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

8

105482

86

89

102

122

138

158

172

174

192

210

222

238

244

250

254

1General introduction

1.1Management o�� patients with neuroendocrine tumours

12

�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.

Man

agem

ent o

�� pat

ient

s w

ith

neur

oend

ocri

ne tu

mou

rs

1.1

�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

14

�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.

Man

agem

ent o

�� pat

ient

s w

ith

neur

oend

ocri

ne tu

mou

rs

1.1

�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

Man

agem

ent o

�� pat

ient

s w

ith

neur

oend

ocri

ne tu

mou

rs

1.1

�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.

18

�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

Man

agem

ent o

�� pat

ient

s w

ith

neur

oend

ocri

ne tu

mou

rs

1.1

�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

20

�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

Man

agem

ent o

�� pat

ient

s w

ith

neur

oend

ocri

ne tu

mou

rs

1.1

�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.

Man

agem

ent o

�� pat

ient

s w

ith

neur

oend

ocri

ne tu

mou

rs

1.1

�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.

Man

agem

ent o

�� pat

ient

s w

ith

neur

oend

ocri

ne tu

mou

rs

1.1

�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.

Man

agem

ent o

�� pat

ient

s w

ith

neur

oend

ocri

ne tu

mou

rs

1.1

�

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

Man

agem

ent o

�� pat

ient

s w

ith

neur

oend

ocri

ne tu

mou

rs

1.1

�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.

Man

agem

ent o

�� pat

ient

s w

ith

neur

oend

ocri

ne tu

mou

rs

1.1

�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.

Man

agem

ent o

�� pat

ient

s w

ith

neur

oend

ocri

ne tu

mou

rs

1.1

�

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.

Man

agem

ent o

�� pat

ient

s w

ith

neur

oend

ocri

ne tu

mou

rs

1.1

�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

Man

agem

ent o

�� pat

ient

s w

ith

neur

oend

ocri

ne tu

mou

rs

1.1

�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.

Man

agem

ent o

�� pat

ient

s w

ith

neur

oend

ocri

ne tu

mou

rs

1.1

�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

Man

agem

ent o

�� pat

ient

s w

ith

neur

oend

ocri

ne tu

mou

rs

1.1

�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.

Man

agem

ent o

�� pat

ient

s w

ith

neur

oend

ocri

ne tu

mou

rs

1.1

�

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

Man

agem

ent o

�� pat

ient

s w

ith

neur

oend

ocri

ne tu

mou

rs

1.1

�REFERENCES

1. BrazeauP,ValeW,BurgusR,LingN,ButcherM,RivierJ,GuilleminHypothalamicpolypeptidethatinhibitsthesecretionofimmunoreactivepituitarygrowthhormone.Science.1973;179:77-79.

2. SchallyAV.Aspectsofhypothalamicregulationofthepituitarygland.Science.1978;202:18-28.

3. YamadaY,PostSR,WangK,TagerHS,BellGI,SeinoS.Cloningandfunctionalcharacterizationofafamilyofhumanandmousesomatostatinreceptorsexpressedinbrain,gastrointestinaltract,andkidney.Proc Natl Acad Sci U S A.1992;89:251-255.

4. YamadaY,KagimotoS,KubotaA, et al.Cloning, functional expression andpharmacologicalcharacterizationofafourth(hSSTR4)andafifth(hSSTR5)humansomatostatinreceptorsubtype.Biochem Biophys Res Commun.1993;195:844-852.

5. PatelYC.Somatostatinanditsreceptorfamily.Front Neuroendocrinol.1999;20:157-198.

6. ReubiJC,KvolsL,KrenningE,LambertsSW.Distributionofsomatostatinreceptorsinnormalandtumortissue.Metabolism.1990;39:78-81.

7. ReubiJC.SomatostatinandotherPeptidereceptorsastoolsfortumordiagnosisandtreatment.Neuroendocrinology.2004;80Suppl1:51-56.

8. TaalBG,VisserO.Epidemiologyofneuroendocrinetumours.Neuroendocrinology.2004;80Suppl1:3-7.

9. ModlinIM,LyeKD,KiddM.A5-decadeanalysisof13,715carcinoidtumors.Cancer.2003;97:934-959.

10. CrocettiE,BuiattiE,AmorosiA.EpidemiologyofcarcinoidtumoursincentralItaly.European Journal of Epidemiology.1997;13:357-359.

11. BergeT,LinellF.Carcinoidtumours.Frequencyinadefinedpopulationduringa12-yearperiod.Acta Pathol Microbiol Scand [A].1976;84:322-330.

12. ModlinIM,SandorA.Ananalysisof8305casesofcarcinoidtumors.Cancer.1997;79:813-829.

13. ModlinIM,ObergK,ChungDC,etal.Gastroenteropancreaticneuroendocrinetumours.Lancet Oncol.2008;9:61-72.

14. OberndorferS.Karzinoidetumorendesdunndarms.Frankf Zschr Pathol.1907;1:426-430.

15. WilliamsED,SandlerM.Theclassificationofcarcinoidtumours.Lancet.1963;1:238-239.

16. WilliamsED.HistologicaltypingofEndocrineTumours.InternatinalHistologicalClassificationofTumours.Geneva: World Health Organization.1980.

17. KloppelG,PerrenA,HeitzPU.TheGastroenteropancreaticNeuroendocrineCellSystemandItsTumors:TheWHOClassification.Ann NY Acad Sci.2004;1014:13-27.

18. SolciaE,KlöppelG,SobinLH.Histologicaltypingofendocrinetumours.2ndEd:Springer.Berlin.,2000.

19. Ramage JK, Davies AH, Ardill J, et al . Guidelines for themanagement ofgastroenteropancreaticneuroendocrine(includingcarcinoid)tumours.Gut.2005;54Suppl4:iv1-16.

20. deHerderWW,LambertsSW.Clinicalendocrinologyandmetabolism.Gutendocrinetumours.Best Pract Res Clin Endocrinol Metab.2004;18:477-495.

21. TherasseP,LeCesneA,VanGlabbekeM,VerweijJ,JudsonI.RECISTvs.WHO:prospectivecomparisonofresponsecriteria inanEORTCphaseIIclinicaltrialinvestigatingET-743inadvancedsofttissuesarcoma.Eur J Cancer.2005;41:1426-1430.

46

�22. JuweidME,ChesonBD.Positron-emissiontomographyandassessmentofcancertherapy.N Engl J Med.2006;354:496-507.

23. RousseauC,DevillersA,SaganC,etal.MonitoringofearlyresponsetoneoadjuvantchemotherapyinstageIIandIIIbreastcancerby[18F]fluorodeoxyglucosepositronemissiontomography.J Clin Oncol.2006;24:5366-5372.

24. RamageJK,DaviesAH.Measurementofqualityoflifeincarcinoid/neuroendocrinetumours.Endocr Relat Cancer.2003;10:483-486.

25. GoedeAC,CaplinME,WinsletMC.Carcinoidtumouroftheappendix.Br J Surg.2003;90:1317-1322.

26. StinnerB,RothmundM.Neuroendocrinetumours(carcinoids)oftheappendix.Best Pract Res Clin Gastroenterol.2005;19:729-738.

27. KulkeMH,MayerRJ.Carcinoidtumors.N Engl J Med.1999;340:858-868.28. AkerstromG,HellmanP,HessmanO,OsmakL.Managementofmidgutcarcinoids.

J Surg Oncol.2005;89:161-169.29. MakridisC,EkbomA,BringJ,etal.Survivalanddailyphysicalactivityinpatients

treatedforadvancedmidgutcarcinoidtumors.Surgery.1997;122:1075-1082.30. YaoKA,TalamontiMS,NemcekA,etal.Indicationsandresultsofliverresectionand

hepaticchemoembolizationformetastaticgastrointestinalneuroendocrinetumors.Surgery.2001;130:677-82;discussion682-685.

31. QueFG,NagorneyDM,BattsKP,LinzLJ,KvolsLK.Hepaticresectionformetastaticneuroendocrinecarcinomas.Am J Surg.1995;169:36-42;discussion42-43.

32. ChamberlainRS,CanesD,BrownKT,etal.Hepaticneuroendocrinemetastases:doesinterventionalteroutcomes?J Am Coll Surg.2000;190:432-445.

33. BoudreauxJP,PuttyB,FreyDJ,etal.Surgicaltreatmentofadvanced-stagecarcinoidtumors:lessonslearned.Ann Surg.2005;241:839-45;discussion845-846.

34. IhseI,PerssonB,TibblinS.Neuroendocrinemetastasesoftheliver.World J Surg.1995;19:76-82.

35. BlonskiWC,ReddyKR,ShakedA,SiegelmanE,MetzDC.Livertransplantationformetastaticneuroendocrinetumor:acasereportandreviewoftheliterature.World J Gastroenterol.2005;11:7676-7683.

36. BechsteinWO,Neuhaus P. Liver transplantation for hepaticmetastases ofneuroendocrinetumors.Ann N Y Acad Sci.1994;733:507-514.

37. LeTreutYP,DelperoJR,DoussetB,etal.Resultsoflivertransplantationinthetreatmentofmetastaticneuroendocrinetumors.A31-caseFrenchmulticentricreport.Ann Surg.1997;225:355-364.

38. LehnertT.Livertransplantationformetastaticneuroendocrinecarcinoma:ananalysisof103patients.Transplantation.1998;66:1307-1312.

39. PascherA,KluppJ,NeuhausP.Transplantationinthemanagementofmetastaticendocrinetumours.Best Practice & Research Clinical Gastroenterology.2005;19:637-648.

40. MoertelCG.Karnofskymemoriallecture.Anodysseyinthelandofsmalltumors.J Clin Oncol.1987;5:1502-1522.

41. Rosenau J, BahrMJ, vonWasielewskiR, et al.Ki67, E-cadherin, andp53 asprognosticindicatorsoflong-termoutcomeafterlivertransplantationformetastaticneuroendocrinetumors.Transplantation.2002;73:386-394.

42. MakarewiczR,MrossM.Radiationtherapyaloneinthetreatmentoftumoursofthetrachea.Lung Cancer.1998;20:169-174.

43. TennvallJ,LjungbergO,AhrenB,GustavssonA,NillsonLO.Radiotherapyforunresectableendocrinepancreaticcarcinomas.Eur J Surg Oncol.1992;18:73-76.

44. ChakravarthyA,AbramsRA.Radiationtherapyinthemanagementofpatientswithmalignantcarcinoidtumors.Cancer.1995;75:1386-1390.

Man

agem

ent o

�� pat

ient

s w

ith

neur

oend

ocri

ne tu

mou

rs

1.1

�45. SchupakKD,WallnerKE.Theroleofradiationtherapyinthetreatmentoflocallyunresectableormetastaticcarcinoidtumors.Int J Radiat Oncol Biol Phys.1991;20:489-495.

46. RuszniewskiP,RougierP,RocheA,etal.Hepaticarterialchemoembolizationinpatientswithlivermetastasesofendocrinetumors.AprospectivephaseIIstudyin24patients.Cancer.1993;71:2624-2630.

47. TherasseE,BreittmayerF,RocheA,etal.Transcatheterchemoembolizationofprogressivecarcinoidlivermetastasis.Radiology.1993;189:541-547.

48. PerryLJ,StuartK,StokesKR,ClouseME.Hepaticarterialchemoembolizationformetastaticneuroendocrinetumors.Surgery.1994;116:1111-6;discussion1116-1117.

49. RocheA,GirishBV,deBaereT,etal.Trans-catheterarterialchemoembolizationasfirst-linetreatmentforhepaticmetastasesfromendocrinetumors.Eur Radiol.2003;13:136-140.

50. RuszniewskiP,O’TooleD.Ablative therapies for livermetastasesof gastro-enteropancreaticendocrinetumors.Neuroendocrinology.2004;80Suppl1:74-78.

51. ToumpanakisC,MeyerT,CaplinME.Cytotoxictreatmentincludingembolization/chemoembolizationforneuroendocrinetumours.Best Pract Res Clin Endocrinol Metab.2007;21:131-144.

