.Ingeneral,mostpa-tientswithHCTCdonotaccumulateradioiodineand,therefore,areunlikelytobenefitfromradioio-dinetherapy.Consequently,localrecurrencesand/ormetastasesaftertheinitialtherapyaredifficulttomanage,whichgivesthediagnosisofHCTCtheworstprognosiswithinDTC.Newtherapeuticoptions,suchasPRRT,areofinterestbecauseanalysisofthereportssummarizedinTable1showsthat35outof39(90%)HCTCpatientswithprovenresidualdiseasehaddetectableuptakeof111In-oc-treotideduringSRS.Assuggestedpreviously47,thisislikelytoresultfromhigherexpressionofsstr2inHCTC,whichgivesamorefavorableprofileoftheexpressionofsomatostatinreceptorsubtypescomparedwithPTCandFTC.However,alargeprospectiveclinicaltrialofPRRTforHCTCisunlikelybecauseoftherarityofthiscondition.Thus,substantialevidenceoftheeffectivenessofPRRTinHCTCisunlikelyinthenearfuture.Therefore,althoughtheresultsinHCTCpatientstreatedwithPRRT,suchasexcellentpalliationandprolongedstabledisease,minorremissionorpartialremissionareanecdotal14,19,47,PRRTmustbeconsideredasanalternativetherapywhenconventionaltreatmentisnolongeranoptionandSRSshowssufficientuptakeof111In-octreotide.
206
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6.2
7 Summary and general discussion
212
Theconceptofradiolabelledpeptideanaloguestotargetcellmembrane-boundreceptors issubjectofan increasingnumberofresearchprojectsandsourceofinspirationformanyresearchersthroughouttheworld.ThefirstapplicationofradiolabelledpeptidesinthehumanwasintroducedbyKrenningetal. in19891.ThesomatostatinanalogueTyr3-octreotidewaslabelledwith123Iandscintigraphytolocalisesomatostatinreceptorpositivetumourswasestablished.However,theuseof123I-Tyr3-octreotideforscintigraphyhadseveralmajordrawbacksregardingitsmetabolicbehaviour,preparationdifficultiesandtherelativelyshortphysicalhalf-lifeoftheradionuclide2.Therefore,anotherradiolabelledanalogueofsomatostatin,111In-DTPA-D-Phe1-octreotidewasintroducedwhichhadseveraladvantagessuchaseasypreparation,generalavailability,appropriatehalf-lifeandabsenceofmajorinterferenceintheupperabdominalregion.In1994,111In-DTPA-D-Phe1-octreotide(OctreoScan®)wasapprovedbytheU.S.FoodandDrugAdministration(FDA)andsincethenOctreoScan®hasbecomeacommonlyusedimagingtechniquetodiagnoseneuroendocrinetumours,suchascarcinoidsandneuroendocrinetumoursofthepancreas.Thesetumourshaveahighexpressionofsomatostatinreceptors,especiallythereceptorsubtype2,incommon3.
Thenextlogicalstepinthisfield,madebyKrenninget al.wastouseradiolabelledsomatostatinanaloguesfortherapyinthosepatientswithneuroendocrinetumours,whohadsomatostatinreceptorpositivetumoursonscintigraphyandinoperabledisease4.Thiswasanimportantnewapproachinthesepatientssinceformostofthesepatientsnoeffectivesystemicanti-tumourtherapy,besidesaggressivechemotherapy,wasavailable.
ThefirstradiolabelledsomatostatinanaloguetherapyinpatientswithadvancedstageneuroendocrinetumourswasbasedontheadministrationofhighdosagesofthetherapeuticAugerelectronemitting111Indium-octreotide.Thetotalcumulativedosevariedfrom3.1GBqupto160GBq.However,besidesencouragingandpromisingresults,suchasbiochemicalreponsesandclinicalbenefitintermsofsymptomaticcontrol,onlysmallnumbersofpatientswithanobjectivemorphologicalresponsewerereported5-7.Therefore,severalresearchgroups,whoinitiallytreatedtheirpatientswith111Indium-octreotide,developedsomatostatinanaloguesthatcouldbelinkedwithaβ-emittingradionuclide,suchas90Yttrium(90Y)or177Lutetium(177Lu).Fortheseradionuclidesabetterefficacywasexpectedduetothelongerradiationpathlengthoftheemittedβ-particlesincomparisonwiththerelativelyshortrangeofAugerelectronsemittedby111Indium.Studieswithvarioussomatostatinanalogueslabelledwiththeβ-emittingradionuclide90Yfollowedandbetterefficacyintermsofthepercentageofpatientswithobjectivetumourresponseswasdemonstrated.Shortlyafterthestartoftheclinicalstudieswith90Y-labelledsomatostatinanalogues,peptidereceptorradionuclidetherapy(PRRT)withtheβ-emittingradionuclide
Sum
mar
y an
d ge
nera
l dis
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177LutetiumcoupledtothesomatostatinanalogueoctreotatewasstartedinRotterdamforthetreatmentofpatientswithinoperableandormetastasisedneuroendocrinegastroenteropancreatictumours(GEP-NETs).
The aimof this thesiswas to evaluate the efficacyof treatmentwith [177Lu-DOTA0,Tyr3]octreotate(177Lu-DOTATATE)therapyinpatientswithsomatostatinreceptorpositiveGEP-NETsintermsoftoxicity,effectsontumoursizeandnumber,side-effectsandqualityof life.Furthermore, itwasquestionedwhether 177Lu-DOTATATEor177Lu-DOTATOCmightbetheradiolabelledanalogueofchoiceinthisformofPRRT.Alltheseaspectsarediscussedinchapter2-5ofthisthesis.
Since177Lu-DOTATATEtherapydemonstratedfavourableclinicalefficacyinGEP-NETs,othersomatostatinreceptorpositivetumourswereconsideredascandidatesforthistherapyandsubsequentlypatientswithnon-radioiodineaviddifferentiatedthyroidcarcinoma,whohadnoalternativetreatmentoptionleft,weretreated.FeasibilityofPRRTwith177Lu-DOTATATEtherapyinthesepatientsisdescribedinchapter6.Inaddition,stagingwithradiolabelledsomatostatinanaloguescintigraphyandtheuseof 177Lu-DOTATATEtherapyindifferentiatedthyroidcarcinomaisreviewed.
An overview of themanagement of patients with GEP-NETs is given inchapter 1.1.Togetherwithalargenumberofothertherapeuticoptionscurrentlyavailable,PRRTwithradiolabelledsomatostatinanaloguesisputintoperspective,addressingimportantresultsandfindingsofeachtherapysuchastoxicity,side-effects,outcomeandsurvival.AnextensiveoverviewofPRRTinpatientswithGEP-NETs,isgiveninchapter 1.2.Theaimsandoutlineofthisthesisarepresentedinchapter1.3.
In chapter 2.1thefirstresultsof177Lu-DOTATATEtherapystudiedin35patientswithGEP-NETs ispresented.Side-effectsofandtoxicityafter treatmentwith177Lu-DOTATATEareinfrequentandmostlytransient,withmildbonemarrowdepressionas themostcommonfinding.Although themainobjectiveofourstudywastoevaluatethefeasibilityofthetreatmentintermsofside-effectsandtoxicity,thereportedeffectsontumoursizewithcompleteandpartialremissionin38%ofpatients compared favourablywith theearlier reportedPRRTwith[90Y-DOTA0,Tyr3]octreotide(90Y-DOTATOC)andthereportedoutcomeofmosttrialswithchemotherapy.However,inclusionofmorepatientswasnecessarytoprovetheseearlypreliminaryfindings.Theresultsinalargernumberofpatientsarepresentedinchapter 2.2,inwhichthefavourableobjectiveresponsesasdescribedinchapter2.1wereconfirmedwithminor,partialorcompleteresponsein47%of125evaluablepatients.Furthermore,wewereabletodelineatepredictivefactors
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oftumourresponse.Ahighuptakeonpretherapy111In-octreotidescintigraphyandlimitedliverinvolvementwerepredictiveforafavourableresponse,whereas,ingeneral,patientswithalowKarnofskyPerformanceScoreand,toalesserextent,ahightumourloadbeforetherapyhadahigherriskofprogressivedisease.Fromtheseresultsweconcludedthatearlytreatment,eveninpatientswithoutevidenceofprogressionorsymptoms,maybebetter.Comparisonofourresults in 177Lu-DOTATATEtreatedpatientswithstudiesinwhich90Y-DOTATOCwasused,isdifficult,asbesidesdifferencesinstudydesign,protocolandadministereddosages,patientselectioncouldhaveinfluencedthestudyoutcome.Therefore,untilnow,itisnotprovenwhichradiolabelledsomatostatinanaloguecanberegardedasthemostoptimalforPRRTinGEP-NETpatients.
Anotherinterestingfindingdescribedinthischapterwasthedecreaseofuptakeonthelastposttherapyscancomparedwiththefirstposttherapyscan,whichwasfrequentlyseeninpatientswhoeventuallyhadobjectivetumourregressiononcomputedtomography.Also,inpatientswhohadstablediseaseoratumoursizereduction,themediantimetoprogressionwasmorethan36months.AdirectcomparisonwithchemotherapeuticregimenswasnotperformedaschemotherapyisrelativelyineffectiveinpatientswithinoperableGEP-NETs.Therefore,wecomparedourresultswithhistoricaldatafromearlierstudieswith,mostly,chemotherapyasthefirstoptionofcytoreductivetherapyininoperableGEP-NETs.Highvariationinreportedobjectivetumourresponsesmadeitdifficulttomakethatcomparison.However,moststudiesreportedaresponsedurationoflessthan18months,whereasthemediantimetoprogressionafter177Lu-DOTATATEtherapywaslongerthan36months.Furthermore,toxicityofmostchemotherapeuticregimensismoresevereandmorefrequentthanwith177Lu-DOTATATEtherapy.However,sinceourstudyisongoingandthemediantimeoffollow-upis16months,evaluationatalatertimepointwillprovidemoredefiniteevidenceoftheseobservations.