52. O’TooleD,RuszniewskiP.Chemoembolizationandotherablativetherapiesforlivermetastasesofgastrointestinalendocrinetumours.Best Practice & Research Clinical Gastroenterology.2005;19:585-594.

53. AjaniJA,CarrascoCH,WallaceS.Neuroendocrinetumorsmetastatictotheliver.Vascularocclusiontherapy.Ann N Y Acad Sci.1994;733:479-487.

54. O’TooleD,MaireF,RuszniewskiP.Ablativetherapiesforlivermetastasesofdigestiveendocrinetumours.Endocr Relat Cancer.2003;10:463-468.

55. ClouseME,PerryL,StuartK,StokesKR.Hepaticarterialchemoembolizationformetastaticneuroendocrinetumors.Digestion.1994;55Suppl3:92-97.

56. DiacoDS,HajarizadehH,MuellerCR,FletcherWS,PommierRF,WolteringEA.Treatmentofmetastaticcarcinoidtumorsusingmultimodalitytherapyofoctreotideacetate,intra-arterialchemotherapy,andhepaticarterialchemoembolization.Am J Surg.1995;169:523-528.

57. MarracheF,VulliermeMP,RoyC,etal.Arterialphaseenhancementandbodymassindexarepredictorsofresponsetochemoembolisationforlivermetastasesofendocrinetumours.Br J Cancer.2007;96:49-55.

58. RuszniewskiP,MalkaD.Hepaticarterialchemoembolizationinthemanagementofadvanceddigestiveendocrinetumors.Digestion.2000;62Suppl1:79-83.

59. GradyED. Intrahepatic aterial90-yttriumresin spheres to treat liver cancer.International Journal of Nuclear Medicine and Biology.1978;5:253-254.

60. SimonN,SilverstoneSM,RoachLC,WarnerRR,BaronMG,RudavskyAZ.Intra-arterialirradiationoftumors,asafeprocedure.Am J Roentgenol Radium Ther Nucl Med.1971;112:732-739.

61. Andrews JC,WalkerSC,AckermannRJ,CottonLA,EnsmingerWD,ShapiroB.Hepatic radioembolizationwithyttrium-90containingglassmicrospheres:preliminaryresultsandclinicalfollow-up.J Nucl Med.1994;35:1637-1644.

62. SatoKT,LewandowskiRJ,MulcahyMF,etal.UnresectableChemorefractoryLiverMetastases:Radioembolizationwith90YMicrospheres--Safety,Efficacy,andSurvival.Radiology.2008:247:507-515.:507-515.

63. MurthyR,KamatP,NunezR,etal.Yttrium-90microsphereradioembolotherapyofhepaticmetastaticneuroendocrinecarcinomasafterhepaticarterialembolization.J Vasc Interv Radiol.2008;19:145-151.

64. McStayMK,MaudgilD,WilliamsM,etal.Large-volumelivermetastasesfromneuroendocrinetumors:hepatic intraarterial 90Y-DOTA-lanreotideaseffectivepalliativetherapy.Radiology.2005;237:718-726.

48

�65. LiuLX,ZhangWH,JiangHC.Currenttreatmentforlivermetastasesfromcolorectalcancer.World J Gastroenterol.2003;9:193-200.

66. WongSL,EdwardsMJ,ChaoC,SimpsonD,McMastersKM.Radiofrequencyablationforunresectablehepatictumors.The American Journal of Surgery.2001;182:552-557.

67. BerberE, FlesherN, SipersteinAE. Laparoscopic radiofrequency ablationofneuroendocrinelivermetastases.World J Surg.2002;26:985-990.

68. MeijV,ZuetenhorstJM,vanHillegersbergR,etal.Localtreatmentinunresectablehepaticmetastasesofcarcinoidtumors:Experienceswithhepaticarteryembolizationandradiofrequencyablation.World J Surg Oncol.2005;3:75-83.

69. VeenendaalLM,BorelRinkesIH,LipsCJ,vanHillegersbergR.Livermetastasesofneuroendocrinetumours;earlyreductionoftumourloadtoimprovelifeexpectancy.World J Surg Oncol.2006;4:35-41.

70. VeenendaalLM,BorelRinkesIH,vanHillegersbergR.Multipolarradiofrequencyablationof largehepaticmetastasesofendocrinetumours.Eur J Gastroenterol Hepatol.2006;18:89-92.

71. deBaereT,EliasD,DromainC,et al.Radiofrequencyablationof 100hepaticmetastaseswithameanfollow-upofmorethan1year.AJR Am J Roentgeno.l2000;175:1619-1625.

72. CozziPJ,EnglundR,MorrisDL.Cryotherapytreatmentofpatientswithhepaticmetastasesfromneuroendocrinetumors.Cancer.1995;76:501-509.

73. ShapiroRS,ShafirM,SungM,WarnerR,GlajchenN.Cryotherapyofmetastaticcarcinoidtumors.Abdom Imaging.1998;23:314-3147.

74. CurleySA,MarraP,BeatyK,etal.Earlyandlatecomplicationsafterradiofrequencyablationofmalignantlivertumorsin608patients.Ann Surg.2004;239:450-458.

75. HennAR,LevineEA,McNultyW,ZagoriaRJ.Percutaneousradiofrequencyablationofhepaticmetastasesforsymptomaticreliefofneuroendocrinesyndromes.AJR Am J Roentgenol.2003;181:1005-1010.

76. PoonRT,NgKK,LamCM,etal.Learningcurveforradiofrequencyablationoflivertumors:prospectiveanalysisofinitial100patientsinatertiaryinstitution.Ann Surg.2004;239:441-449.

77. KvolsL,MoertelC,O’ConnellM,SchuttA,RubinJ,HahnR.Treatmentofthemalignantcarcinoidsyndrome.Evaluationofalong-actingsomatostatinanalogue.N Engl J Med.1986;315:663-666.

78. GunnSH,SchwimerJE,CoxM,AnthonyCT,O’DorisioMS,WolteringEA.Invitromodelingoftheclinicalinteractionsbetweenoctreotideand111In-pentetreotide:isthereevidenceofsomatostatinreceptordownregulation?J Nucl Med.2006;47:354-359.

79. DorrU,RathU,Sautter-BihlML,etal.Improvedvisualizationofcarcinoidlivermetastasesbyindium-111pentetreotidescintigraphyfollowingtreatmentwithcoldsomatostatinanalogue.Eur J Nucl Med.1993;20:431-433.

80. DorrU,WurmK,HoringE,GuzmanG,RathU,BihlH.Diagnosticreliabilityofsomatostatinreceptorscintigraphyduringcontinuoustreatmentwithdifferentsomatostatinanalogs.Horm Metab Res Suppl.1993;27:36-43.

81. GordenP,ComiRJ,MatonPN,GoVL.NIHconference.Somatostatinandsomatostatinanalogue(SMS201-995)intreatmentofhormone-secretingtumorsofthepituitaryandgastrointestinaltractandnon-neoplasticdiseasesofthegut.Ann Intern Med.1989;110:35-50.

82. RubinJ,AjaniJ,SchirmerW,etal.OctreotideAcetateLong-ActingFormulationVersusOpen-LabelSubcutaneousOctreotideAcetate inMalignantCarcinoidSyndrome.J Clin Oncol.1999;17:600-606.

Man

agem

ent o

�� pat

ient

s w

ith

neur

oend

ocri

ne tu

mou

rs

1.1

�83. ÖbergK,KvolsL,CaplinM,etal.Consensusreportontheuseofsomatostatinanalogsforthemanagementofneuroendocrinetumorsofthegastroenteropancreaticsystem.Ann Oncol.2004;15:966-973.

84. HussainiSH,PereiraSP,MurphyGM,etal.Compositionofgallbladderstonesassociatedwithoctreotide:responsetooralursodeoxycholicacid.Gut.1995;36:126-132.

85. WolteringEA,MamikunianPM,ZietzS,etal.EffectofoctreotideLARdoseandweightonoctreotidebloodlevelsinpatientswithneuroendocrinetumors.Pancreas.2005;31:392-400.

86. HejnaM,SchmidingerM,RadererM.Theclinicalroleofsomatostatinanaloguesasantineoplasticagents:muchadoaboutnothing?Ann Oncol.2002;13:653-668.

87. ÖbergK,FunaK,AlmG.Effectsofleukocyteinterferononclinicalsymptomsandhormonelevelsinpatientswithmid-gutcarcinoidtumorsandcarcinoidsyndrome.N Engl J Med.1983;309:129-133.

88. ÖbergK.InterferoninthemanagementofneuroendocrineGEP-tumors:areview.Digestion.2000;62Suppl1:92-97.

89. JansonET,ÖbergK.Long-termmanagementofthecarcinoidsyndrome.Treatmentwithoctreotidealoneandincombinationwithalpha-interferon.Acta Oncol.1993;32:225-229.

90. FrankM,KloseKJ,WiedM,IshaqueN,Schade-BrittingerC,ArnoldR.Combinationtherapywithoctreotideandalpha-interferon:effectontumorgrowthinmetastaticendocrinegastroenteropancreatictumors.Am J Gastroenterol.1999;94:1381-1387.

91. FaissS,PapeUF,BohmigM,etal.Prospective,randomized,multicentertrialontheantiproliferativeeffectoflanreotide,interferonalfa,andtheircombinationfortherapyofmetastaticneuroendocrinegastroenteropancreatictumors--theInternationalLanreotideandInterferonAlfaStudyGroup.J Clin Oncol.2003;21:2689-2696.

92. MoertelCG, LefkopouloM, Lipsitz S,HahnRG,KlaassenD. Streptozocin-doxorubicin,streptozocin-fluorouracilorchlorozotocininthetreatmentofadvancedislet-cellcarcinoma.N Engl J Med.1992;326:519-523.

93. MoertelCG,HanleyJA,JohnsonLA.Streptozocinalonecomparedwithstreptozocinplusfluorouracilinthetreatmentofadvancedislet-cellcarcinoma.N Engl J Med.1980;303:1189-1194.

94. ErikssonB,SkogseidB,LundqvistG,WideL,WilanderE,ObergK.Medicaltreatmentandlong-termsurvivalinaprospectivestudyof84patientswithendocrinepancreatictumors.Cancer.1990;65:1883-1890.

95. ChengPN,SaltzLB.Failure toconfirmmajorobjectiveantitumoractivity forstreptozocinanddoxorubicininthetreatmentofpatientswithadvancedisletcellcarcinoma.Cancer.1999;86:944-948.

96. MoertelCG.Treatmentofthecarcinoidtumorandthemalignantcarcinoidsyndrome.J Clin Oncol.1983;1:727-740.

97. RiveraE,AjaniJA.Doxorubicin,streptozocin,and5-fluorouracilchemotherapyforpatientswithmetastaticislet-cellcarcinoma.Am J Clin Oncol.1998;21:36-38.

98. DelaunoitT,DucreuxM,BoigeV,etal.Thedoxorubicin-streptozotocincombinationforthetreatmentofadvancedwell-differentiatedpancreaticendocrinecarcinoma:ajudiciousoption?European Journal of Cancer.2004;40:515-520.

99. O’TooleD,HenticO,CorcosO,Ruszniewski P. Chemotherapy for gastro-enteropancreaticendocrinetumours.Neuroendocrinology.2004;80Suppl1:79-84.

100. FrameJ,KelsenD,KemenyN,etal.AphaseIItrialofstreptozotocinandadriamycininadvancedAPUDtumors.Am J Clin Oncol.1988;11:490-495.

101. SingalPK,IliskovicN.Doxorubicin-InducedCardiomyopathy.N Engl J Med.1998;339:900-905.

50

�102. BukowskiRM,TangenCM,PetersonRF,etal.PhaseIItrialofdimethyltriazenoimidazolecarboxamideinpatientswithmetastaticcarcinoid.ASouthwestOncologyGroupstudy.Cancer.1994;73:1505-1508.

103. RitzelU,LeonhardtU,StockmannF,RamadoriG.Treatmentofmetastasizedmidgutcarcinoidswithdacarbazine.Am J Gastroenterol.1995;90:627-631.