Asdescribedinchapter 3,thequalityoflifeofpatientstreatedwith177Lu-DOTATATEtherapyimproves,especiallyinpatientswhohaveanobjectivetumourresponseorstabledisease.Tooursurprise,thequalityoflifeinpatientswhohadprogressivediseasedidalsoshowsignificantimprovement.Besidebiasfromaplaceboeffect,anotherexplanationofthisunexpectedresultmightbetherelativelylownumberofpatientsinthisgroup,causedbythefactthatpatientswithhighlyaggressivetumourswerenotabletofilloutthequestionnaireorevendiedbeforethelast intendedtherapeuticcyclewasgiven.Therefore,theinterpretationofthedatainthiscategoryofpatientsisdifficultandhastobelookedatwithcaution.Inadditiontotheglobalhealth-relatedqualityoflife,thescalesofrole,emotional,andsocialfunctionaswellasthesymptomscalesfatigue,painandthesingleiteminsomniaimprovedsignificantlyafterPRRT.Finally,weconcludedthatthefavourableobjectivetumour
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responsesfoundinourpatientswereaccompaniedbyanimprovementoftheirhealth-relatedqualityoflifeinmostpatients.
Inchapter 4, theshort-and long-termeffectof 177Lu-DOTATATEtherapyonendocrinefunctionisdescribedanddiscussed.AsPRRTisasystemictherapyandmanyendocrineorgansareknowntopossesssomatostatinreceptors,theseorgansarepotentialunwantedtargetsofPRRT.Inlinewiththeobservationsinmentreatedwithhighdosesof radioiodineafter thyreoidectomybecauseofdifferentiatedthyroidcarcinoma8,ourmalepatientsdemonstratedatemporarilydecreaseofinhibinBlevelsandamirroredcourseofFSHlevels.Althoughnosemenanalysiswasperformed,thisindicatedatemporarilyimpairedspermatogenesis.Increasedserumlevelsofgonadotropinsandsubnormalserumlevelsoftestosteronewerealsodocumentedinmenwithrectalcarcinomatreatedwithexternalbeamradiation9.Becausenodirectevidenceofthepresenceofsomatostatinreceptorproteininthetestesisavailableandbecauseofthesimilarityofthesefindingsinmentreatedwithhighdosesofradioiodineorexternalbeamradiationinproximityofthegonads,thisobservedradiotoxicityisprobablynotsomatostatinreceptorrelated.Moreobviousreasonsareradiationfromthecirculationand(scattered)radiationinproximityoftheradiosensitivegonadssuchasthebladderurineorfaecesfromtherectumafterPRRT.
Another interestingobservation is thedecreaseofbothLHandFSH levels inpostmenopausalwomen.Thisdecrease ismore thancouldbeexpected fromageingalone10.Assomatostatinreceptorsarepresentinthepituitaryandbecausepostmenopausalwomenlackthepremenopausalnegativefeedbackmechanism,areceptordependentradiationdeliverymechanismislikely.
Althoughremainingwithinthereferencerange,themeanFT4levelofthegroupavailableforthyroidhormoneanalysesdecreasedsignificantly.Furthermore,twopatientsdevelopedprimaryhypothyroidismduringandafter 177Lu-DOTATATEtherapy.Whethertheoccurrenceoftheprimaryhypothyroidismcasesinourseriesofpatientsiscausedbythe177Lu-DOTATATE,orcanberegardedasnormalincidenceofthediseaseisdifficulttodetermine.However,theobserveddecreaseofthemeanFT4levelissuggestiveforasomatostatinreceptor-mediated,butlimitedradiationdosetothethyroidglandresultinginthesubtledecreasedemonstrated,whichisprobablynotclinicallyimportant.Furthermore,wedemonstratedadecreaseofmeanrT3levelsdirectlyafter 177Lu-DOTATATEtherapy,whichwaselevatedatbaseline.Thisdecreaseissuggestiveforachangeindiseasestatusaccordingtotheobservedchangesofthyroidhormonelevelsinpatientswithchronicdiseasewiththenon-thyroidalillnesssyndrome11.Noadrenalinsufficiency,aswasassessedbyalow-doseACTHstimulationtest,wasobservedinpatientsbeforeandafter
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177Lu-DOTATATEtherapy.Additionally,fivepatientsdevelopedelevatedlevelsofHbA1cwithoutanyobviouscausesuchaspancreaticsurgery.Becausepancreasisletsareknowntoexhibitsomatostatinreceptors,areceptor-mediateddetrimentaleffectof177Lu-DOTATATEtherapyontheglucosehomeostasiscannotbeexcluded.Alsotheeffectofchronic‘cold’somatostatinanaloguetherapyinthesepatientsmighthavecontributedtothisobservation.Overallweconcludethatpatientswhoaretreatedwith177Lu-DOTATATEtherapymaydevelopradiation-inducedhormonedisturbances,someofwhicharetemporary,butwhichingeneralaremild.Althoughthetreatingphysicianshouldbeawareofthepossibilityofhormonalchanges,suchasinyoungmenplanningtohavechildren,177Lu-DOTATATEtherapy,intermsofendocrinesequelae,canberegardedassafe.
Todatemanydifferentsomatostatinanalogueshavebeensynthesised,whichexhibitdiverseaffinityprofilesforthecurrentlyknownsomatostatinreceptorsubtypes.Toevaluatewhichanaloguehasthebestprofileregardingtheidealbalancebetweenuptakeinthetumour(s)anddose-limitingorgansortherapeuticwindowwecomparedthe twomostcommonlyusedsomatostatinanalogues inPRRT,DOTATATEandDOTATOC,coupledto177Lu.Theresultsofthisstudyaredescribedinchapter 5.AdirectcomparisonbetweenbothanaloguesinaPRRTsettingwasperformed.Residencetimesoftheradioactivity,whicharedirectlyrelatedtoabsorbedtumourdose,withinthespleen,kidneysandtumourswaslongerwiththeuseof177Lu-DOTATATEthan 177Lu-DOTATOC.Theratiosofmeanresidencetimeof177Lu-DOTATATEversus177Lu-DOTATOCwere1.5,1.4and2.1,forspleen,kidneysandtumours,respectively.Consequently,higherabsorbedtumourdosesareexpectedtobeachievablewith 177Lu-DOTATATEthanwith177Lu-DOTATOC.Thehigherkidneyresidencetimewiththeuseof177Lu-DOTATATEcanbeaprobleminPRRT,asbesidethebonemarrow,thekidneysareoneofthedoselimitingorgans.However,inanycaseofPRRTinwhichthedoseis limitedbecauseofreachedmaximumcalculateddosetothekidneys(23Gy)theabsorbeddosewithinthetumour(s)willstillbehighersincethemeantumourresidencetimeratio(2.1)exceedsthemeankidneysresidencetimeratio(1.4)withafactorof1.5infavourof177Lu-DOTATATE.Furthermore,inmostofourpatientsthebonemarrow(maximumalloweddoseof2Gy)isthedoselimitingfactorinsteadofthekidneys.
Asimilar studywasperformedbyForrer andcolleagues inBasel, comparing111In-DOTATOCwith111In-DOTATATE12.Itwasassumedthatfordosimetrypurposes111Incouldbeusedasasurrogatefor90Y,frequentlyusedforPRRTattheirinstitution.Threeoutof fivepatientsdemonstratedabetter tumour-to-kidneyratiowith111In-DOTATOCcomparedto111In-DOTATATE.Basedonthesedata,itwasdecidedthattheywouldcontinuetousethesomatostatinanalogueDOTATOClabelledwith90YforPRRT.However,theassumptionthat111Inisausefulsurrogatefor90Y,
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isquestionable.Differentradionuclidescoupledtoonesomatostatinanaloguemayhavedifferentaffinityprofiles 13whichsubsequentlymayresultindifferencesinradiopharmaconbiodistributionaswasshowninaneuroendocrinetumourmodelinrats14.Also,thediagnosticquantityofpeptideusedinthestudybyForreret al.wasmuchlessthanthequantitiesusedinPRRT.Differencesinamountofpeptidecanintroducedifferentbiodistributionpatternsaswasdemonstratedbyseveralauthors15-17.Breemanet al.reportedthattheuptakeof 111In-pentetreotideinsomatostatinereceptorpositiveorganswhenpresentedasafunctionoftheinjectedmassoftheradiopharmaceuticalresemblesatissuespecificbell-shapedcurve.Thesamebell-shapedcurvewasdemonstratedinnormaltissueaswellasintumoursbyBernhardtet al. inSSTRpositivetumourbearingnudemice 18.Thus, thebiodistributionpatternscanhaveasignificanteffectontheabsorbedkidneydoseaswellastumourdoseand,thus,onthetumour-to-kidneyratioswhichwerefoundbyForreret al.12.Furthermoreandincontrasttothediagnosticsettingamino-acidco-infusioniscurrentlyusedinPRRTatmostinstitutions.Co-infusionoftheamino-acidslysineand/orarginineinPRRTresultsinasignificantinhibitionofrenalradioactivityand,thereby,hasitseffectonthetumour-to-kidneyratio19.Thus,incontrastwiththestudyfromtheBaselgroup,ourstudyresemblesthetherapeuticsettingbetteronseveralimportantpoints.Furthermore,wecomparedtheresidencetimesinthetumourandkidneys,reflectingabsoluteabsorbedtumourdose,insteadoftherelativeuptakemethodoftumour-to-kidneyratios.
Finally,in177Lu-DOTATATEand90Y-DOTATOCbasedPRRTthecriticalorgansarethekidneysandbonemarrow.Thecorrespondingmaximaltolerateddoses(MTD)forexternalradiationofthesetissuesare23and2Gy,respectively,andareusedasdoseconstraintstoavoidradiation-inducednephropathyandseverebonemarrowtoxicity,suchasmyelodysplasticsyndromeorleukaemia.Inapproximately30%ofthepatientstreatedwith177Lu-DOTATATEtheMTDforthekidneyswasreachedbeforetheintendedcumulativedoseof29.6GBq,whichcorrespondswiththeacceptedMTDforthebonemarrowof2Gy.Theremaining70%ofpatientsreceivedthecumulativedoseof29.6GBq,whichformostpatientsresultedinacumulativedosetothekidneyslessthan23Gy.Thus,onlyinaminorityofthepatientstreatedwith177Lu-DOTATATEthetumour-to-kidneyratioplaysaroleinthemaximumcumulativedoseof29.6GBqgiven.
Incontrast,inpatientswith90Y-DOTATOC,thekidneysmustbeconsideredasthemain,ifnot,theonlydose-limitingorgan,sincetheMTDforthekidneyisreachedbeforethebonemarrowMTDcomesinview20.
Takenintoconsiderationalloftheaforementionedarguments,weconcludedthatDOTATATEhasabettertherapeuticwindowthanDOTATOCandthereforeisthe
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preferredsomatostatinanaloguetobecoupledto177LuwhenusedinPRRT.
Inchapter 6.1,wedescribethefeasibilitytotreatpatientswithdifferentiatedthyroidcarcinoma,whohadprovennon-radioiodineaviddiseaseandwereinoperable,with177Lu-DOTATATE.Fivepatientswithmetastaticdifferentiatedthyroidcarcinoma(3withHürthlecellcarcinoma,1withpapillarythyroidcarcinomaand1withfollicularthyroidcarcinoma)weretreatedwith22.1–30.1GBq177Lu-DOTATATE.AfterPRRT,twopatientshadstabledisease,twohadtumourshrinkageandonehadprogressivedisease.Besidesobjectivetumourresponsefavourabletimetoprogressionwasdemonstrated.Sincethesepatientshadnoalternativetreatmentoptionleft, itwasconcludedthattreatmentwith177Lu-DOTATATEcanbebenificial.Obviously,studieswithalargergroupofpatientsarenecessarytoestablishthetruepotentialofthisapproach.Inaddition,otherradiolabelledsomatostatinanalogues,suchas[DOTA-1-Nal3]octreotidecoupledtoeither90Yor 177Luwhichexhibitadifferentaffinityprofiletothesomatostatinreceptor21,areofinterest.Thissomatostatinanaloguehasinadditiontothehighaffinitytothesomatostatinreceptorsubtype2,favourableaffinitytothesubtypes3and5whichispotentiallymoreeffectiveinthetreatmentofdifferentiatedthyroidcarcinoma.ThisisbecausetheexpressionprofileofsomatostatinreceptorsindifferentiatedthyroidcarcinomaislikelytobedifferentfromGEP-NETs,withevidenceof(co-)expressionofsubtypes3and522.
Inchapter 6.2 thecurrentuseofsomatostatinreceptorimagingandtherapyinnon-radioiodineaviddifferentiatedthyroidcarcinomaisreviewed.TheoverallconclusionregardingscintigraphyisthatitcanbeusefultolocalizetumorsitesinpatientsinwhomdiseaseissuspectedbecauseofanelevatedserumTglevelbutwithoutapparentuptakeduringpostradioiodinetherapywholebodyscintigraphy.Inmorethan50%ofthecasessomatostatinreceptorscintigraphyisabletolocalizediseaseandhencehelpfulinthefurthermanagementofthesepatients.PRRTindifferentiatedthyroidcarcinomahasbeendescribedinonly62patientsupuntilnow.Threedifferentradionuclides(111In,90Yand177Lu)coupledto4differentsomatostatinanalogues(DOTATOC,[DTPA0]octreotide,lanreotideandDOTATATE)wereusedwithcumulativedosagesintherangeof0.9to30.1GBq.The90Yand177Lucoupledsomatostatinanaloguesdemonstratedtobethemostpromisingintermsoftumourresponsecomparedto111In,andthereforetheusageofthelatterisnotrecommendedanymoreforPRRTindifferentiatedthyroidcarcinomawhichisalsotrueforPRRTinGEP-NETpatients.
Final conclusionsPRRTwith177Lu-DOTATATEisthechoiceoftherapyinpatientswithinoperable,metastasisedwell-differentiatedsomatostatinreceptorpositiveGEP-NETs.Theoutcomeoftherapyintermsofobjectiveresponse,qualityoflife,timetoprogression
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andpreliminarysurvivalanalysiscomparesfavourablywiththehistoricaldataofalternativetherapeuticapproaches,includingthecurrentlyavailablechemotherapy.Also, side-effectsand toxicityprofileare ingeneral favourable.Furthermore,177Lu-DOTATATEtherapycanbeanoptionaltherapyinselectedpatientswithnon-radioiodine-aviddifferentiatedthyroidcarcinoma.Especiallyinnon-radioiodine-aviddifferentiatedcarcinoma,radiolabelledsomatostatinanalogueswithadifferent,morespecific,somatostatinreceptorprofilemaybepromising.
ToincreasetheeffectivenessofPRRT,administrationofhighercumulativedosestotheindividualpatientcouldbeoneofthemethods.Thiscanonlybeachievedviatheintroductionofindividuallyassesseddosimetryinordertoestimatetheexactdosetothedose-limitingorgans.However,sincethisapproachisdifficult,time-consumingandthereforecostly,individualaccuratepre-therapydosimetryiscurrentlynotavailableinanytherapeuticinstitution23.Furtherresearchtowardspatient-baseddosimetry, includingthekidneysandbonemarrow, isnecessarytoprovidepracticalmethodsfortailoredPRRTsothat itcanbepartofpatientmanagementinthefuture.Furthermore,besidesindividualdosimetrytoprovideoptimaltreatmentdose,thedevelopmentofkidneyprotectiveagentscouldwidenthetherapeuticwindow.Withtheuseofkidneyprotectiveagents,higherdosagescanbegivenwhichcouldincreasePRRTefficacy.
BesidesattemptstowidenthetherapeuticwindowofPRRT,newapproachesforfuturestudiesincludethedevelopmentofnewsomatostatinanalogueswithmorefavourableaffinityprofiles,combinationaltherapywithotherradionuclides,suchas90Yor111In,andtheuseofradiosensitizingagents.Amulti-centrerandomisedcontrolledtrialwith 177Lu-DOTATATEtherapyincombinationwiththeradiosensitizingagentcapecitabineversusmonotherapywith177Lu-DOTATATEhasbeenstartedatourdepartmentin2007.
Finally,theuseofPRRTinpatientswithsomatostatinreceptorpositivetumoursdemonstratesthatatherapybasedonaradionuclidecoupledtoapeptidecanbesuccesfulandholdsgreatpromiseforfuturetreatmentofvariousothercancers.Frequently,newtumour-specific receptorsarediscovered thatmightbecomepotentialtargetsforhighaffinityradiolabelledpeptidesandthusPRRT.Therefore,itisnotunlikelythatPRRTwillbecomeanimportanttherapeuticmodalityinotherpartsofthechallengingfieldofoncology.
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�Hetconceptvanradioactiefgelabeldepeptidendiezichkunnenbindenaanmembraangebondenreceptoreniseeninspiratiebronvoorveelonderzoekersenresulteerdeineengrootaantal interessanteonderzoeksprojectenopditgebied.DeallereerstehumanetoepassingvanradioactiefgelabeldepeptidenwerdgeïntroduceerddoordegroepvanKrenningin19891.HetsomatostatineanaloogTyr3-octreotidewerdgelabeldmetJodium-123(123I).Doormiddelvanscintigrafiemetditradiofarmaconkondenneuroendocriene tumoren,diesomatostatinereceptoren totexpressiebrengen,wordenaangetoond.Hetgebruikvan123I-Tyr3-octreotidehadechtereenaantalnadelenzoalsdehoge fysiologischeactiviteit indebuikna toediening,demoeizameproductiemethodeenderelatiefkortehalfwaardetijd 2.Omdezeproblemen tevoorkomenwerdeenander radioactiefgelabeldsomatostatine-analoogontwikkeld,het111Indium-DTPA-D-Phe1-octreotide(111In-octreotide).Het111In-octreotideheefteenaantalvoordelenzoalsderelatiefgemakkelijkebereiding,degoedebeschikbaarheid,depraktischehalfwaardetijdenminimalefysiologischeopnameindebuik.In1994werd111In-octreotide(OctreoScan®)goedgekeurddoordeAmerikaanseFoodandDrugAdministration.VanafdietijdisscintigrafiemetOctreoScan®demeestgebruiktemethodevoorhetdiagnosticerenvangastro-intestinaleneuroendocrienetumoren,zoalshetcarcinoidendeneuroendocrienetumorenvandepancreas.Dezetumorenhebbeninhetalgemeeneenhogeexpressievansomatostatinereceptoren,metnamevansubtype2ophuncelmembraan3.
Devolgende logischestapopditgebied, tevensuitgevoerddoordegroepvanKrenning,washetgebruikvan radioactief gelabelde somatostatine-analogenvoor therapiebijpatiëntenmet inoperabele, somatostatinereceptorpositieveneuroendocrienetumoren,aangetoondopdeOctreoScan®4.Ditwaseenbelangrijkenieuwetherapeutischebenaderingvoordezegroeppatiënten,aangezieneropdatmomentgeeneffectievesystemischetherapiebeschikbaarwas.
Deeerstetherapiemeteenradioactiefgelabeldsomatostatine-analoogwasgebaseerdophogedosesvanhet 111In-octreotide.DeradiotoxiciteitvanmetnamedeAugerelectronendiedoorhet 111Indiumwordenuitgezondenzijnvanbelangvoorheteventueletherapeutischeeffect.Vanwegehetexperimentelekaraktervandezetherapiekwamenvoornamelijkpatiëntenmetuitgebreidgemetastaseerdeneuroendocrienetumoreninaanmerking.Detotaalgecumuleerdedosisdieaandezepatiëntenwerdgegeven,varieerdevan3,1totenmet160Gigabecquerel(GBq).Hoewelderesultaten,zoalsbiochemischeenklinischeverbeteringen,bemoedigendenveelbelovendwarenkonslechtsineenkleinaantalpatiënteneenobjectiveerbareverkleiningvandetumoren(tumorrespons)wordenaangetoond5-7.Hetisdanooknietverwonderlijkdatverschillendeonderzoeksgroepen,dieeersthunpatiëntenbehandeldenmet111In-octreotide,somatostatine-analogenontwikkeldendiegekoppeldkondenwordenaaneenradionuclidedatbètastralinguitzendt,zoalshet90Yttrium(90Y)of177Lutetium
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(177Lu).Vandezeradionuclidenwaseenbetereeffectiviteitteverwachten,gezienhetlangereemissiepadvandeuitgezondenbètadeeltjes(2-12mm)invergelijkingmetderelatiefkorteafstand(≈10µm)diewordtafgelegddoordeAugerelectronenuitgezonden door het 111Indium (111In). Klinische studiesmet verschillendesomatostatine-analogengelabeldmet90Yvolgdenentoondeninderdaadeenhogerpercentagepatiëntenmeteentumorresponsinvergelijkingmet111In-octreotide.BijnagelijktijdigwerdinhetErasmusMCinRotterdamgestartmetdebehandelingvanpatiëntenmetinoperabeleofgemetastaseerdegastro-intestinaleneuroendocrienetumorenmet177Lugelabeld[DOTA0,Tyr3]octreotaat(177Lu-DOTATAAT).