104. vanHazelGA,RubinJ,MoertelCG.Treatmentofmetastaticcarcinoidtumorwithdactinomycinordacarbazine.Cancer Treat Rep.1983;67:583-585.

105. AndreyevHJ,Scott-MackieP,CunninghamD,etal.PhaseIIstudyofcontinuousinfusion fluorouracil and interferon alfa-2b in the palliation ofmalignantneuroendocrinetumors.J Clin Oncol.1995;13:1486-1492.

106. NeijtJP,LacaveAJ,SplinterTA,etal.Mitoxantroneinmetastaticapudomas:aphaseIIstudyoftheEORTCGastro-IntestinalCancerCooperativeGroup.Br J Cancer.1995;71:106-108.

107. AnsellSM,PitotHC,BurchPA,KvolsLK,MahoneyMR,RubinJ.APhaseIIstudyofhigh-dosepaclitaxelinpatientswithadvancedneuroendocrinetumors.Cancer.2001;91:1543-1548.

108. KwekkeboomDJ,TeunissenJJ,BakkerWH,etal.Radiolabeledsomatostatinanalog[177Lu-DOTA0,Tyr3]octreotateinpatientswithendocrinegastroenteropancreatictumors.J Clin Oncol.2005;23:2754-2762.

109. KulkeMH,KimH,ClarkJW,etal.APhaseIItrialofgemcitabineformetastaticneuroendocrinetumors.Cancer.2004;101:934-939.

110. KulkeMH,KimH,StuartK,etal.AphaseIIstudyofdocetaxelinpatientswithmetastaticcarcinoidtumors.Cancer Invest.2004;22:353-359.

111. DucreuxMP,BoigeV,LeboulleuxS,etal.AphaseIIstudyofirinotecanwith5-fluorouracilandleucovorininpatientswithpretreatedgastroenteropancreaticwell-differentiatedendocrinecarcinomas.Oncology.2006;70:134-140.

112. KulkeMH,StuartK,EnzingerPC, et al. Phase II studyof temozolomideandthalidomideinpatientswithmetastaticneuroendocrinetumors.J Clin Oncol.2006;24:401-406.

113. MoertelCG,KvolsLK,O’ConnellMJ,Rubin J.Treatmentofneuroendocrinecarcinomaswithcombinedetoposideandcisplatin.Evidenceofmajortherapeuticactivityintheanaplasticvariantsoftheseneoplasms.Cancer.1991;68:227-232.

114. FjallskogML,GranbergDP,WelinSL,etal.Treatmentwithcisplatinandetoposideinpatientswithneuroendocrinetumors.Cancer.2001;92:1101-1107.

115. HainsworthJD,SpigelDR,LitchyS,GrecoFA.PhaseIItrialofpaclitaxel,carboplatin,andetoposideinadvancedpoorlydifferentiatedneuroendocrinecarcinoma:aMinniePearlCancerResearchNetworkStudy.J Clin Oncol.2006;24:3548-554.

116. SteinmüllerT,KianmaneshR,FalconiM,et al.ConsensusGuidelines for theManagementofPatientswithLiverMetastasesfromDigestive(Neuro)endocrineTumors:Foregut,Midgut,Hindgut,andUnknownPrimary.Neuroendocrinology.2008;87:47-62.

117. RamageJK,GoretzkiPE,ManfrediR,etal.Consensusguidelinesforthemanagementofpatientswithdigestiveneuroendocrinetumours:well-differentiatedcolonandrectumtumour/carcinoma.Neuroendocrinology.2008;87:31-39.

118. NilssonO,vanCutsemE,DelleFaveG,etal.PoorlyDifferentiatedCarcinomasoftheForegut(Gastric,DuodenalandPancreatic).Neuroendocrinology.2006;84:212-215.

119. AhlmanH,NilssonO,McNicolAM,etal.Poorly-differentiatedendocrinecarcinomasofmidgutandhindgutorigin.Neuroendocrinology.2008;87:40-46.

120. WafelmanAR,HoefnagelCA,MaesRA,Beijnen JH.Radioiodinatedmeta-iodobenzylguanidine:areviewofitsbiodistributionandpharmacokinetics,druginteractions,cytotoxicityanddosimetry.Eur J Nucl Med.1994;21:545-559.

Man

agem

ent o

�� pat

ient

s w

ith

neur

oend

ocri

ne tu

mou

rs

1.1

�121. SissonJC,WielandDM.Radiolabeledmeta-iodobenzylguanidine:pharmacologyandclinicalstudies.Am J Physiol Imaging.1986;1:96-103.

122. HoefnagelCA,denHartogJagerFC,TaalBG,AbelingNG,EngelsmanEE.TheroleofI-131-MIBGinthediagnosisandtherapyofcarcinoids.Eur J Nucl Med.1987;13:187-191.

123. ShapiroB.TenyearsofexperiencewithMIBGapplicationsandthepotentialofnewradiolabeledpeptides:apersonaloverviewandconcludingremarks.Q J Nucl Med.1995;39:150-155.

124. Modlin IM,Latich I,ZikusokaM,KiddM,EickG,ChanAK.Gastrointestinalcarcinoids:theevolutionofdiagnosticstrategies.J Clin Gastroenterol.2006;40:572-582.

125. ModlinIM,KiddM,LatichI,ZikusokaMN,ShapiroMD.Currentstatusofgastro-intestinalcarcinoids.Gastroenterology.2005;128:1717-1751.

126. KaltsasG,KorbonitsM,HeintzE,etal.ComparisonofSomatostatinAnalogandMeta-IodobenzylguanidineRadionuclides intheDiagnosisandLocalizationofAdvancedNeuroendocrineTumors.J Clin Endocrinol Metab.2001;86:895-902.

127. TaalBG,HoefnagelCA,ValdesOlmosRA,BootH.Combineddiagnosticimagingwith131I-metaiodobenzylguanidineand111In-pentetreotideincarcinoidtumours.Eur J Cancer.1996;32A:1924-1932.

128. KaltsasGA,MukherjeeJJ,GrossmanAB.ThevalueofradiolabelledMIBGandoctreotideinthediagnosisandmanagementofneuroendocrinetumours.Ann Oncol.2001;12Suppl2:S47-S50.

129. HoefnagelCA.Metaiodobenzylguanidineandsomatostatininoncology:roleinthemanagementofneuralcresttumours.Eur J Nucl Med.1994;21:561-581.

130. BomanjiJB,WongW,GazeMN,etal.Treatmentofneuroendocrinetumoursinadultswith131I-MIBGtherapy.Clin Oncol (R Coll Radiol).2003;15:193-198.

131. BuscombeJR,CaplinME,TibbalsJ,WatkinsonAJ,HilsonAJW.Optimizingtherapyof liverneuroendocrinetumourmetastases.Nucl Med Commun.2003;24:449(Abstract).

132. SaffordSD,ColemanRE,GockermanJP,etal.Iodine-131metaiodobenzylguanidinetreatmentformetastaticcarcinoid.Resultsin98patients.Cancer.2004;101:1987-1993.

133. PathiranaAA,VinjamuriS,ByrneC,GhanehP,Vora J, PostonGJ. 131I-MIBGradionuclidetherapyissafeandcost-effectiveinthecontrolofsymptomsofthecarcinoidsyndrome.Eur J Surg Oncol.2001;27:404-408.

134. TaalBG,HoefnagelCA,ValdesOlmosRA,BootH,BeijnenJH.Palliativeeffectofmetaiodobenzylguanidineinmetastaticcarcinoidtumors.J Clin Oncol.1996;14:1829-1838.

135. SywakMS,PasiekaJL,McEwanA,KlineG,RorstadO.131I-meta-iodobenzylguanidineinthemanagementofmetastaticmidgutcarcinoidtumors.World J Surg.2004;28:1157-1162.

136. BongersV,deKlerkJMH,ZonnenbergBA,deKortG,LipsCJM,vanRijkPP.AcuteLiverNecrosisInducedbyIodine-131-MIBGintheTreatmentofMetastaticCarcinoidTumors.J Nucl Med.1997;38:1024-1026.

137. BlakeGM,LewingtonVJ,FlemingJS,ZivanovicMA,AckeryDM.Modificationby ni fedipine of 13 1I -meta-iodobenzylguanidine kinetics in malignantphaeochromocytoma.Eur J Nucl Med.1988;14:345-348.

138. HoefnagelCA,TaalBG,SivroF,BootH,ValdesOlmosRA.Enhancementof 131I-MIBGuptakeincarcinoidtumoursbyadministrationofunlabelledMIBG.Nucl Med Commun.2000;21:755-61.

139. BrogsitterC,PinkertJ,BredowJ,KittnerT,KotzerkeJ.EnhancedTumorUptakeinNeuroendocrineTumorsAfterIntraarterialApplicationof131I-MIBG.J Nucl Med.2005;46:2112-2116.

52

�140. DrukerBJ,TalpazM,RestaDJ,etal.EfficacyandSafetyofaSpecificInhibitoroftheBCR-ABLTyrosineKinaseinChronicMyeloidLeukemia.N Engl J Med.2001;344:1031-1037.

141. DemetriGD,vonMehrenM,BlankeCD,etal.EfficacyandSafetyof ImatinibMesylateinAdvancedGastrointestinalStromalTumors.N Engl J Med.2002;347:472-480.

142. YaoJC,ZhangJX,RashidA,etal.ClinicalandInvitroStudiesofImatinibinAdvancedCarcinoidTumors.Clin Cancer Res.2007;13:234-240.

143. Duran I, SalazarR,CasanovasO, et al.Newdrugdevelopment indigestiveneuroendocrinetumors.Ann Oncol.2007;18:1307-1313.

144. YaoJC.Moleculartargetedtherapyforcarcinoidandislet-cellcarcinoma.Best Practice & Research Clinical Endocrinology & Metabolism.2007;21:163-172.

145. YaoJC,NgC,HoffPM,etal.Improvedprogressionfreesurvival(PFS),andrapid,sustaineddecreaseintumorperfusionamongpatientswithadvancedcarcinoidtreatedwithbevacizumab.J Clin Oncol (Meeting Abstracts).2005;23:4007.

146. MotzerRJ,RiniBI,BukowskiRM,etal.Sunitinibinpatientswithmetastaticrenalcellcarcinoma.JAMA.2006;295:2516-2524.

147. KulkeMH,LenzHJ,MeropolNJ.Aphase2studytoevaluatetheefficacyandsafetyofSU11248inpatients(pts)withunresectableneuroendocrinetumors(NETs).Journal of Clinical Oncology (Meeting Abstracts).2005;23:310s.

148. HobdayTJ,HolenK,DonehowerR,etal.AphaseIItrialofgefitinibinpatients(pts)withprogressivemetastaticneuroendocrinetumors(NET):APhaseIIConsortium(P2C)study.J Clin Oncol (Meeting Abstracts).2006;24:4043.

149. BjornstiMA,Houghton PJ. The TORpathway a target for cancer therapy.Nat Rev Cancer.2004;4:335-348.

150. YaoJC,PhanA,ChangDZ,etal.PhaseIIstudyofRAD001(everolimus)anddepotoctreotide(sandostatinLAR)inadvancedlowgradeneuroendocrinecarcinoma(LGNET).J Clin Oncol (Meeting Abstracts).2007;25:4503.

151. DuranI,KortmanskyJ,SinghD,etal.AphaseIIclinicalandpharmacodynamicstudyoftemsirolimusinadvancedneuroendocrinecarcinomas.Br J Cancer.2006;95:1148-1154.

152. O’DonnellPH,RatainMJ.Evaluatingtheactivityoftemsirolimusinneuroendocrinecancer.Br J Cancer.2007;96:177;authorreply178-179.

Man

agem

ent o

�� pat

ient

s w

ith

neur

oend

ocri

ne tu

mou

rs

1.1

��

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.

1.2

58

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

Pept

ide

rece

ptor

radi

onuc

lide

ther

apy

(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).

1.2

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

Pept

ide

rece

ptor

radi

onuc

lide

ther

apy

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.

Pept

ide

rece

ptor

radi

onuc

lide

ther

apy

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%

1.2

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.