Hetdoelvanditproefschriftwasomdeeffectiviteitvan177Lu-DOTATAATtherapiebijpatiëntenmetsomatostatinereceptorpositievegastro-intestinaletumorenteevalueren.Hierbijkomenachtereenvolgensdetoxiciteit,bijwerkingen,heteffectopdetumorgrootteendekwaliteitvanlevenna177Lu-DOTATAATtherapieaandeorde.Vervolgensisonderzochtwelksomatostatine-analooghetmeestgeschiktisomtegebruikenbijpeptidereceptorradionuclidetherapy(PRRT)met177Lu;DOTATAATof[DOTA-D-Phe1-Tyr3]octreotide(DOTATOC).Dezeonderwerpenkomenaandeordeinheteerstegedeeltevanditproefschrift(hoofdstuk2t/m5).
Aangezien 177Lu-DOTATAATtherapiesuccesvolbleektezijn inpatiëntenmetgastro-intestinaleneuroendocrienetumoren,werddezetherapiemogelijkookgeschiktgeachtvoordebehandelingvananderesomatostatinereceptorpositievetumoren.Mogelijkekandidatenvoor177Lu-DOTATAATtherapieblekenpatiëntenmetgedifferentieerdschildkliercarcinoom,waarbijdetumornietmeerinstaatwasomradioactiefjodium(131I)optenemen.Voordezespecifiekepatiëntengroepbestaater,naasthetgebruikelijke131I,geengoedealternatievesystemischetherapie.WanneererwelduidelijkeactiviteitsstapelingwerdgezienopdeOctreoScan®werdendezepatiëntenbehandeldmet 177Lu-DOTATAAT.DeeffectiviteitvanPRRTmet177Lu-DOTATAATbijeenaantalvandezepatiëntenisbeschreveninhettweedegedeeltevanditproefschrift(hoofdstuk6.1).Daarnaastiseenuitgebreidoverzichtvande stageringvangedifferentieerdschildkliercarcinoommetOctreoScan®enhetgebruikvanPRRTbijdezespecifiekepatiëntenpopulatieweergegeven(hoofdstuk6.2).
Hoofdstuk 1.1geefteenoverzichtvandebehandelingsmogelijkhedenvanpatiëntenmetgastro-intestinaletumoren.Eengrootaantaltherapeutischeopties,inclusiefPRRTmetradioactiefgelabeldesomatostatine-analogen, isbeschrevenwaarbijuitkomstmatenenbevindingenzoalstoxiciteit,bijwerkingen,therapieresponsenoverlevingsduurtersprakekomen.Hoofdstuk 1.2bevateenuitgebreidoverzichtvanPRRTbijpatiëntenmetgastro-intestinaleneuroendocrienetumoren.Inhoofdstuk 1.3zijnhetdoelendeopzetvanditproefschriftuiteengezet.
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�In hoofdstuk 2.1 zijndeeersteresultatenvan177Lu-DOTATAATtherapiebij35patiëntenmetgastro-intestinaleneuroendocrienetumorenbeschreven.Hetdoelvandezestudiewas ineerste instantiehetevaluerenvandemogelijkheidvanbehandelingvanpatiëntenmet177Lu-DOTATAATmetdaarbijdenadrukopevaluatievandemogelijkebijwerkingenendetoxiciteitvandebehandeling.Toxiciteitenbijwerkingennabehandelingmet 177Lu-DOTATAATkwamennietfrequentvoorenwarenmeestalkortdurend.Tijdelijkemildebeenmergdepressiewasdemeestvoorkomendebijwerking.Naastdezeresultatenzijnookdeeffectenoptumorgroottebeschreven.Completeenpartiëleremissiewerdgevondenin38%vandeonderzochtepatiënten,hetgeeneenbeterresultaatwasdandatvandeeerderbeschrevenPRRTstudiesmet90Y-DOTATOCenchemotherapie.Hetwasechternoodzakelijkomdezeeersteveelbelovendebevindingentebevestigenineengroteregroeppatiënten.Dezeresultatenbijeengroteregroeppatiëntenzijnbeschreveninhoofdstuk 2.2, waarindegoedetherapierespons,zoalseerderbeschreveninhoofdstuk2.1,werdbevestigd.Minimale,partiëleofcompletetumorreponswerdgevondenin47%vande125geëvalueerdepatiënten.VoorspellendefactorenvooreengoederesponswarenzoweleenhogeopnamevanhetradiofarmaconindetumorenopdeOctreoScan®voorafgaandeaandetherapiealsookeenminimalehoeveelheidmetastasenindelever.DaarentegenhaddenpatiëntenmeteenlageKarnofskyPerformanceScoreofeenhogetumorload,eenhogerrisicoopprogressieveziektenatherapie.
Uitderesultatenvanditonderzoekconcludeerdenwijdatvroegebehandelingmet177Lu-DOTATAATtherapie,zelfsbijpatiëntenzonderduidelijkaantoonbaretumorgroei,waarschijnlijktotbeteretherapieresultatenleidt.Eengoedevergelijkingvanonzebevindingenomtrentdebehandelingmet 177Lu-DOTATAATmetderesultatenvan90Y-DOTATOCtherapieismoeilijktegeven,aangeziennaastdeverschilleninstudie-opzet,protocolendehoogtevandegegevendoses,deselectievanbepaaldecategoriënpatiëntendeuitkomstenvanonsonderzoekmogelijkheeftbeïnvloed.Totopdedagvanvandaagishetopbasisvandeklinischestudiesnognietgoedmogelijkomaantegevenwelkradioactiefgelabeldsomatostatine-analoognuechtbeschouwdmagwordenalshetidealeradiofarmaconomtegebruikenbijPRRTinpatiëntenmetgastro-intestinaleneuroendocrienetumoren.
Eenandereinteressantebevindingbeschreveninhoofdstuk2.2isdeverminderde177Lu-DOTATAATopnameophetlaatsteposttherapiescintigraminvergelijkingmetheteersteposttherapiescintigram.MeerderemalenbleekeenverminderingvanopnamesamentegaanmeteenobjectiveerbaretumorresponsopdeCTscan.Ookwerdduidelijkdatbijpatiëntenmetstabieleziekteofregressiealstherapierespons,demedianeperiodetotprogressiemeerdan36maandenbedroeg.Eendirectvergelijkmetchemotherapiewerdnietverricht,aangezienchemotherapierelatiefineffectiefisbijpatiëntenmetinoperabelegastro-intestinaleneuroendocrienetumoren.Wel
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werdenonzeresultatenvergelekenmethistorischedatavanstudieswaarbijmeestalchemotherapiewerdgebruiktalssystemischecytotoxischetherapie.Eengrotevariatieindebeschrevenobjectiveerbaretumorresponsenmaakthetechternogsteedsmoeilijkomdestudiesgoedmetelkaartekunnenvergelijken.Tochkwamnaarvorendatindemeestestudieseenresponsduurvanminderdan18maandenwerdbeschreven,hetgeenduidelijkminderisdandedooronsgevondenmedianeperiodetotprogressievan36maanden.Verderevergelijkingbrachtnaarvorendatdetoxiciteitvandegebruiktechemotherapieschema’sduidelijkernstiger isenfrequenterwerdgeconstateerddanmet177Lu-DOTATAATtherapie.Opditmomentwordenernogsteedspatiëntenindestudiegeïncludeerdenisdemedianeperiodevanfollow-up16maanden.Waarschijnlijkzalevaluatieopeenlatertijdstipmeerdefinitiefbewijsvooronzehuidigebevindingenopleveren.
In hoofdstuk 3wordtdekwaliteitvanlevenvan50patiëntenna177Lu-DOTATAATtherapiebeschreven.DekwaliteitvanlevenwerdbepaalddoormiddelvaneengestandaardiseerdeengestructureerdevragenlijstvandeEuropeanOrganisationforResearchandTreatmentofCancer(EORTC),deEORTCQLQ-C30.Binnendegehelepatiëntengroepverbeterdedekwaliteitvanleven,metnamebijpatiëntendielaterookeengoedetumorresponslietenzien.Totonzeverrassingbleekechterookdekwaliteitvanlevensignificantteverbeterenbijpatiëntendielaterbewezenprogressieveziekteblekentehebben.Naasthetplacebo-effectzalookhetkleineaantalpatiëntenindezegroepeenrolhebbengespeeldbijdezeverrassendeuitkomst.Hetkleineaantalpatiëntendatdegestructureerdevragenlijsthadingevuldisteverklarenuithetfeitdatpatiëntenmetdemeestagressievetumorensomsfysieknietinstaatwarendevragenlijstintevullen.Daaromzijnderesultatenindezecategoriepatiëntennietergbetrouwbaarenmoetenzemetenigeterughoudendheidwordengeïnterpreteerd.
Naastdealgemenekwaliteitvan levenwasereensignificanteverbeteringvaneenaantalzogenaamdefunctioneringsschalen(hetemotioneel,rol(gezin,werk)ensociaalfunctioneren),symptoomschalen(moeheidenpijn)enhetsingleitemslapeloosheid.
Tenslotteconcludeerdenwedateengoedetherapieresponsmeestalgepaardgingmeteenverbeteringvandealgemenekwaliteitvanlevenindeonderzochtepatiënten.
Inhoofdstuk 4 wordt ingegaan op de korte- en langetermijneffecten van177Lu-DOTATAATtherapieopdehormonalefuncties.AangezienPRRTeensystemischtoegediendetherapieisenomdatveleendocrieneorganensomatostatinereceptorentot expressie brengen,wordendeze organenmogelijk blootgesteld aan eenongewenstehoeveelheidstralenbelasting.Wetoondenaandat,netzoalsbijmannen
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�behandeldmethogedoses131Inathyreoidectomie,ereentijdelijkedalingwasvandeconcentratievanhethormooninhibineBvanongeveer24maanden,terwijldeconcentratievanhetFSHeengelijktijdigetijdelijkestijginglietzien.Hoewelergeenanalysevanhetspermavandezemannenwasverricht,gevendezewaardenaandatdespermatogenesetijdelijkverminderdmoetzijngeweest.
Verderwerdduidelijkdat,hoeweldeserumconcentratievanzowelhet totaletestosteronalsvanhetsexhormoonbindendglobulineeendalinglietenzienna177Lu-DOTATAATtherapie,deongebondentestosteronconcentratienietveranderde.Tegelijkertijdwasersprakevaneentijdelijketoenamevandeconcentratievanhetluteïniserendhormoon(LH).Ditsuggereertdathormonalefeedbackmechanismenhebbengezorgdvoorhetoppeilhoudenvandeongebondentestosteronconcentratieinhetbloed.
Verhoogdeserumconcentratiesvandegonadotropehormonenendesubnormaletestosteronconcentratieinhetserumzijnrecentookgerapporteerdbijmannenmetrectumcarcinoomnabehandelingmetexterneradiotherapie9.Omdatergeengoeddirectbewijsisvoordeaanwezigheidvaneiwitexpressievansomatostinereceptorenindetestesenvanwegedeovereenkomstenmetdebevindingenbijmannenbehandeldmethogedoses 131Ienexterneradiotherapie,isdegeconstateerderadiotoxiciteitwaarschijnlijknietgerelateerdaandeexpressievansomatostatinereceptoren.Demeestwaarschijnlijkeoorzaakhiervoorisdaterbestralingvanderadiosensitievetestesvanuitdesystemischecirculatieplaatsvindt.DaarnaastiserookeenbijdragevangescatterdestralingaanwezigdoorradioactieveurineindeblaasofontlastinginhetrectumnaPRRTteverwachten.
EenandereopmerkelijkebevindingisdedalingvanzowelLHalsFSHconcentratiesinpostmenopauzalevrouwen.Dezedalingisduidelijkmeerdanverwachtkanwordenopbasisvanverouderingalleen10.Aangeziensomatostatinereceptorentotexpressiewordengebrachtindehypofyseenomdatpostmenopauzalevrouwenhetpremenopauzale feedbackmechanismemissen, iseenreceptorafhankelijkmechanismeeenvoordehandliggendeoorzaak.
Daarnaastdaaldedegemiddeldeserumconcentratievanhetschildklierhormoonvrij-T4indegroeppatiëntensignificant.Dewaardenblevenechternogruimbinnendereferentiewaarden.Tweepatiëntenontwikkeldeneenprimairehypothyreoidietijdensenna177Lu-DOTATAATtherapie.Hetisechterdevraagofdezehypothyreoidieveroorzaakt isdoordePRRTofdathetbeschouwdmagwordenalsberustendopvariatiebinnendenormalepopulatie.Desubtiele,maarsignificantedalingvandegemiddeldevrij-T4concentratie is echter suggestiefvooreenbeperktreceptorgerelateerdedosiseffect.
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Vandegeobserveerdesubtieledalingmagwordenaangenomendatdezeinhetalgemeenklinischnietrelevantis.
Vervolgenstoondenweaandatereendalingisvandegemiddeldeserumconcentratievan het schildkierhormoon reverse T3 (rT3) direct na behandeling met177Lu-DOTATAATtherapie.DerT3concentratiewasoverigensalverhoogdvoordeeerstetherapie.Eendergelijkedalingisookbeschrevenbijpatiëntenmeteenchronischeziekte,hetzogenaamde“non-thyroidillness”syndroom.EendalingvanhetrT3correleertmetdeernstvandeziekte11.DedalingvanhetrT3bijonzepatiëntenwijstdaarommogelijkopeenveranderingindeernstvandeziekte.
Metbehulpvande lagedosisACTH-stimulatie testwerd aangetoonddatna177Lu-DOTATAATtherapiegeenbijnierschorsdeficiëntieontstaat.
BijvijfpatiëntenwerdenverhoogdeHbA1cwaardengeconstateerd,zonderdatersprakewasvaneenaanwijsbareoorzaak,zoalsbijvoorbeeldpancreaschirurgieinhetverleden.OmdathetbekendisdatdeeilandjesvanLangerhanssomatostatinereceptorentotexpressiebrengeniseenreceptorafhankelijkstralingseffectvan177Lu-DOTATAATtherapieopdeglucosehuishoudingnietuitgesloten.Ookheteffectvanlangduriggebruikvaneen“koud”somatostatine-analoog,hetgeennietongebruikelijkisbijdezegroeppatiënten,kaneventueelhebbenbijgedragenaanonzebevindingen.
Inhetalgemeenconcludeerdenwedatpatiënten,behandeldmet177Lu-DOTATAAT,stralingsgeïnduceerdehormonaleveranderingenkunnenontwikkelen.Vaakzijndergelijkeveranderingentijdelijkenklinischnietrelevant.Debehandelendartsdientechterrekeningtehoudenmeteventueleveranderingenindehormoonhuishouding,bij bijvoorbeeld jonge mannen met een kinderwens . Desondanks kan177Lu-DOTATAATtherapieopbasisvandooronsgeobserveerdeendocrieneeffectenalsveiligwordenbeschouwd.
Inhoofdstuk 5 wordenderesultatenbeschrevenvaneenonderzoeknaarwelkvandetweemeestgebruiktesomatostatine-analogen,DOTATAATofDOTATOC,hetmeestgeschikt isom,gekoppeld aan 177Lu,gebruikt tewordenbijPRRT.Beidesomatostatine-analogenhebbenverschillendeaffiniteitenvoordebekendesomatostatinereceptorsubtypen.VoorPRRTisdebalanstussenopnameindetumorenindedosislimiterendeorganenvanbelang,aangezienditdetherapeutischebreedtevanhetradiofarmaconbepaalt.Eendirectevergelijkingvanbeideanalogenineentherapeutischesettingwerduitgevoerd.Verblijftijdenvanradioactiviteitinmilt,nierenenaanwezigetumoren,diedirectgerelateerdzijnaandegeabsorbeerdetumordosis,warenlangermetgebruikvan177Lu-DOTATAATinvergelijkingmet177Lu-DOTATOC.Daarbijwarenderatio’svandegemiddeldeverblijftijdenvan
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�17 7Lu-DOTATAAT versus 17 7Lu-DOTATOC respectievelijk 1 ,5 , 1 , 4 en 2 ,1Dientengevolgeisteverwachtendathogeregeabsorbeerdetumordoseswordenbereiktmet177Lu-DOTATAATdanmet177Lu-DOTATOC.Delangereverblijftijdindenierenbijgebruikvan177Lu-DOTATAATkanechtereenprobleemvormenbijPRRT.Denierenkunnennamelijknaasthetbeenmergookdosislimiterendzijn.Indiendenierenechterinderdaaddelimiterendefactorzijn,doordatbijeventuelevoortgangvantherapiedemaximaletolereerbaredosislimiet(MTD)van23Gyvoordenierenwordtoverschreden,danzaldegeabsorbeerdetumordosismet177Lu-DOTATAATaltijdhogerzijndanmet 177Lu-DOTATOC.Deratiovandegemiddeldeverblijftijdindetumor(en)(2,1)isnamelijkeenfactor1,5hogerdandegemiddeldeverblijftijdratiovandenieren(1,4),inhetvoordeelvan177Lu-DOTATAAT.Overigensbleekdatbijdemeestepatiëntennietdenieren,maarhetbeenmerg(MTDvan2Gy)hetdosisbeperkendeorgaanwas.
Eenvergelijkbare studie isuitgevoerddoorForrer en zijn collega’s inBazel,waarbij 111In-DOTATOCwerdvergelekenmet 111In-DOTATAAT12.Aangenomenwerddatvoordosimetrieberekeningen 111Ingebruiktkonwordenalssurrogaatfor90Y,hetradionuclidedatinBazelwordtgebruiktvoorPRRT.Drievandevijfpatiënten,vanwietweemaaleenscintigramwerdvervaardigd,haddeneenbeteretumor/achtergrondratioophetscintigramna111In-DOTATOCinvergelijkingmet111In-DOTATAAT.Opbasisvandezegegevenswerdbeslotenomhetgebruikvanhetsomatostatine-analoogDOTATOCgelabeldmet90YinPRRTtecontinueren.Deaannamedat111Ineenbruikbaarsurrogaatisvoor90Y,isechterniethelemaalvalide.Verschillenderadionuclidengebondenaanéénsomatostatine-analoogkunnengeheelandereaffiniteitsprofielenhebben13.Ditzoukunnenleidentoteenverschilinbiodistributievandeverschillenderadiofarmaca,hetgeenisaangetoondineenonderzoeksmodelinrattenmetneuroendocrienetumoren14.OokdediagnostischehoeveelheidvanhetpeptidedatgebruiktwerdindestudievanForreret al.wasveelkleinerdandegebruikelijkehoeveelheidbijPRRT.Doorverschillendeauteursisaangetoonddathetverschilindehoeveelheidpeptideeenverschilinbiodistributiekanbetekenen15-17.Breemanet al.beschrevendatindiendeopnamevan111In-octreotideinsomatostatinereceptorpositieveorganenwordtweergegevenalsfunctievandehoeveelheidtoegediendemassaereenweefsel-specifiekeklokvormigecurveontstaat.Vervolgenswerdhetbestaanvandezelfdeklokvormigecurveaangetoond,zowelinhetnormaleweefselalsinsomatostatinereceptorpositievetumoreninzogenaamdenaaktemuizendoorBernhardtet al18.Debiodistributiekanduszoweleeneffecthebbenopdegeabsorbeerdedosisindenierenalsintumoren.Hetdirectegevolgiseeneffectopdetumor/nierenratiozoalsgevondendoorForreret al. 12.Tevensishetindemeesteinstitutengebruikelijkom,gelijktijdigmetradioactiefgelabeldesomatostatinereceptoren,aminozuren intraveneustoetedienen.GelijktijdigetoedieningvandeaminozurenlysineenargininetijdensPRRTbewerkstelligteen
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significanteafnamevanrenaleradioactiviteitenheeftdusookeeneffectopdetumor/nierenratio19.
Concluderendisonzestudie,integenstellingtotdestudieuitBazel,opverschillendepuntenbetervergelijkbaarmetdeuiteindelijketherapeutischesetting.Daarbijgevendedooronsgeanalyseerdeverblijftijdenvanradioactiviteitindetumorenniereneenbetereindrukvandeabsolutegeabsorbeerdedosisdanderelatieveuptakemethodemettumor/nierenratio’s.
Tenslotte zijn, zoals eerder genoemd, bij PRRTmet 17 7Lu-DOTATAAT of90Y-DOTATOC,denierenenhetbeenmergdekritischeorganen.DebijbehorendeMTDvoorexternebestralingvandezeorganenzijnrespectievelijk23en2Gyenwordengebruiktalsdosisgrensomstralingsgeïnduceerdenefropathieenbeenmergtoxiciteit,zoalshetmyelodysplastischesyndroomofleukemietevoorkomen.