Pept

ide

rece

ptor

radi

onuc

lide

ther

apy

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

1.2

66

[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.

Pept

ide

rece

ptor

radi

onuc

lide

ther

apy

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

B

1.2

68

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.

Pept

ide

rece

ptor

radi

onuc

lide

ther

apy

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

1.2

70

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

Pept

ide

rece

ptor

radi

onuc

lide

ther

apy

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

1.2

72

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.

Pept

ide

rece

ptor

radi

onuc

lide

ther

apy

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,

1.2

74

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.

Pept

ide

rece

ptor

radi

onuc

lide

ther

apy

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.

1.2

76

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

Pept

ide

rece

ptor

radi

onuc

lide

ther

apy

REFERENCES

1. KrenningEP,KwekkeboomDJ,BakkerWHetal.Somatostatinreceptorscintigraphywith[111In-DTPAD-Phe1]-and[123I-Tyr3]-octreotide:theRotterdamexperiencewithmorethan1000patients.Eur J Nucl Med.1993;20:716–731.

2. KwekkeboomD,KrenningEP&deJongM.Peptidereceptorimagingandtherapy.J Nucl Med.2000;41:1704–1713.

3. AnderssonP,Forssell-AronssonE,JohansonVetal.InternalizationofIndium-111intohumanneuroendocrinetumorcellsafterincubationwithIndium-111-DTPA-D-Phe1-octreotide.J Nucl Med.1996;37:2002–2006.

4. HoflandLJ,vanKoetsveldPM,WaaijersM.Internalizationoftheradioiodinatedsomatostatinanalog[125I-Tyr3]octreotidebymouseandhumanpituitarytumorcells:increasebyunlabeledoctreotide.Endocrinology.1995;136:3698–3706.

5. deJongM,BreemanWA,BakkerWHetal.Comparisonof111In-labeledsomatostatinanaloguesfortumorscintigraphyandradionuclidetherapy.Cancer Res.1998;58:437–441.

6. ValkemaR,DeJongM,BakkerWHetal.PhaseIstudyofpeptidereceptorradionuclidetherapywith[111In-DTPA0]octreotide:theRotterdamexperience.Semin Nucl Med.2002;32:110–122.

7. McCarthyKE,WolteringEA,AnthonyLB.Insituradiotherapywith111In-pentetreotide.Stateoftheartandperspectives.Q J Nucl Med.2000;44:88–95.

8. KrenningEP,KooijPP,BakkerWHetal.Radiotherapywitharadiolabeledsomatostatinanalogue,[111In-DTPA-D-Phe1]-octreotide.Acasehistory.Ann N Y Acad Sci.1994;733:496–506.

9. CapelloA,KrenningEP,BreemanWAetal.Peptidereceptorradionuclidetherapyinvitrousing[111In-DTPA0]octreotide.J Nucl Med.2003;44:98–104.

10. KrenningEP,deJongM,KooijPPetal.Radiolabelledsomatostatinanalogue(s)forpeptide receptorscintigraphyandradionuclide therapy.Ann Oncol.1999;10(supplement2):S23–S29.

11. SmithMC,LiuJ,ChenTetal.OctreoTher:ongoingearlyclinicaldevelopmentofasomatostatinreceptor-targetedradionuclideantineoplastictherapy.Digestion.2000;62(supplement1):69–72.

12. O’DonoghueJA,BardiesM,WheldonTE.Relationshipsbetweentumorsizeandcurabilityforuniformlytargetedtherapywithbeta-emittingradionuclides.J Nucl Med.1995;36:1902–1909.

13. ReubiJC,WaserB,FoekensJAetal.Somatostatinreceptorincidenceanddistributioninbreastcancerusingreceptorautoradiography:relationshiptoEGFreceptors.Int J Cancer.1990;46:416–420.

14. deJongM,ValkemaR,JamarFetal.Somatostatinreceptor-targetedradionuclidetherapyoftumors:preclinicalandclinical findings.Semin Nucl Med.2002;32:133–140.

15. VirgoliniI,BrittonK,BuscombeJetal.In-andY-DOTA-lanreotide:resultsandimplicationsoftheMAURITIUStrial.Semin Nucl Med.2002;32:148–155.

16. WaldherrC,PlessM,MaeckeHRetal.Tumorresponseandclinicalbenefit inneuroendocrinetumorsafter7.4GBq90Y-DOTATOC.J Nucl Med.2002;43:610–616.

17. KwekkeboomDJ,BakkerWH,KamBLetal.Treatmentofpatientswithgastro-entero-pancreatic(GEP)tumourswiththenovelradiolabelledsomatostatinanalogue[177Lu-DOTA0,Tyr3]octreotate.Eur J Nucl Med Mol Imaging.2003;30:417–422.

18. deJongM,BreemanWA,BernardBFetal.Receptor-targetedradionuclidetherapyusingradiolabelledsomatostatinanalogues:tumoursizeversuscurability.J Nucl Med.2001;28:1026.(abstract).

1.2

78

19. de Jong M , Breeman WA , Bernard BF e t a l . Tumor r e sponse a f t e r[90Y-DOTA0,Tyr3]octreotideradionuclidetherapyinatransplantablerattumormodelisdependentontumorsize.J Nucl Med.2001;42:1841–1846.

20. deJongM,BreemanWAP,ValkemaRetal.Combinationradionuclidetherapyusing177Lu-and90Y-labeledsomatostatinanalogs.J Nucl Med.2005;46:13S–17S.

21. RohrerL,RaulfF,BrunsCetal.Cloningandcharacterizationofafourthhumansomatostatinreceptor.Proc Natl Acad Sci USA.1993;90:4196–4200.

22. PanettaR,GreenwoodMT,WarszynskaAetal.Molecularcloning, functionalcharacterization,andchromosomallocalizationofahumansomatostatinreceptor(somatostatinreceptortype5)withpreferentialaffinityforsomatostatin-28.Mol Pharmacol.1994;45:417–427.

23. YamadaY,PostSR,WangKetal.Cloningandfunctionalcharacterizationofafamilyofhumanandmousesomatostatinreceptorsexpressedinbrain,gastrointestinaltract,andkidney.Proc Natl Acad Sci USA.1992;89:251–255.

24. BrunoJF, BerelowitzM.Somatostatinreceptors:orphanthatfoundfamilyandfunction.Mol Cell Neurosci.1993;4:307–309.

25. YamadaY,Kagimoto S,KubotaA et al. Cloning, functional expression andpharmacologicalcharacterizationofafourth(hSSTR4)andafifth(hSSTR5)humansomatostatinreceptorsubtype.Biochem Biophys Res Commun.1993;195:844–852.

26. ReubiJC,ScharJC,WaserBetal.AffinityprofilesforhumansomatostatinreceptorsubtypesSST1-SST5ofsomatostatinradiotracersselectedforscintigraphicandradiotherapeuticuse.EurJ Nucl Med.2000;27:273–282.

27. HoflandLJ,LambertsSWJ,vanHagenPMetal.Crucialroleforsomatostatinreceptorsubtype2indeterminingtheuptakeof[111In-DTPA-D-Phe1]octreotideinsomatostatinreceptor-positiveorgans.J Nucl Med.2003;44:1315–1321.

28. JohnM,MeyerhofW,RichterDetal.Positivesomatostatinreceptorscintigraphycorrelateswiththepresenceofsomatostatinreceptorsubtype2. Gut.1996;38:33–39.

29. KwekkeboomDJ,BakkerWH,KooijPPetal.[177Lu-DOTAOTyr3]octreotate:comparisonwith[111In-DTPAo]octreotideinpatients.Eur J Nucl Med.2001;28:1319–1325.

30. AnthonyLB,WolteringEA,EspenanGDetal.Indium-111-pentetreotideprolongssurvivalingastroenteropancreaticmalignancies.Semin Nucl Med.2002;32:123–132.

31. BuscombeJR,CaplinME, HilsonAJ.Long-termefficacyofhigh-activity 111In-pentetreotidetherapyinpatientswithdisseminatedneuroendocrinetumors.J Nucl Med.2003;4:1–6.

32. SlooterGD,BreemanWA,MarquetRLetal.Anti-proliferativeeffectofradiolabelledoctreotideinametastasesmodelinratliver. Int J Cancer.1999;81:767–771.33.OtteA,Mueller-BrandJ,DellasSetal.Yttrium-90-labelledsomatostatin-analogueforcancertreatment.Lancet.1998;351:417–418.

34. WaldherrC,PlessM,MaeckeHRetal.Theclinicalvalueof[90Y-DOTA]-D-Phe1-Tyr3-octreotide(90YDOTATOC)inthetreatmentofneuroendocrinetumours:aclinicalphaseIIstudy.Ann Oncol.2001;12:941–945.

35. WaldherrC,SchumacherT,MackeHRetal.Doestumorresponsedependonthenumberoftreatmentsessionsatconstantinjecteddoseusing90Yttrium-DOTATOCinneuroendocrinetumors?Eur J Nucl Med.2002;29:S100.(abstract).

36. ChinolM,BodeiL,CremonesiM, PaganelliG.Receptor-mediatedradiotherapywithY-DOTA-D-Phe-Tyr-octreotide:theexperienceoftheEuropeanInstituteofOncologyGroup.Semin Nucl Med.2002;32:141–147.

37. PaganelliG,BodeiL,HandkiewiczJunakDetal.90Y-DOTA-D-Phe1-Tyr3-octreotideintherapyofneuroendocrinemalignancies. Biopolymers.2002;66:393–398.

Pept

ide

rece

ptor

radi

onuc

lide

ther

apy

38. PaganelliG,ZoboliS,CremonesiMetal.Receptor-mediatedradiotherapywith90Y-DOTA-D-Phe1-Tyr3-octreotide.J Nucl Med.2001;28:426–434.

39. BodeiL,CremonesiM,ZoboliSetal.Receptor-mediatedradionuclidetherapywith90Y-DOTATOCinassociationwithaminoacidinfusion:aphaseIstudy.Eur J Nucl Med Mol Imaging.2003;30:207–216.

40. BodeiL,CremonesiM,GranaCetal.Receptorradionuclidetherapywith 90Y-[DOTA]0-Tyr3-octreotide(90Y-DOTATOC)inneuroendocrinetumours.Eur J Nucl Med Mol Imaging.2004;31:1038–1046.

41. ValkemaR,PauwelsS,KvolsLetal.Long-termfollow-upofaphaseIstudyofpeptidereceptorradionuclidetherapy(PRRT)with(90Y-DOTA0,Tyr3)octreotideinpatientswithsomatostatinreceptorpositivetumours.Eur J Nucl Med.2003;30(supplement2):S232.(abstract).

42. ValkemaR,PauwelsS,KvolsLetal.Survival inpatientswithneuroendocrinetumorsaftertreatmentwith[90Y-DOTA,Tyr)inaphase-1study.J Nucl Med.2003;44(supplement2):136P.

43. BaumRP,SöldnerJ,SchmückingM,NiesenA.Intravenousandintra-arterialpeptidereceptorradionuclidetherapy(PRRT)usingY-90-DOTA-Tyr3-octreotate(Y-90-DOTATATE)inpatientswithmetastaticneuroendocrinetumors. Eur J Nucl Med.2004;31(supplement2):S238.(abstract).

44. BaumRP, Söldner J, SchmückingM, NiesenA. PeptidrezeptorvermittelteRadiotherapie(PRRT)neuroendokrinerTumorenKlinischenIndikationenundErfahrungmit90Yttrium-markiertenSomatostatinanaloga.Der Onkologe.2004;10:1098–1110.

45. KwekkeboomDJ,BakkerWH,TeunissenJJetal.TreatmentwithLu-177-DOTA-Tyr3-octreotateinpatientswithneuroendocrinetumors:interimresults.Eur J Nucl Med Mol Imaging.2003;30(supplement2):S231.(abstract).

46. KwekkeboomDJ,TeunissenJJ,BakkerWHetal.Radiolabelledsomatostatinanalog[177Lu-DOTAO,Tyr3]octreotateinpatientswithendocrinegastroenteropancreatictumors.J Clin Oncol.2005;23:2754–2762.