WanneerPRRTmet177Lu-DOTATAATof90Y-DOTATOCwordtoverwogen,danisdetumor/nierenratiobijhetgebruikvan177Lu-DOTATAATnietzobelangrijkalsbijhetgebruikvan90Y-DOTATOC,aangezieninongeveer30%vandepatiëntenbehandeldmet 177Lu-DOTATAATdeMTDvandenieren(23Gy)werdbereiktvoordatdeMTDvanhetbeenmergwerdbereikt.Dientengevolgeontvingendezepatiëntenminderdandevoorafbeoogde29,6GBq(4x7400MBq)177Lu-DOTATAAT,overeenkomstigmetdegeaccepteerdeMTDvanhetbeenmergvan2Gy.Uiteindelijkontvingongeveer70%vandepatiëntendevolledigedosisvan29,6GBq.BijPRRTmet90Y-DOTATOCwordendenierenbeschouwdalshetbelangrijkstedosislimiterendorgaan,aangeziendeMTDvandenierenvrijwelaltijdeerderbereiktisdandeMTDvanhetbeenmerg20.
Deeerdergenoemdeargumenteninogenschouwnemend,concluderenwedathetsomatostatine-analoogDOTATAATeenbeteretherapeutischebreedteheeftdanDOTATOCendaaromdevoorkeurgenietom,gekoppeldaan177Lu,tewordengebruiktbijPRRT.
Inhoofdstuk 6.1 wordendeeerstepatiëntenmetinoperabelenJodium-131(131I)negatiefgedifferentieerdschildkliercarcinoomdiebehandelingmet177Lu-DOTATAAThebbenondergaan,beschreven.
Vijfpatiëntenmetgemetastaseerdgedifferentieerdschildkliercarcinoom(3xHürthlecelcarcinoom;1xpapillairschildkliercarcinoom;1xfolliculairschildkliercarcinoom)werdenbehandeldmet22,1-30,1GBq 177Lu-DOTATAAT.Nabehandelingmet177Lu-DOTATAAThadden2patiëntenstabieleziekte,2patiëntenhaddeneenverkleiningvandetumoren1patiënthadprogressieveziekte.Naastdezeobjectieve
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�therapieresponswasereengunstigeperiodetotprogressie.Aangeziendezepatiëntengeenalternatievetherapeutischeoptiesmeerhadden,werdgeconcludeerddattherapiemet177Lu-DOTATAATbijdezepatiëntengroepeengoedebehandelingsoptiekanzijn.Vanzelfsprekendiseenstudiemetinclusievaneengroteregroeppatiëntennoodzakelijkomdeechtewaardevandezetherapeutischebenaderingvasttestellen.Naasthet 177Lu-DOTATAATzijnandere radioactiefgelabelde somatostatine-analogen,zoalshet[DOTA-1-Nal3]octreotide,gelabeldmet90Yof177Lu,interessant21.Dezesomatostatine-analogenverschillenmethet 177Lu-DOTATAATinhunaffiniteitsprofielvoordesomatostatinereceptor,waarbijernaasteenhogeaffiniteitvoorsubtype2,ookeenhogeaffiniteitvoordesubtypen3en5bestaat.Behandelingvanschildkliercarcinoommetdezegelabeldesomatostatine-analogenzouinteressantkunnen zijn, aangezien er aanwijzingen zijn dat het somatostatinereceptorexpressieprofielbijschildkliercarcinomenandersisdanbijdegastro-intestinaleneuroendocrienetumoren,methogereexpressievanzowelsubtype3als5,naastsubtype222.
In hoofdstuk 6.2iseenoverzichtgegevenvanhetgebruikvansomatostatinereceptorscintigrafieenPRRTbijhet 131Inegatiefgedifferentieerdschildkliercarcinoom.De conclusie die getrokken kanworden uit dit literatuuroverzicht is datsomatostatinereceptorscintigrafiebehulpzaamkanzijnomdetumorentelocaliserenindieneraanwijzingenzijnvooraanwezigheidvanziektedoorbijvoorbeeldeenverhoogde thyroglobulineconcentratie inhet serum,echterzonderduidelijkestapelingvan131Ibijtotalelichaamsscintigrafiena131Ibehandeling.Inmeerdan50%vandepatiëntenissomatostatinereceptorscintigrafiealsnoginstaatomdeziektetelocaliseren.Opdezewijzespeeltsomatostatinereceptorscintigrafieeenrolbijdestageringenhetverdertebepalenbehandeltraject.
PRRTbij gedifferentieerd schildkliercarcinoom is beschreven in slechts 62patiënten.Drieverschillenderadionucliden(111In,90Yand177Lu)gekoppeldaan4verschillendesomatostatine-analogen(DOTATOC,[DTPA0]octreotide,lanreotideandDOTATAAT)zijngebruiktmetcumulatievedosesvariërendvan0,9tot30,1GBq.Desomatostatine-analogengekoppeldaan90Yen177Luwarenveelbelovendermetbetrekkingtottumorresponsdanwanneergekoppeldaan111In.Het111Inwordtdaarom,netzoalsbijdebehandelingvangastro-intestinaleneuroendocrienetumoren,nietmeeraanbevolenvoorPRRTbijgedifferentieerdschildkliercarcinoom.
Slotconclusies PRRTmet 17 7Lu-DOTATAAT is de aangewezen therapie bij patiëntenmetinoperabel,gemetastaseerde,goedgedifferentieerde,somatostatinereceptorpositievegastro-intestinaleneuroendocrienetumoren.Deuitkomstenophetgebiedvanobjectiveerbaretumorrespons,kwaliteitvanleven,gemiddeldeperiodetotprogressie
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endeeersteoverlevingsduuranalyselatenziendatinvergelijkingmetdehistorischedatavananderebeschikbaretherapeutischebenaderingen, inclusiefdehuidigechemotherapie,PRRTmet177Lu-DOTATAATbeteris.Daarbijzijndegeobserveerdebijwerkingenminderenishettoxiciteitsprofielgunstig.
Ookkanbijhetontbrekenvanchirurgischeoptiesbij 131Inegatiefgedifferentieerdschildkliercarcinoombehandelingmet 177Lu-DOTATAATals therapeutischebehandelingoverwogenworden.Metnameindezegroepzijnderadioactiefgelabeldesomatostatine-analogenmeteenanderaffiniteitsprofielveelbelovend.
EenmethodeomdeeffectiviteitvanPRRTnogverdertevergrotenisdoortoedieningvanhogerecumulatievedosesbijdeindividuelepatiënt.Ditisalleenmogelijkdoorgebruiktemakenvandosimetriebijiedereafzonderlijkepatiënt.Doordeexactedosisopdedosis-beperkendeorganenperbehandelingenperpatiëntteberekenenkanwordenbepaaldofernog(dosis)ruimteisvoorverderebehandeling.Omdatdezemethodelastig,zeerarbeidsintensiefenduskostbaaris,wordtdezemaniervanbehandelennognietinalleinstitutentoegepast23.
Verderonderzoeknaardezepatiëntgebondendosimetrie,metnamevandenierenenhetbeenmerg,isessentieelomtotpraktischeoplossingentekomenvoorzogenaamdePRRTopmaat,zodatdit indetoekomsttoegepastkanwordenbijde integralebenaderingenbehandelingvandepatiënten.
Ookdeontwikkelingvanzogenaamdenierbeschermendemiddelenisvanbelangomdetherapeutischebreedtetevergroten.DoorgebruiktemakenvannierbeschermendemiddelenwordthetmogelijkomhogeredosestoetedienenomzodeeffectiviteitvanPRRTtevergroten.
Naasthetvergrotenvandetherapeutischebreedtebijdebestaanderadioactiefgelabelde somatostatine-analogenzijnerverscheidenenieuwebenaderingenzoalsdeontwikkelingvannieuwesomatostatine-analogenmeteengunstigersomatostatinereceptor affiniteitsprofiel , combinatietherapiemet andereradionuclidenzoals90Yof111Inofcombinatiemetradiosensitizers.Eenmulticentrumgerandomiseerdestudiemet177Lu-DOTATAATincombinatiemetderadiosensitizercapecitabineversusmonotherapiemet 177Lu-DOTATAATisreedsgestartopdeafdelingNucleaireGeneeskundeinhetErasmusMC(Rotterdam).
Tenslotte laathetgebruikvanPRRTbijpatiëntenmetsomatostatinereceptorpositievetumorenziendateentherapiegebaseerdopeenradionuclidegekoppeldaaneenpeptidezeersuccesvolkanzijn.PRRTisdaaromveelbelovendvoordebehandelingvananderevormenvankanker.Nieuwetumor-specifiekereceptoren
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�wordenveelvuldigontdekt.DezereceptorenzijninprincipeallemaaleenpotentiëeldoelwitvoorradioactiefgelabeldepeptidenendusookvoorPRRT.Het isdanooknietondenkbaardatPRRTindetoekomstookinanderedeelgebiedenvandeoncologieeenbelangrijketherapeutischeoptiezalzijn.
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Abbreviations
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Abb
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5-FU fluorouracil5-HIAA 5-hydroxyindoleaceticacidACTH adrenocorticotropichormoneAML acutemyeloidleukemiaANOVA analysisofvarianceBMI bodymassindexCARC carcinoidCCDP cisplatinCNS centralnervoussystemCR completeremissionCT computedtomographyDOTA 1,4,7,10-tetraazacyclododecane-N,N’,N’’,N’’’-tetra-aceticacidDOTALAN DOTA-lanreotideDOTANOC [DOTA0-1-naphthyl3]octreotideDOTA-OC DOTA-octreotideDOTATOC [DOTA0,Tyr3]octreotideDOX doxorubicin(adriamycin)DNA deoxyribonucleicacidDTPA diethylenetriaminepenta-aceticacidDOTATATE [DOTA0,Tyr3]octreotateDTC differentiatedthyroidcarcinomaDTIC dimethyltriazenoimidazolecarboxamideE2 oestradiolEBRT externalbeamradiationtherapyEGFR epidermalgrowthfactorreceptorENETS EuropeanNeuroendocrineTumourSocietyEORTC EuropeanOrganizationforResearchandTreatmentofCancerFDA FoodandDrugAdministration18F-FDG 18F-fluorodeoxyglucoseFDG-PET fluorodeoxyglucose-positronemissiontomographyFSH folliclestimulatinghormoneFT4 freethyroxineFTC follicularthyroidcarcinomaGBq Gigabecquerel(109Bq)GEP gastroenteropancreaticGEP-NET gastroenteropancreaticneuroendocrinetumourGLP-1 glucagon-likepeptide-1Gy GrayHACE hepaticarterychemoembolisationHAE hepaticarteryembolisationHbA1c haemoglobinA1corglycolysatedhemoglobin
HCTC hürthlecellthyroidcarcinomaHPA-axis hypothalamo-pituitary-adrenalaxisHPF highpowerfieldHRQoL healthrelatedquality-of-lifeHYNIC hydrazinonicotinylICC isletcelltumourIFN interferonITT insulintolerancetestIU internationalunitkeV kiloelectronvoltKPS KarnofskyPerformanceScaleLAN lanreotideLDST low-doseACTHstimulationtestLH luteinizinghormoneLITT laserinducedthermotherapyMBq Megabecquerel(106Bq)mCi millicurieMDS myelodysplasticsyndromeMMC mitomycinCMR minorremissionMRI magneticresonanceimagingmTOR mammaliantargetofrapamycinNE neuroendocrineNEP neuroendocrinepancreatictumourNET neuroendocrinetumourNOC Nal3-octreotideNTI non-thyroidalillnessOLT orthotopiclivertransplantationOS overallsurvivalPD progressivediseasePDEC poorlydifferentiatedendocrinecarcinomaPDGF plateletderivedgrowthfactorPFS progressionfreesurvivalPRRT peptidereceptorradionuclidetherapyPR partialremissionPRS peptidereceptorscintigraphyPTC papillarythyroidcarcinomaQLQ-C30 Cancer30-itemQualityofLifeQuestionnaireQoL qualityoflifeRECIST ResponseEvaluationCriteriainSolidTumorsRFA radiofrequencyablation
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rT3 reversetriiodothyronineSD stablediseaseSEER Surveillance,Epidemiology,andEndResultsdatabaseSEM standarderrorofthemeanSHBG sexhormonebindingglobulinSPECT single-photonemissioncomputedtomographySRS somatostatinreceptorscintigraphySS somatostatinSSTR somatostatinreceptorSTZ streptozotocinSWOG SouthWestOncologyGroupT testosteroneT3 triiodothyronineTATE Tyr3-Thr8-octreotideTg thyroglobulinTOC Tyr3-octreotideTPO thyroidperoxidaseTK tyrosinekinaseTSH thyroid-stimulatinghormoneTT totaltestosteroneTTP timetoprogressionTyr tyrosineUS ultrasoundVEGF vascularendothelialgrowthfactorVIP vasoactiveintestinalpeptideWBS wholebodyscanWHO WorldHealthOrganization
Abb
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Dankwoord
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Dan
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Promoverenistevergelijkenmetaanboordvaneenzeilbootstappenzonderdatjepreciesweetwaarjenaartoezalgaan,wieertijdensdereisnogzullenaanmonsteren,hoe langde reis gaatdurenenof jewel genoegzeilervaringhebtomdeveleweersveranderingentetrotseren.Gedurendedeafgelopenjarenhebikmethetschrijvenvanmijnproefschriftelkweertypeeniederewindrichtingmogenervaren.Gelukkigisdehavennuinzichtenisdetijdgekomenommetplezierterugtekijkenopeenlange,maarmooieenleerzamereis.
Hetisonmogelijkomiedereendiedeafgelopenjarenbetrokkenisgeweestbijalleonderzoekenpersoonlijktenoemenineendankwoord.Tochwil ikeenaantalmenseninhetbijzonderbedanken.Opdeeersteplaatskomenvoormijallepatiëntendiehebbenmeegewerktaandediverseonderzoekenbeschreveninditproefschrift.
Mijnpromotor,Prof.dr.E.P.Krenning.BesteEric,mededankzijjouwenthousiasme,optimismeengedrevenheidisditproefschrifttotstandgekomen.Dankvoordemogelijkhedendiejemehebtgegevenvoorhetverrichtenvanhetonderzoekendekansomopdediverseinternationalebijeenkomstenencongressentespreken.
Mijncopromotor,dr.D.J.Kwekkeboom.BesteDik,bedanktvoordesamenwerkingenjebegeleidingdeafgelopenjaren.Nietalleenbenikjedankbaarvoorjehulpbijhetschrijvenvandemanuscriptenendediscussiesbijsomslastigeklinischebeslissingen,maarookvoorjehumor(alleennietvóór10uur….)enaanmoediging(“..Ishetalaf?...”).
Ledenvandekleinecommissie:
Prof.dr.ir.M.deJong.BesteMarion,zonderdeprekliniekenhetCILuiteindelijkgeenklinischestudies.Ikbewonderjeenthousiasmeendemanierwaaropjeallesvoorelkaarhebtgekregen,metonderanderehethuidigeAnimalImagingFacilityalsmooiresultaat.
Prof.dr.F.H.deJong.BesteFrank,bedanktdat je indekleinecommissiewildeplaatsnemenenvoorhetuiterstkritischlezenenbeoordelenvanhetproefschrift.
Dr.W.W.deHerder.BesteWouter,bedanktvoordesamenwerkingindekliniek,jehelderekijkopdebehandelingvanonzepatientenvanuitdeendocrinologischehoekenjemedewerkingbijdebeoordelingvanmijnmanuscripten.En,bedanktvoordezeerpersoonlijkeringtone!
Demedischestafleden:Jan-PaulEsser,besteJan-Paul,‘JeePee’,hetisalweereentijdgeleden,datwesamenverantwoordelijkwarenvoordeLu-taatbehandelingen.Bedanktvoordeprimasamenwerkingbijdeveletoedieningen.BoenKam,besteBoen,detransformatievanjoualscollegaAIOSnaarbaaswasbijzonderommeetemaken.Gelukkiggeentransformatievanonzevriendschap.LidekeFröberg,besteLideke,dankvoorjekritischeblikenopmerkingen.BartdeKeizer,besteBart,samenstondenweopcongressenonzeervaringmetradionuclidetherapietevertellenzonderdatwewistendatweooitsamenzoudenwerken.Helaaswasditvankorteduur.VeelsuccesinUtrecht.RoelfValkema,besteRoelf,netalsikweetjijalsgeenander:Leidenenomstrekeniszogeknogniet.Hoewelanderendaarsomsandersoverdenken…Bedanktvoorjebijdragenaandediversemanuscriptenennuttigediscussies.JoVerhaegen,besteJo,mijnvroegerekamergenoot,nooitzalikvergetenwathetbetekentalsikbijdeachterasvanmijnautoietshoorrammelenendatjeindetijdvanmijnpromotiemakkelijkkantrouwenenvadervandriekinderenkanworden.Bedanktvooraljeverhalen,gezelligheiden‘jijooknogeenbakkiekoffie?’.PetervanNoorden,bestePeter,helaaswerktenwealleenmaaropdedinsdagsamen.Jenuchterekijkopdelopendeklinischezakenwarenergleerzaam.
Overigestafleden:PeterKooij,bestePeter,dankzijjouwklinischfysischekenniseninzethieldenweeniginzichtindegeabsorbeerdenierdosisbijonzepatienten.Bedanktvooraldieberekeningen,jeuitlegenvaaknuchtereblik.WillemBakker,BesteWillem,zonderjouwleidingzouergeen‘veilig’Lutetium-octreotaat’zijngeweest.Bedanktvooralles.WoutBreeman,besteWout,hoeweljenietdirectbetrokkenbentgeweestbijdevooralklinischeresultatenvanmijnproefschrift,dankikjevoorallewetenschappelijkeopmerkingen,handigetipsenhumor.
Researchverpleegkundigen:Beste ‘Lu-dames’; Jolande,Daniëlle,ElsenAgnes,zonderjulliezouhetonderzoeknietmogelijkzijngeweest.Vaninhetbegin‘samenmetJolande’,zijnjullieinmiddelsuitgegroeidtoteensoepeldraaiendtopklinischgespecialiseerdresearchverpleegkundigteam,waardeafdelingtrotsopkanzijn.
Mijnopvolgers,collegaarts-onderzoekers,MartijnenSaima;het is fijnomtewetendathetwerknuverdeeldisovertweeartsonderzoekers,zodatdenogsteedsgroeiendegroeppatiëntenblijvendgoedwordtbegeleidenvoldoendemedischeaandachtkrijgen.Bedanktvoorjullieinteresseinmijnproefschriftensuccesmetdievanjullie!
Mijnmede-AIOSdeafgelopenjaren,Albert,Sergio,Marc,KathleenenHanneke.Eengrotediversiteitvanboeiendepersonendieallenvoorhetzelfdegeweldigevakhebbengekozen.Dankvoordegezelligheidopcursussen,nietalleennationaal,maarookinternationaal(zeerleerzamecombi-cursusbotanischetuinenengeologievan
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deFranseAlpendoorMarcinNiceenomstreken..)enopdepistenvandeFranseAlpen.Datsoortevenementenwarenzeernuttigomzoafentoedestressvanhetpublicerentedoenvergeten.
Iedereenvandeafdelingnucleairegeneeskunde:zondereengoedfunctionerendteamopdeafdelingmetdeverschillendegroepenzoalsde‘ADMI’-medewerkers,deMNAA’ers,MNW’ersendemannenvandesoft-enhardware(Ambroos,Ron,Tuki,RonaldenPaul)ishetonmogelijkomzoveelpatiëntengoedenprofessioneelte behandelen, te scannen envervolgens te begeleiden.Dankvoorde goedesamenwerking,professionaliteitenmetnameookflexibiliteit;eigenschappenvanonzeafdelingdiehunnutalmeerderemalenhebbenbewezen.
Isabel,speciaalvoorjouookeenwoordvandank;jouwhulpwasbelangrijkvoormij.Nietalleenquasecretariëleondersteuning,maarookals luisterendoorengeheugensteuntjerichtingEric.
Naastonzeafdelingwil ikookdeafdelingInterneGeneeskundebedanken.TeneerstedemedischespecialistenWouterdeHerder,RichardFeeldersenMaartenvanAken.Alledriestondenjulliealtijdklaarvooroverlegenopvangvanonzepatiënten,waarvoordank.