47. ValkemaR,KvolsL , JamarFet al.Phase 1 studyof therapywith 90Y-SMT487(OctreoTher)inpatientswithsomatostatinreceptor(SS-R)positivetumors.J Nucl Med.2002;43(supplement):33P.(abstract).

48. OtteA,HerrmannR,HeppelerAetal.Yttrium-90DOTATOC:firstclinicalresults.Eur J Nucl Med.1999;26:1439–1447.

49. BakkerWH,KrenningEP,ReubiJCetal.Invivoapplicationof[111In-DTPA-D-Phe1]-octreotidefordetectionofsomatostatinreceptor-positivetumorsinrats.Life Sci.1991;49:1593–1601.

50. KrenningEP,BakkerWH,KooijPPet al. Somatostatin receptor scintigraphywithindium-111-DTPA-D-Phe-1-octreotideinman:metabolism,dosimetryandcomparisonwithiodine-123-Tyr-3-octreotide. J Nucl Med.1992;33:652–658.

51. EmamiB,LymanJ,BrownAetal.Toleranceofnormaltissuetotherapeuticirradiation.Int J Radiat Oncol Biol Phys.1991;21:109–122.

52. Moll S,NickeleitV,Mueller-Brand J et al.Anew cause of renal thromboticmicroangiopathy:Yttrium-90-DOTATOCinternalradiotherapy. Am J Kidney Dis.2001;37:847–851.

53. CybullaM,WeinerSM,OtteA.End-stagerenaldiseaseaftertreatmentwith90Y-DOTATOC.Eur J Nucl Med.2001;28:1552–1554.

54. StoffelMP,PollokM,FriesJ,BaldamusCA.Radiationnephropathyafterradiotherapyinmetastaticmedullarythyroidcarcinoma. Nephrol Dial Transplant.2001; 16:1082–1083.

55. BaroneR,Borson-ChazotF,ValkemaRetal.Patient-specificdosimetryinpredictingrenaltoxicitywith90Y-DOTATOC:relevanceofkidneyvolumeanddoserateinfindingadose–effectrelationship.J Nucl Med.2005;46:99S–106S.

1.2

80

56. ValkemaR,PauwelsSA,KvolsLKetal.Long-termfollow-upofrenalfunctionafterpeptidereceptorradiationtherapywith90Y-DOTA0,Tyr3-octreotideand177Lu-DOTA0,Tyr3-octreotate.J Nucl Med.2005;46:83S–91S.

57. deJongM,RollemanEJ,BernardBFetal.InhibitionofrenaluptakeofIndium-111-DTPA-octreotideinvivo.J Nucl Med.1996;37:1388–1392.

58. JamarF,BaroneR,MathieuIetal.86Y-DOTA0-D-Phe1-Tyr3-octreotide(SMT487)–aphase1clinicalstudy:pharmacokinetics,biodistributionandrenalprotectiveeffectofdifferentregimensofaminoacidco-infusion.Eur J Nucl Med Mol Imaging.2003;30:510–518.

59. RollemanEJ,ValkemaR,deJongMetal.Safeandeffectiveinhibitionofrenaluptakeofradiolabelledoctreotidebyacombinationoflysineandarginine.Eur J Nucl Med Mol Imaging.2003;30:9–15.

60. BaroneR,PauwelsS,DeCampsJetal.Metaboliceffectsofaminoacidsolutionsinfusedforrenalprotectionduringtherapywithradiolabelledsomatostatinanalogues.Nephrol Dial Transplant.2004;19:2275–2281.

61. BushnellD,MendaY,MadsenMetal.Assessmentofhepatictoxicityfromtreatmentwith90Y-SMT487(OctreoTher(TM))inpatientswithdiffusesomatostatinreceptorpositivelivermetastases.Cancer Biother Radiopharm.2003;18:581–588.

62. Toth-FejelS,PommierRF.Relationshipsamongdelayofdiagnosis,extentofdisease,andsurvivalinpatientswithabdominalcarcinoidtumors.Am J Surg.2004;187:575–579.

63. deJongM,KwekkeboomD,ValkemaR, KrenningEP.Radiolabelledpeptidesfortumourtherapy:currentstatusandfuturedirections.PlenarylectureattheEANM2002.Eur J Nucl Med Mol Imaging.2003;30:463–469.

64. SandersC,EggerM,DonovanJetal.Reportingonqualityoflifeinrandomisedcontrolledtrials:bibliographicstudy.BMJ (Clin Res Ed.).1998;317:1191–1194.

65. BushnellD,O’DorisioT,MendaYetal.Evaluatingtheclinicaleffectivenessof90Y-SMT487inpatientswithneuroendocrinetumors.J Nucl Med.2003;44:1556–1560.

66. Teunissen JJ,KwekkeboomDJ, KrenningEP.Qualityof life inpatientswithgastroenteropancreatictumorstreatedwith[177Lu-DOTA0,Tyr3]octreotate.J Clin Oncol.2004;22:2724–2729.

67. WildD,SchmittJS,GinjMetal.DOTA-NOC,ahigh-affinityligandofsomatostatinreceptorsubtypes2,3and5forlabellingwithvariousradiometals.Eur J Nucl Med Mol Imaging.2003;30:1338–1347.

68. BéhéM,PuskenM,HenzelMetal.Upregulationofgastrinandsomatostatinreceptorafterirradiation.Eur J Nucl Med.2003;44(supplement2):S218.(abstract).

69. Reubi JC, WaserB.Concomitant expressionof severalpeptide receptors inneuroendocrinetumours:molecularbasisforinvivomultireceptortumourtargeting.Eur J Nucl Med Mol Imaging.2003;30:781–793.

70. vanPuttenJWG,PriceA,vanderLeestAHDetal.AphaseIstudyofgemcitabinewithconcurrentradiotherapyinstageIII,locallyadvancednon-smallcelllungcancer.Clin Cancer Res.2003;9:2472–2477.

Pept

ide

rece

ptor

radi

onuc

lide

ther

apy

1.2

1.3Aims and outline o�� the thesis

84

Aim

s an

d ou

tlin

e o��

the

thes

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.

Trea

tmen

t o�� p

atie

nts

wit

h ga

stro

ente

ropa

ncre

atic

(GEP

)�� tum

ours

wit

h th

e no

vel r

adio

labe

lled

som

atos

tati

n an

alog

ue [17

7 Lu-D

OTA

0 ,Tyr

3 ]oct

reot

ate

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.

Trea

tmen

t o�� p

atie

nts

wit

h ga

stro

ente

ropa

ncre

atic

(GEP

)�� tum

ours

wit

h th

e no

vel r

adio

labe

lled

som

atos

tati

n an

alog

ue [17

7 Lu-D

OTA

0 ,Tyr

3 ]oct

reot

ate

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.

2.1

96

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

Trea

tmen

t o�� p

atie

nts

wit

h ga

stro

ente

ropa

ncre

atic

(GEP

)�� tum

ours

wit

h th

e no

vel r

adio

labe

lled

som

atos

tati

n an

alog

ue [17

7 Lu-D

OTA

0 ,Tyr

3 ]oct

reot

ate

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.

2.1

98

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.

Trea

tmen

t o�� p

atie

nts

wit

h ga

stro

ente

ropa

ncre

atic

(GEP

)�� tum

ours

wit

h th

e no

vel r

adio

labe

lled

som

atos

tati

n an

alog

ue [17

7 Lu-D

OTA

0 ,Tyr

3 ]oct

reot

ate

REFERENCES

1. ArnoldR,BenningR,NeuhausC,RolwageM,TrautmannME.Gastroenteropancreaticendocrinetumours:effectofSandostatinontumourgrowth.TheGermanSandostatinStudyGroup.Digestion.1993;54(Suppl1):72–75.

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.

5. McCarthyKE,WolteringEA,EspenanGD,CroninM,MaloneyTJ,AnthonyLB.Insituradiotherapywith111Inpentetreotide:initialobservationsandfuturedirections.Cancer J Sci Am.1998;4:94-102.

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.

2.1

100

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.

Trea

tmen

t o�� p

atie

nts

wit

h ga

stro

ente

ropa

ncre

atic

(GEP

)�� tum

ours

wit

h th

e no

vel r

adio

labe

lled

som

atos

tati

n an

alog

ue [17

7 Lu-D

OTA

0 ,Tyr

3 ]oct

reot

ate

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.

2.2

106

�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.

Rad

iola

bele

d so

mat

osta

tin

anal

og [17

7 Lu-D

OTA

0 ,Tyr

3 ]oct

reot

ate

in p

atie

nts

wit

h en

docr

ine

gast

roen

tero

panc

reat

ic tu

mor

s

�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.

2.2

108

�

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

Rad

iola

bele

d so

mat

osta

tin

anal

og [17

7 Lu-D

OTA

0 ,Tyr

3 ]oct

reot

ate

in p

atie

nts

wit

h en

docr

ine

gast

roen

tero

panc

reat

ic tu

mor

s

�

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).

110

�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).

Rad

iola

bele

d so

mat

osta

tin

anal

og [17

7 Lu-D

OTA

0 ,Tyr

3 ]oct

reot

ate

in p

atie

nts

wit

h en

docr

ine

gast

roen

tero

panc

reat

ic tu

mor

s

�

2.2

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.

Rad

iola

bele

d so

mat

osta

tin

anal

og [17

7 Lu-D

OTA

0 ,Tyr

3 ]oct

reot

ate

in p

atie

nts

wit

h en

docr

ine

gast

roen

tero

panc

reat

ic tu

mor

s

�

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.

Rad

iola

bele

d so

mat

osta

tin

anal

og [17

7 Lu-D

OTA

0 ,Tyr

3 ]oct

reot

ate

in p

atie

nts

wit

h en

docr

ine

gast

roen

tero

panc

reat

ic tu

mor

s

�

2.2

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

Rad

iola

bele

d so

mat

osta

tin

anal

og [17

7 Lu-D

OTA

0 ,Tyr

3 ]oct

reot

ate

in p

atie

nts

wit

h en

docr

ine

gast

roen

tero

panc

reat

ic tu

mor

s

�

2.2

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.

Rad

iola

bele

d so

mat

osta

tin

anal

og [17

7 Lu-D

OTA

0 ,Tyr

3 ]oct

reot

ate

in p

atie

nts

wit

h en

docr

ine

gast

roen

tero

panc

reat

ic tu

mor

s

�

2.2

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

�REFERENCES

1. ArnoldR,BenningR,NeuhausC,etal.Gastroenteropancreaticendocrinetumours:EffectofSandostatinontumourgrowth—TheGermanSandostatinStudyGroup.Digestion 1993; 54(suppl1):72-75.

2. JansonET,ObergK.Long-termmanagementofthecarcinoidsyndrome:Treatmentwithoctreotidealoneandincombinationwithalphainterferon.Acta Oncol1993;32:225-229.

3. DucreuxM,RuszniewskiP,ChayvialleJA,etal.Theantitumoraleffectofthelong-actingsomatostatinanaloglanreotideinneuroendocrinetumors.Am J Gastroenterol2000;95:3276-3281.

4. ValkemaR,deJongM,BakkerWH,etal.PhaseIstudyofpeptidereceptorradionuclidetherapywith[111In-DTPA0]octreotide:TheRotterdamexperience.Seminars Nucl Med2002;32:110-122.

5. AnthonyLB,WolteringEA,EspananGD,etal.Indium-111-pentetreotideprolongssurvivalingastroenteropancreaticmalignancies.Seminars Nucl Med2002;32:123-132.

6. WaldherrC,PlessM,MaeckeHR,etal.Theclinicalvalueof[90Y-DOTA]-D-Phe1-Tyr3-octreotide(90Y-DOTATOC)inthetreatmentofneuroendocrinetumours:AclinicalphaseIIstudy.Ann Oncol2001; 12:941-945.

7. WaldherrC,PlessM,MaeckeHR,etal.Tumorresponseandclinicalbenefit inneuroendocrinetumorsafter7.4GBq90Y-DOTATOC.J Nucl Med2002;43:617-620.

8. PaganelliG,BodeiL,HandkiewiczJunakD,etal.90Y-DOTA-D-Phe1-Tyr3-octreotideintherapyofneuroendocrinemalignancies.Biopolymers2002;66:393-398.

9. BodeiL,CremonesiM,ZoboliS,etal.Receptor-mediatedradionuclidetherapywith90Y-DOTATOCinassociationwithaminoacidinfusion:AphaseIstudy.Eur J Nucl Med Mol Imag2003;30:207-216.

10. ValkemaR,PauwelsS,KvolsL,etal.Long-termfollow-upofaphase1studyofpeptidereceptorradionuclidetherapy(PRRT)with[90Y-DOTA0,Tyr3]octreotideinpatientswithsomatostatinreceptorpositivetumours.Eur J Nucl Med Mol Imaging 2003;30(suppl2,abstr):S232.

11. WaldherrC,SchumacherT,MaeckeHR,etal.Doestumorresponsedependonthenumberoftreatmentsessionsatconstantinjecteddoseusing90Yttrium-DOTATOCinneuroendocrinetumors?Eur J Nucl Med 2002;29(suppl,abstr):S100.

12. ReubiJC,ScharJC,WaserB,etal.AffinityprofilesforhumansomatostatinreceptorsubtypesSST1-SST5ofsomatostatinradiotracersselectedforscintigraphicandradiotherapeuticuse.Eur J Nucl Med 2000;27:273-282.

13. Erion JL ,Bugaj JE,SchmidtMA,et al.High radiotherapeutic efficacyof [Lu-177]-DOTAY(3)-octreotate ina rat tumormodel. J Nucl Med 1999;40(suppl,abstr):223P.

14. KwekkeboomDJ, BakkerWH,Kooij PP, et al. [17 7Lu-DOTA0Tyr3]octreotate:Comparisonwith[111In-DTPA0]octreotideinpatients.Eur J Nucl Med 2001;28:1319-1325.

15. KwekkeboomDJ,BakkerWH,KamBL,etal.Treatmentofpatientswithgastro-enteropancreatic(GEP)tumourswiththenovelradiolabelledsomatostatinanalogue[177Lu-DOTA0,Tyr3]octreotate.Eur J Nucl Med Mol Imaging 2003;30:417-422.

16. GreenS,WeissGR.SouthwestOncologyGroupstandardresponsecriteria,endpointdefi-nitionsandtoxicitycriteria.Invest New Drugs 1992;10:239-253.

17. OtteA,HerrmannR,HeppelerA,etal.Yttrium-90DOTATOC:Firstclinicalresults.Eur J Nucl Med 1999;26:1439-1447.

Rad

iola

bele

d so

mat

osta

tin

anal

og [17

7 Lu-D

OTA

0 ,Tyr

3 ]oct

reot

ate

in p

atie

nts

wit

h en

docr

ine

gast

roen

tero

panc

reat

ic tu

mor

s

�

2.2

18. WichersM,BenzE,PalmedoH,etal.Testicularfunctionafterradioiodinetherapyforthyroidcarcinoma.Eur J Nucl Med 2000; 27:503-507.

19. FaissS,PapeUF,BohmigM,etal.Prospective,randomized,multicentertrialontheantiproliferativeeffectoflanreotide,interferonalfa,andtheircombinationfortherapyofmetastaticneuroendocrinegastroenteropancreatictumors:TheInternationalLanreotideandInterferonAlfaStudyGroup.J Clin Oncol 2003;21:2689-2696.

20. MoertelCG.Treatmentofthecarcinoidtumorandthemalignantcarcinoidsyndrome.J Clin Oncol 1983;1:727-740.

21. MoertelCG,HanleyJA,JohnsonLA.Streptozocinalonecomparedwithstreptozocinplusfluorouracilinthetreatmentofadvancedislet-cellcarcinoma.N Engl J Med 1980;303:1189-1194.

22. MoertelCG,LefkopouloM,LipsitzS,etal.Streptozocin-doxorubicin,streptozocin-fluorouracilorchlorozotocininthetreatmentofadvancedislet-cellcarcinoma.N Engl J Med 1992;326:519-523.

23. ChengPN,SaltzLB.Failure toconfirmmajorobjectiveantitumoractivity forstreptozocinanddoxorubicininthetreatmentofpatientswithadvancedisletcellcarcinoma.Cancer1999;86:944-948.

24. VanHazelGA,RubinJ,MoertelCG.Treatmentofmetastaticcarcinoidtumorwithdactinomycinordacarbazine.Cancer Treat Rep 1983;67:583-585.

25. BukowskiRM,TangenCM,PetersonRF,etal.PhaseIItrialofdimethyltriazenoimidazolecarboxamideinpatientswithmetastaticcarcinoid.Cancer1994;73:1505-1508.

26. RitzelU,LeonhardtU,StockmannF,etal.Treatmentofmetastasizedmidgutcarcinoidswithdacarbazine.Am J Gastroenterol 1995;90:627-631

27. AndreyevHJ,Scott-MackieP,CunninghamD,etal.PhaseIIstudyofcontinuousinfusion fluorouracil and interferon alfa-2b in the palliation ofmalignantneuroendocrinetumors.J Clin Oncol 1995;13:1486-1492.

28. NeijtJP,LacaveAJ,SplinterTA,etal.Mitoxantroneinmetastaticapudomas:AphaseIIstudyoftheEORTCGastro-IntestinalCancerCooperativeGroup.Br J Cancer 1995;71:106-108.

29. AnsellSM,PitotHC,BurchPA,etal.AphaseIIstudyofhigh-dosepaclitaxelinpatientswithadvancedneuroendocrinetumors.Cancer2001;91:1543-1548.

30. O’TooleD,HenticO,CorcosO,etal.Chemotherapyforgastro-enteropancreaticendocrinetumours.Neuroendocrinology2004;80(suppl1):79-84.

31. PelosiG,BresaolaE,BoginaG,etal.Endocrine tumorsof thepancreas:Ki-67immunoreactivityonparaffinsectionsisanindependentpredictorformalignancy—Acomparativestudywithproliferating-cellnuclearantigenandprogesteronereceptorproteinimmunostaining,mitoticindex,andotherclinicopathologicvariables.Human Pathol 1996;27:1124-1134.

32. LaRosaS,SessaF,CapellaC,etal.Prognosticcriteriainnonfunctioningpancreaticendocrinetumours.Virchows Arch 1996;429:323-333.

33. JordaM,GhorabZ,FernandezG,etal.Lownuclearproliferativeactivityisassociatedwithnonmetastaticisletcelltumors.Arch Pathol Lab Med 2003;127:196-199.

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

33

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

126

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.

Qua

lity

o�� L

i��e in

pat

ient

s w

ith

gast

roen

tero

panc

reat

ic tu

mor

s tr

eate

d w

ith

[177 Lu

-DO

TA0 ,T

yr3 ]o

ctre

otat

e

33

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.

128

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).

Qua

lity

o�� L

i��e in

pat

ient

s w

ith

gast

roen

tero

panc

reat

ic tu

mor

s tr

eate

d w

ith

[177 Lu

-DO

TA0 ,T

yr3 ]o

ctre

otat

e

33

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).

130

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).

Qua

lity

o�� L

i��e in

pat

ient

s w

ith

gast

roen

tero

panc

reat

ic tu

mor

s tr

eate

d w

ith

[177 Lu

-DO

TA0 ,T

yr3 ]o

ctre

otat

e

33

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.

132

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

Qua

lity

o�� L

i��e in

pat

ient

s w

ith

gast

roen

tero

panc

reat

ic tu

mor

s tr

eate

d w

ith

[177 Lu

-DO

TA0 ,T

yr3 ]o

ctre

otat

e

33

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

134

scale,itsuggeststhat,inpatientswithPD,evenasmallchangeinanyotherscalecouldhavehadalargeimpactontheiroverallhealth/QoL.BecauseourgroupwithPDrepresentedasmallnumberofpatientsand,moreover,onepatientwaslosttofollow-up,theaccuracyoftheseobservationsremainsquestionable.Also,aplaceboeffectcannotberuledoutcompletely.

Inconclusion,wefoundthat177Lu-octreotatetherapyimprovedtheQoLinpatientswithmetastasizedGEPtumors,especiallyinthepatientswithprovenregression.

ACKNOWLEDGMENTWewishtothankallthepatientswhoparticipatedinthisstudyandthesupportingpersonneloftheDepartmentofNuclearMedicinefortheirexperthelpandeffort.

Qua

lity

o�� L

i��e in

pat

ient

s w

ith

gast

roen

tero

panc

reat

ic tu

mor

s tr

eate

d w

ith

[177 Lu

-DO

TA0 ,T

yr3 ]o

ctre

otat

e

33

REFERENCES

1. Crocetti E , Paci E .Malignant carcinoids in theUSA, SEER 1992-1999. Anepidemiologicalstudywith6830cases.Eur J Cancer Prev.2003;12:191-194.

2. KulkeMH,MayerRJ:Carcinoidtumors.N Engl J Med.1999;340:858-868.3. ArnoldR,SimonB,WiedM.TreatmentofneuroendocrineGEPtumourswith

somatostatinanalogues.Digestion.2000;62:84-91.4. LeongWL,PasiekaJL.Regressionofmetastaticcarcinoidtumorswithoctreotide

therapy:Twocasereportsandareviewoftheliterature.J Surg Oncol.2002;79:180-187.

5. ImtiazKE,MonteithP,KhaleeliA.Completehistologicalregressionofmetastaticcarcinoidtumouraftertreatmentwithoctreotide.Clin Endocrinol (Oxf).200053:755-758.

6. DucreuxM,RuszniewskiP,ChayvialleJA,etal.Theantitumoraleffectofthelong-actingsomatostatinanaloglanreotideinneuroendocrinetumors.Am J Gastroenterol.2000;95:3276-3281.

7. OtteA,Mueller-BrandJ,DellasS,etal.Yttrium-90-labelledsomatostatine-analogueforcancertreatment.Lancet.1998;351:417-418.

8. KwekkeboomD,KrenningEP,deJongM:Peptidereceptorimagingandtherapy.J Nucl Med.2000;41:1704-1713.

9. KwekkeboomDJ,BakkerWH,KamBL,etal.Treatmentofpatientswithgastro-enteropancreatic(GEP)tumourswiththenovelradiolabelledsomatostatinanalogue[177Lu-DOTA0,Tyr3]octreotate.Eur J Nucl Med Mol Imaging2003;30:417-422.

10. AaronsonNK,AhmedzaiS,BergmanB,et al.TheEuropeanOrganization forResearchandTreatmentofCancerQLQ-C30:aquality-of-lifeinstrumentforuseininternationalclinicaltrialsinoncology.J Natl CancerInst1993;85:365-376.

11. KarnofskyDA,AbelmanWH,CranerLF,etal.Theuseofnitrogenmustardsinpalliativetreatmentofcarcinoma.Cancer 1948;1:634-656.

12. FayersPM,AaronsonNK,BjordalK,etal.TheEORTCQLQ-C30ScoringManual(2ndEdition).EuropeanOrganizationforResearchandTreatmentofCancer1999,Brussels,Belgium

13. OsobaD,RodriguesG,MylesJ,etal.Interpretingthesignificanceofchangesinhealth-relatedquality-of-lifescores.J Clin Oncol. 1998;16:139-144.

14. FayersPM,CurranD,MachinD.Incompletequalityoflifedatainrandomizedtrials:Missingitems.Stat Med.1998;17:679-696.

15. LarssonG,vonEssenL,SjodenPO.Health-relatedqualityoflifeinpatientswithendocrinetumoursofthegastrointestinaltract.Acta Oncol. 1999;38:481-490.

16. CoatesA,PorzsoltF,OsobaD.Qualityoflifeinoncologypractice:PrognosticvalueofEORTCQLQ-C30scoresinpatientswithadvancedmalignancy.Eur J Cancer. 1997;33:1025-1030.

17. FayersPM,SprangersMA.Understandingself-ratedhealth.Lancet. 2002;359:187-188.

18. GlausA,CrowR,HammondS.Aqualitativestudytoexploretheconceptoffatigue/tirednessincancerpatientsandinhealthyindividuals.Support Care Cancer. 1996;4:82-96.