Daarnaastgaatmijndankuitnaariedereenvandeklinischeafdelingendocrinologie(voorheen4Noord,maarwaarzenuweerzitten…?),zoalsdeverpleegkundigenendeveleAIOS,diedaaropdeafdelingzorgdroegenvooronzepatiënten.Bedanktvoorjullieopvangvanalle‘optewerken’patiëntenendesoms‘stralende’,maartochwelziekepatiëntennatoediening.
CILpromovendi:Monique,Suzanne,AstridenEdgar,metveelplezierkijkikterugnaardegezelligheidtijdensmetnamede(internationale)congressen(Wenen,Capri,Gent,Londenetc).Ookwarenjullie,alsvoorgangers,mijnvoorbeelden‘hoetepromoveren‘eneeninspiratiebronomvooraldoortegaan.
DeandereCILmedewerkers:Magda,RiaenBert.Tijdensdekorteperiodesdatikinhet‘oudeCIL’bengeweest,warenjulliealtijdbereidmetehelpen,waarvoormijndank.
KarlijnenVincent,nademooie lay-outenvoorkantvanhetproefschriftvanMaaike,koniknietomjullieheen.Bedanktvoorjullieinzetbijhetmakenvaneenprofessionelelay-outenomslag.Wederomziethetergeweldiguit!
Allevriendenenvriendinnen,vaakhadikgeentijdomietsaftespreken,tegaan
zeilen,ergensteborrelen,flipperenoftefeesten.Metnamehetlaatstejaarhebikjullieeenbeetjeverwaarloosd.Ditgaanwedekomendejarenzekerweerinhalen!Paranimfen:MerijnenMichiel,goedevriendenzijnbelangrijkinhetleven,ikwasdanooksuperblijdatjulliebereidwarenommijbijtestaandeafgelopenperiodeenopdepromotiezelf.Dankzijhetsamensporten,gamenenkortevakantieshebikmeelkekeerweergoedkunnenopladenvoorhetvolgendeonderzoeksprojectofteschrijvenmanuscript.
Mijnschoonfamiliewilikbedankenvoordeontspannendevakantiesdiewesamenhebbenmogenbeleven,nietalleeninDubai,maarookin‘LeBiot’.Bedanktvoordemogelijkheidomindewinterhethoofdgoedleegtemakenopdeverschillendepistenen indezomerverder tekunnenschrijvenop jullieeigenAlpenweide.MaartenenEllen,bedanktvoordevelegezelligeaprès-skiavondenen4-wheeldriveavonturen.
Broersen(schoon)zussen,bedanktvoorjulliebegripensteundeafgelopenjaren.Dooralledeadlineswashethelaasnietmogelijkomaanwezigtezijnbijsommigefamilieaangelegenheden.VerderwilikPetrabedankenvoorhetcorrigerenvandenederlandsedocumentenensamenvattingvanditproefschrift.
Mijnouders,dankzij julliehebikquastudie(s)alleskunnendoen.Hoewelhetvoorjullieeerstschrikkenwasnamijn‘carrièreswitch’,hebbenjulliemeblijvendgesteund.HelaasisPapopdepromotiedagernietbij.Maarikweethoetrotshijopmezouzijn.Ikbenoneindigdankbaarvooraljullieliefde,steun,zorgenvertrouwen.
Mijn lieveMaaike,zoals jijhetalzomooiaangaf inhetdankwoordvan jouwproefschrift;deafgelopenjarenwarenomgedraaid; jij indeklinieken ikmijnpromotieafmaken.Gelukkighadjenogtijdoverommeopdecrucialemomentenmetraadendaadbijtestaan.Bedanktvoorjehulp,steun,liefde,aanmoedigingengeduld.Opnaardevolgendeuitdaging!
Curriculum Vitae
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�JaapTeunissenwasbornonAugust25th,1972inArnhem,theNetherlands.In1990hegraduatedfromhighschool (VWO;VanLingenCollege) inArnhem. InthesameyearhestartedhisstudyBiomedicalSciencesattheUniversityofLeiden.In1995hestartedhismedicaltrainingattheFacultyofMedicineattheUniversityofLeiden.FromSeptember1997tillMarch1998,heparticipatedinaprojectcalled‘An Assessment of Steroid Cover during Pituitary Surgery’atthedepartmentofInternalMedicine,divisionofEndocrinology,RadcliffeInfirmary,Oxford,UKunderthesupervisionofProf.dr.J.A.H.Wass.In1999heobtainedhisbiomedicaldegree,followedbyhismedicaldegreein2000.Hestartedtoworkasa resident in Internalaresident in InternalresidentinInternalMedicineatthedepartmentofInternalMedicineoftheRodeKruisHospitalinTheHague(head:Dr.R.M.Valentijn).FromNovember2001tillDecember2008heworkedasaresearchfellowatthedepartmentofNuclearMedicineoftheErasmusMCinRotterdam(supervisedbyProf.dr.E.P.KrenningandDr.D.J.Kwekkeboom)ontheresearchpresentedinthisthesis.InSeptember2005hestartedhisclinicalnuclearmedicineresidencyintraining(AIOS)attheErasmusMCinRotterdam(head:Prof.dr.E.P.Krenning).Aspartofhis training,heworkedasaresidentat thedepartmentof InternalMedicineoftheRijnlandHospital inLeiderdorp(head:Dr.F.H.M.Cluitmans),atthedepartmentofRadiologyoftheErasmusMCinRotterdam(head:Prof.dr.G.P.Krestin)andatthedepartmentofNuclearMedicineoftheTheNetherlandsCancerInstitute/AntonivanLeeuwenhoekHospital inAmsterdam(head:Dr.C.Hoefnagel).AttheendofFebruary2009,hewillfinishhistrainingperiodandbecomeaNuclearMedicinespecialistandastaffmemberofthedepartmentofNuclearMedicine,ErasmusMC,Rotterdam.Since2003,heislivinghappilytogetherwithMaaikeSchaartinLeiden.
List o�� publications
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journals
2008 Teunissen JJM,KrenningEP,deJongFH,deRijkeYB,FeeldersRA,vanAkenMO,deHerderWW,KwekkeboomDJ.Effectsoftherapywith[177Lu-DOTA0,Tyr3]octreotateonendocrinefunction.Eur J Nucl Med Mol Imaging.(Submitted)
NasirA,GardnerNM,StrosbergJ,AhmadN,ChoiJ,MalafaMP,CoppolaD,KwekkeboomDJ,Teunissen JJ,KvolsLK.Multimodalitymanagementofapolyfunctionalpancreaticendocrinecarcinomawithmarkedlyelevatedserumvasoactiveintestinalpolypeptideandcalcitoninlevels.Pancreas.2008;36:309-313.
2007 KwekkeboomDJ,Teunissen JJM,KamBL,ValkemaR,deHerderWW,KrenningEPTreatmentofpatientswhohaveendocrinegastroenteropancreatictumorswithradiolabeledsomatostatinanalogues.Hematology/Oncology Clinics of North America. 2007;21:561-573.
2006 EsserJP, KrenningEP,Teunissen JJ,KooijPP,vanGamerenAL,BakkerWH,KwekkeboomDJ.Comparisonof[177Lu-DOTA0,Tyr3]octreotateand[177Lu-DOTA0,Tyr3]octreotide:whichpeptideispreferableforPRRT?Eur J Nucl Med Mol Imaging. 2006;33:1346-1351.
Teunissen JJM,KwekkeboomDJ,KrenningEP.Stagingandtreatmentofdifferentiatedthyroidcarcinomawithradiolabelledsomatostatinanalogues.Trends Endocrinol Metab.2006;17:19-25.
2005 Krenning EP,Teunissen JJ, ValkemaR, deHerderWW, de JongM,KwekkeboomDJ.Molecularradiotherapywithsomatostatinanalogs for(neuro-)endocrinetumors. J Endocrinol Invest.2005;28(Suppl):146-150.
Teunissen JJM,KwekkeboomDJ,DeJongM,EsserJP,ValkemaR,KrenningEP.Endocrine tumoursof the gastrointestinal tract. PeptideReceptorRadionuclideTherapy.Best Pract Res Clin Gastroenterol.2005;19:595-5616.
KwekkeboomDJ,Teunissen JJ,BakkerWH,KooijPP,deHerderWW,FeeldersRA,VanEijckCH,EsserJP,KamBL,KrenningEP.Radiolabeledsomatostatinanalog[177Lu-DOTA0,Tyr3]octreotateinpatientswithendocrinegastroenteropancreatictumors.J Clin Oncol.2005;23:2754-2762.
Teunissen JJ,KwekkeboomDJ,KooijPP,BakkerWH,KrenningEP,Peptidereceptorradionuclidetherapyfornon-radioiodine-aviddifferentiatedthyroidcarcinoma.J Nucl Med.2005;46(Suppl):107S-114S.
2004 Teunissen JJ,KwekkeboomDJ,KrenningEP,Qualityoflifeinpatientswithgastroenteropancreatictumorstreatedwith[177Lu-DOTA0,Tyr3]octreotate.J Clin Oncol.2004;22:2724-2729.
2003 KwekkeboomDJ,BakkerWH,KamBL,Teunissen JJ,KooijPP,deHerderWW,FeeldersRA,VanEijckCH,DeJongM,SrinivasanA,ErionJL,KrenningEP.Treatmentofpatientswithgastroenteropancreatic(GEP)tumourswiththenovelradiolabelledsomatostatinanalogue[177Lu-DOTA0,Tyr3]octreotate.Eur J Nucl Med Mol Imaging.2003;30:417-422.
1996 TakPP,HintzenRQ,Teunissen JJM,SmeetsTJM,DahaMR,VanLierRAW,KluinPM,MeindersAE,SwaakAJG,andBreedveldFC.ExpressionoftheActivationantigenCD27inrheumatoidarthritis.Clin Immunol Immunopathol.1996;80:129-138.
Books
2008 Gastrointestinal oncoloGy: a critical Multidisciplinary teaM approach
Edited by:JankowskiJ,SamplinerR,KerrDandFongY
Chapter23:NeuroendocrineTumors (EditedbyUrsulaPlöckinger) Radiolabeledsomatostatinanalogs.KwekkeboomDJ,Teunissen
JJM,KamBLR,ValkemaR,deHerderWW,KrenningEP
2007 clinical nuclear Medicine Edited by:BiersackH-J–FreemanL
Chapter24:PeptideReceptorRadionuclideTherapywithLutetium-octreotate.Teunissen JJM,KwekkeboomDJ,deJongM,EsserJP,ValkemaR,KrenningEP