19. MorrowGR,AndrewsPL,HickokJT,etal.Fatigueassociatedwithcanceranditstreatment.Support Care Cancer. 2002;10:389-398.

20. BergerA.Treatingfatigueincancerpatients.Oncologist.2003;8(suppl1):10-14.21. SavardJ,MorinCM.Insomniainthecontextofcancer:Areviewofaneglected

problem.J Clin Oncol. 2001;19:895-908.22. SchaafsmaJ,OsobaD.TheKarnofskyPerformanceStatusScalere-examined:A

crossvalidationwiththeEORTC-C30.Qual Life Res. 1994;3:413-424.

136

23. KobayashiK,TakedaF,TeramukaiS,etal.Across-validationof theEuropeanOrganizationforResearchandTreatmentofCancerQLQ-C30(EORTCQLQ-C30)forJapanesewithlungcancer.Eur J Cancer. 1998;34:810-815.

24. LarssonG,vonEssenL,SjodenPO.Qualityoflifeinpatientswithendocrinetumorsofthegastrointestinaltract:Patientandstaffperceptions.Cancer Nurse.1998;21:411-420.

25. WaldherrC,PlessM,MaeckeHR,etal.Tumorresponseandclinicalbenefit inneuroendocrinetumorsafter7.4GBq90Y-DOTATOC.J Nucl Med.2002;43:610-616.

Qua

lity

o�� L

i��e in

pat

ient

s w

ith

gast

roen

tero

panc

reat

ic tu

mor

s tr

eate

d w

ith

[177 Lu

-DO

TA0 ,T

yr3 ]o

ctre

otat

e

33

�

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

4

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

142

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.

E����e

cts

o�� th

erap

y w

ith

[177 Lu

-DO

TA0 ,T

yr3 ]o

ctre

otat

e on

end

ocri

ne ��u

nctio

n

4

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.

144

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

E����e

cts

o�� th

erap

y w

ith

[177 Lu

-DO

TA0 ,T

yr3 ]o

ctre

otat

e on

end

ocri

ne ��u

nctio

n

4

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.

146

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.

E����e

cts

o�� th

erap

y w

ith

[177 Lu

-DO

TA0 ,T

yr3 ]o

ctre

otat

e on

end

ocri

ne ��u

nctio

n

4

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

148

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.

E����e

cts

o�� th

erap

y w

ith

[177 Lu

-DO

TA0 ,T

yr3 ]o

ctre

otat

e on

end

ocri

ne ��u

nctio

n

4

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.

150

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

E����e

cts

o�� th

erap

y w

ith

[177 Lu

-DO

TA0 ,T

yr3 ]o

ctre

otat

e on

end

ocri

ne ��u

nctio

n

4

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

152

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

E����e

cts

o�� th

erap

y w

ith

[177 Lu

-DO

TA0 ,T

yr3 ]o

ctre

otat

e on

end

ocri

ne ��u

nctio

n

4

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.

154

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.

E����e

cts

o�� th

erap

y w

ith

[177 Lu

-DO

TA0 ,T

yr3 ]o

ctre

otat

e on

end

ocri

ne ��u

nctio

n

4

REFERENCES

1. BodeiL,CremonesiM,ZoboliS,GranaC,BartolomeiM,RoccaP,CaraccioloM,MäckeHR,ChinolM,Paganelli,G.Receptor-mediatedradionuclidetherapywith90Y-DOTATOCinassociationwithaminoacidinfusion:aphaseIstudy.Eur J Nucl Med Mol Imaging.2003;30,207-216.

2. WaldherrC,PlessM,MäckeHR,SchumacherT,Crazzolara,A,NitzscheEU,HaldemannA,Müller-BrandJ.Tumorresponseandclinicalbenefitinneuroendocrinetumorsafter7.4GBq90Y-DOTATOC.J Nucl Med.2002;43,610-616.

3. KwekkeboomDJ,Müller-BrandJ,PaganelliG,AnthonyLB,PauwelsS,KvolsLK,O’DorisioTM,ValkemaR,BodeiL,ChinolM,MäckeHR,KrenningEP.OverviewofResultsofPeptideReceptorRadionuclideTherapywith3RadiolabeledSomatostatinAnalogs.J Nucl Med.2005;46,62S-66S.

4. WaldherrC,PlessM,MäckeHR,HaldemannA,Müller-Brand, J.Theclinicalvalueof[90Y-DOTA]-D-Phe1-Tyr3-octreotide(90Y-DOTATOC)inthetreatmentofneuroendocrinetumours:aclinicalphaseIIstudy.Ann Oncol.2001;12,941-945.

5. KwekkeboomDJ,TeunissenJJ,BakkerWH,KooijPP,deHerderWW,FeeldersRA,vanEijckCH,EsserJP,KamBL,KrenningEP.Radiolabeledsomatostatinanalog[177Lu-DOTA0,Tyr3]octreotateinpatientswithendocrinegastroenteropancreatictumors.J Clin Oncol.2005;23,2754-2762.

6 MollS,NickeleitV,Müller-BrandJ,BrunnerFP,MäckeHR,MihatschMJ.Anewcauseofrenalthromboticmicroangiopathy:yttrium90-DOTATOCinternalradiotherapy.Am J Kidney Dis.2001;37,847-851.

7 StoffelMP,PollokM,FriesJ,BaldamusCA.Radiationnephropathyafterradiotherapyinmetastaticmedullarythyroidcarcinoma.Nephrol Dial Transplant.2001;16,1082-1083.

8 CybullaM,WeinerSM,OtteA.End-stage renaldiseaseafter treatmentwith90Y-DOTATOC.Eur J Nucl Med.2001;28,1552-1554.

9 RollemanE,ValkemaR,de JongM,KooijPP,Krenning,EP.Safeandeffectiveinhibitionofrenaluptakeofradiolabelledoctreotidebyacombinationoflysineandarginine.European Journal of Nuclear Medicine and Molecular Imaging.2003;30,9-15.

10 KimuraN,SchindlerM,KasaiN,KimuraI.Immunohistochemicallocalizationofsomatostatinreceptortype2Ainratandhumantissues.Endocr J.2001;48,95-102.

11 ZatelliMC,degliUbertiEC.Somatostatinreceptors:frombasicsciencetoclinicalapproach-thyroid.Digestive and Liver Disease.2004;36,S86-S92.

12 BaouN,BourasM,DrozJP,BenahmedM,KranticS.Evidenceforaselectivelossofsomatostatinreceptorsubtypeexpressioninmalegermcelltumorsofseminomatype.Carcinogenesis.2000;21,805-810.

13 SasakiA,YoshinagaK.Immunoreactivesomatostatininmalereproductivesysteminhumans.J Clin Endocrinol Metab.1989;68,996-999.

14 ReubiJC,SchärJC,WaserB,WengerS,HeppelerA,SchmittJS,MäckeHR.AffinityprofilesforhumansomatostatinreceptorsubtypesSST1-SST5ofsomatostatinradiotracersselectedforscintigraphicandradiotherapeuticuse.Eur J Nucl Med.2000;27,273-282.

15 SödergardR,BackstromT,ShanbhagV,CarstensenH.Calculationoffreeandboundfractionsoftestosteroneandestradiol-17betatohumanplasmaproteinsatbodytemperature.J Steroid Biochem.1982;16,801-810.

16 VisserTJ,DocterR,HennemannG.Radioimmunoassayofreversetri-iodothyronine.J Endocrinol.,1977;73,395-396.

156

17 DruckenthanerM,SchwarzerC,EnsingerC,GabrielM,PrommeggerR,RiccabonaG,DecristoforoC.EvidenceforSomatostatinreceptor2inthyroidtissue.Regul Pept.2007;138,32-39.

18 ReubiJC,WaserB,SchaerJC,LaissueJA.Somatostatinreceptorsst1-sst5expressioninnormalandneoplastichumantissuesusingreceptorautoradiographywithsubtype-selectiveligands.Eur J Nucl Med.2001;28,836-846.

19 FombonneJ,CsabaZ,vonBoxbergY,ValayerA,ReyC,BenahmedM,DournaudP&KranticS.Expressionofsomatostatinreceptortype-2(sst2A)inimmatureporcineLeydigcellsandapossibleroleinthelocalcontroloftestosteronesecretion.Reprod Biol Endocrinol.2003;1,19.

20 HoflandLJ,LambertsSW,vanHagenPM,ReubiJC,SchaefferJ,WaaijersM,vanKoetsveldPM,SrinivasanA,KrenningEP,BreemanWA.Crucialroleforsomatostatinreceptorsubtype2indeterminingtheuptakeof[111In-DTPA-D-Phe1]octreotideinsomatostatinreceptor-positiveorgans.J Nucl Med.2003;44,1315-1321.

21 ChlebowskiRTandHeberD.Hypogonadisminmalepatientswithmetastaticcancerpriortochemotherapy.Cancer Res.1982;42,2495-2498.

22 TurnerHEandWass, JA.Gonadal function inmenwithchronic illness.Clin Endocrinol (Oxf).1997;47,379-403.

23 deRondeW,vanderSchouwYT,PierikFH,PolsHA,MullerM,GrobbeeDE,GoorenLJ,WeberRF,deJongFH.Serumlevelsofsexhormone-bindingglobulin(SHBG)arenotassociatedwithlowerlevelsofnon-SHBG-boundtestosteroneinmalenewbornsandhealthyadultmen.Clin Endocrinol (Oxf).2005;62,498-503.

24 UkkolaO,GagnonJ,RankinenT,ThompsonPA,HongY,LeonAS,RaoDC,SkinnerJS,WilmoreJH,BouchardC.Age,bodymassindex,raceandotherdeterminantsofsteroidhormonevariability:theHERITAGEFamilyStudy.Eur J Endocrinol.2001;145,1-9.

25 CavaliereH,AbelinN,Medeiros-NetoG.SerumlevelsoftotaltestosteroneandsexhormonebindingglobulininhypothyroidpatientsandnormalsubjectstreatedwithincrementaldosesofL-T4orL-T3.J Androl.1988;9,215-219.

26 WichersM,BenzE,PalmedoH,BiersackHJ,GrunwaldF,KlingmullerD.Testicularfunctionafterradioiodinetherapyforthyroidcarcinoma.Eur J Nucl Med.2000;27,503-507.

27 RosarioPW,BarrosoAL,RezendeLL,PadraoEL,BorgesMA,GuimaraesVC,PurischS.Testicularfunctionafterradioiodinetherapyinpatientswiththyroidcancer.Thyroid.2006;16,667-670.

28 HandelsmanDJandTurtleJR.Testiculardamageafterradioactiveiodine(I-131)therapyforthyroidcancer.Clin Endocrinol (Oxf).1983;18,465-472.

29 SawkaAM,LakraDC,LeaJ,AlshehriB,TsangRW,BrierleyJD,StrausS,ThabaneL,GafniA,EzzatS,GeorgeSR,GoldsteinDP.Asystematicreviewexaminingtheeffectsoftherapeuticradioactiveiodineonovarianfunctionandfuturepregnancyinfemalethyroidcancersurvivors.Clin Endocrinol (Oxf).2008 [epubaheadforprint]

30 AnawaltBD,BebbRA,MatsumotoAM,GroomeNP,IllingworthPJ,McNeillyAS,BremnerWJ.SeruminhibinBlevelsreflectSertolicellfunctioninnormalmenandmenwithtesticulardysfunction.J Clin Endocrinol Metab.1996;81,3341-3345.

31 HayesFJ,PitteloudN,DeCruzS,CrowleyWFJr.,BoepplePA.ImportanceofinhibinBintheregulationofFSHsecretioninthehumanmale.J Clin Endocrinol Metab.2001;86,5541-5546.

E����e

cts

o�� th

erap

y w

ith

[177 Lu

-DO

TA0 ,T

yr3 ]o

ctre

otat

e on

end

ocri

ne ��u

nctio

n

4

32 JensenTK,AnderssonA-M,HjollundNHI,ScheikeT,KolstadH,GiwercmanA,HenriksenTB,ErnstE,BondeJP,OlsenJ,McNeillyA,GroomeNP,SkakkebakNE.InhibinBasaSerumMarkerofSpermatogenesis:CorrelationtoDifferencesinSpermConcentrationandFollicle-StimulatingHormoneLevels.AStudyof349DanishMen.J Clin Endocrinol Metab.1997;82,4059-4063.

33 PierikFH,VreeburgJTM,StijnenT,deJongFH,WeberRFA.SerumInhibinBasaMarkerofSpermatogenesis.J Clin Endocrinol Metab.1998;83,3110-3114.

34 KwekkeboomDJ,deJongFH,vanHemertAM,VandenbrouckeJP,ValkenburgHA,LambertsSW.Serumgonadotropinsandalpha-subunitdeclineinagingnormalpostmenopausalwomen.J Clin Endocrinol Metab.1990;70,944-950.

35 PeetersRP,WoutersPJ,vanToorH,KapteinE,VisserTJ,VandenBergheG.SerumrT3andT3/rT3areprognosticmarkersincriticallyillpatientsandareassociatedwithpost-mortemtissuedeiodinaseactivities. J Clin Endocrinol Metab.2005;90,4559-4565.

36 AbduTAM,ElhaddTA,NearyR,ClaytonRN.ComparisonoftheLowDoseShortSynacthenTest(1µg),theConventionalDoseShortSynacthenTest(250µg),andtheInsulinToleranceTestforAssessmentoftheHypothalamo-Pituitary-AdrenalAxisinPatientswithPituitaryDisease. J Clin Endocrinol Metab.1999;84,838-843.

37 DorinRI,QuallsCR,CrapoLM.DiagnosisofAdrenalInsufficiency.Ann Intern Med.2003;139,194-204.

38 SchmiegelowM,Feldt-RasmussenU,RasmussenAK,LangeM,PoulsenHS,MullerJ.Assessmentofthehypothalamo-pituitary-adrenalaxisinpatientstreatedwithradiotherapyandchemotherapyforchildhoodbraintumor. J Clin Endocrinol Metab.2003;88,3149-3154.

39 TaniyamaY,SuzukiT,MikamiY,MoriyaT,SatomiS,SasanoH.Systemicdistributionofsomatostatinreceptorsubtypesinhuman:animmunohistochemicalstudy.Endocr J.2005;52,605-611.

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.

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

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

pep

tide

is p

re��e

rabl

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

1. KwekkeboomDJ,TeunissenJJ,BakkerWH,KooijPP,deHerderWW,FeeldersRA,etal.Radiolabeledsomatostatinanalog[177Lu-DOTA0,Tyr3]octreotateinpatientswithendocrinegastroenteropancreatictumors.J Clin Oncol.2005;23:2754–2762.

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.

11. KwekkeboomDJ,BakkerWH,KooijPP,KonijnenbergMW,SrinivasanA,ErionJL,etal.[177Lu-DOTA0Tyr3]octreotate:comparisonwith[111In-DTPA0]octreotideinpatients.Eur J Nucl Med.2001;28:1319–1325

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.

14. VenookAP.Embolizationandchemoembolizationtherapyforneuroendocrinetumors.Curr Opin Oncol.1999;11:38–41.

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

iodi

ne-a

vid

di����e

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

� REFERENCES

1. MazzaferriEL,JhiangSM.Long-termimpactofinitialsurgicalandmedicaltherapyonpapillaryandfollicularthyroidcancer.Am J Med. 1994;97:418–428.

2. SchlumbergerMJ.Papillaryandfollicularthyroidcarcinoma.N Engl J Med. 1998;338:297–306.

3. CooperDS,SchneyerCR.FollicularandHurthlecellcarcinomaofthethyroid.Endocrinol Metab Clin North Am. 1990;19:577–591.

4. MaxonHR,SmithHS.Radioiodine-131inthediagnosisandtreatmentofmetastaticwelldifferentiatedthyroidcancer.Endocrinol Metab Clin North Am. 1990;19:685–718.

5. CaplanRH,AbelleraRM,KiskenWA.Hurthlecellneoplasmsofthethyroidgland:reassessmentoffunctionalcapacity.Thyroid. 1994;4:243–248.

6. ShermanSI.Thyroidcarcinoma.Lancet. 2003;361:501–511.7. SissonJC,GiordanoTJ,JamadarDA,etal.131-Itreatmentofmicronodularpulmonary

metastasesfrompapillarythyroidcarcinoma.Cancer. 1996;78:2184–2192.8. ShimaokaK,SchoenfeldDA,DeWysWD,CreechRH,DeContiR.Arandomized

trialofdoxorubicinversusdoxorubicinpluscisplatininpatientswithadvancedthyroidcarcinoma.Cancer. 1985;56:2155–2160.

9. DrozJP,SchlumbergerM,RougierP,GhosnM,GardetP,ParmentierC.Chemotherapyinmetastaticnonanaplasticthyroidcancer:experienceattheInstitutGustave-Roussy.Tumori. 1990;76:480–483.

10. PostemaPT,DeHerderWW,ReubiJC,etal.Somatostatinreceptorscintigraphyinnon-medullarythyroidcancer.Digestion. 1996;57(suppl1):36–37.

11. Haslinghuis LM,KrenningEP,DeHerderWW,ReijsAE,KwekkeboomDJ.Somatostatinreceptorscintigraphyinthefollow-upofpatientswithdifferentiatedthyroidcancer.J Endocrinol Invest. 2001;24;415–422.

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.

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

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

196

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.

Stag

ing

and

trea

tmen

t o�� d

i����er

entia

ted

thyr

oid

carc

inom

a w

ith

radi

olab

eled

som

atos

tati

n an

alog

s

6.2

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

198

�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).

Stag

ing

and

trea

tmen

t o�� d

i����er

entia

ted

thyr

oid

carc

inom

a w

ith

radi

olab

eled

som

atos

tati

n an

alog

s

6.2

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.

200

�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

Stag

ing

and

trea

tmen

t o�� d

i����er

entia

ted

thyr

oid

carc

inom

a w

ith

radi

olab

eled

som

atos

tati

n an

alog

s

6.2

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).

202

�

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.

Stag

ing

and

trea

tmen

t o�� d

i����er

entia

ted

thyr

oid

carc

inom

a w

ith

radi

olab

eled

som

atos

tati

n an

alog

s

6.2

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

Stag

ing

and

trea

tmen

t o�� d

i����er

entia

ted

thyr

oid

carc

inom

a w

ith

radi

olab

eled

som

atos

tati

n an

alog

s

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

�REFERENCES

1. HundahlSA,FlemingID,FremgenAM,MenckHR.ANationalCancerDataBasereporton53,856casesofthyroidcarcinomatreatedintheU.S.,1985-1995.Cancer.1998;83:2638-48.

2. ShermanSI.Thyroidcarcinoma.Lancet.2003;361:501-11.3. SchlumbergerMJ.Papillaryandfollicularthyroidcarcinoma.N Engl J Med.1998;

338:297-306.4. CooperDS,SchneyerCR.FollicularandHurthlecellcarcinomaofthethyroid.

Endocrinol Metab Clin North Am.1990;19:577-91.5. MaxonHR,SmithHS.Radioiodine-131inthediagnosisandtreatmentofmetastatic

welldifferentiatedthyroidcancer.Endocrinol Metab Clin North Am.1990;19:685-718.

6. SissonJC,GiordanoTJ,JamadarDA,etal.131-Itreatmentofmicronodularpulmonarymetastasesfrompapillarythyroidcarcinoma.Cancer.1996;78:2184-92.

7. CaplanRH,AbelleraRM,KiskenWA.Hurthlecellneoplasmsofthethyroidgland:reassessmentoffunctionalcapacity.Thyroid.1994;4:243-8.

8. PostemaPTE,DeHerderWW,OeiHY,etal. [In-111-DTPA-D-Phe1]octreotidescintigraphyinnon-medullarythyroidcarcinoma[abstract]. J Nucl Med.1994;35:163P.

9. KrenningEP,KwekkeboomDJ,PauwelsS,KvolsLK,ReubiJC.SomatostatinReceptorScintigraphy.In:FreemanLM,ed.Nuclear Medicine Annual:LippincottWilliams&Wilkins,1995:1-50.

10. TenenbaumF,LumbrosoJ,SchlumbergerM,CaillouB,FraguP,ParmentierC.Radiolabeledsomatostatinanalogscintigraphyindifferentiatedthyroidcarcinoma.J Nucl Med.1995;36:807-10.

11. BaudinE,SchlumbergerM,LumbrosoJ,TravagliJP,CaillouB,ParmentierC.Octreotidescintigraphyinpatientswithdifferentiatedthyroidcarcinoma:contributionforpatientswithnegativeradioiodinescan.J Clin Endocrinol Metab.1996;81:2541-4.

12. PostemaPT,DeHerderWW,ReubiJC,etal.Somatostatinreceptorscintigraphyinnon-medullarythyroidcancer.Digestion.1996;57(suppl1):36-7.

13. Haslinghuis LM,KrenningEP,DeHerderWW,ReijsAE,KwekkeboomDJ.Somatostatinreceptorscintigraphyinthefollow-upofpatientswithdifferentiatedthyroidcancer.J Endocrinol Invest.2001;24:415-22.

14. ChristianJA,CookGJ,HarmerC.Indium-111-labelledoctreotidescintigraphyinthediagnosisandmanagementofnon-iodineavidmetastaticcarcinomaofthethyroid.Br J Cancer.2003;89:258-61.

15. StokkelMP,VerkooijenRB,SmitJW.Indium-111octreotidescintigraphyforthedetectionofnon-functioningmetastases fromdifferentiated thyroid cancer:diagnosticandprognosticvalue.Eur J Nucl Med Mol Imaging.2004;31:950-7.

16. GarinE,DevillersA,LeCloirecJ,etal.Useofindium-111pentetreotidesomatostatinreceptorscintigraphytodetectrecurrentthyroidcarcinomainpatientswithoutdetectableiodineuptake.Eur J Nucl Med.1998;25:687-94.

17. ValliN,CatargiB,RonciN,etal.Evaluationofindium-111pentetreotidesomatostatinreceptorscintigraphytodetectrecurrentthyroidcarcinomainpatientswithnegativeradioiodinescintigraphy.Thyroid.1999;9:583-9.

18. GiammarileF,HouzardC,BournaudC,HafdiZ,SassolasG,Borson-ChazotF.Diagnosticmanagementofsuspectedmetastaticthyroidcarcinoma:clinicalvalueofoctreotidescintigraphyinpatientswithnegativehigh-doseradioiodinescans.Eur J Endocrinol.2004;150:277-283.

Stag

ing

and

trea

tmen

t o�� d

i����er

entia

ted

thyr

oid

carc

inom

a w

ith

radi

olab

eled

som

atos

tati

n an

alog

s

6.2

19. GörgesR,KahalyG,Muller-BrandJ,MackeH,RoserHW,BockischA.Radionuclide-labeled somatostatin analogues for diagnostic and therapeutic purposes innonmedullarythyroidcancer.Thyroid.2001;11:647-59.

20. KwekkeboomDJ,Mueller-BrandJ,PaganelliG,etal.Overviewofresultsofpeptidereceptorradionuclidetherapywith3radiolabeledsomatostatinanalogs.J Nucl Med.2005;46Suppl1:62S-6S.

21. BachelotA,CailleuxAF,KlainM,etal.Relationshipbetweentumorburdenandserumthyroglobulinlevelinpatientswithpapillaryandfollicularthyroidcarcinoma.Thyroid.2002;12:707-11.

22. JohnM,MeyerhofW,RichterD,etal.Positivesomatostatinreceptorscintigraphycorrelateswiththepresenceofsomatostatinreceptorsubtype2.Gut.1996;38:33-9.

23. ReubiJC,WaserB,SchaerJC,LaissueJA.Somatostatinreceptorsst1-sst5expressioninnormalandneoplastichumantissuesusingreceptorautoradiographywithsubtype-selectiveligands.Eur J Nucl Med.2001;28:836-46.

24. AinKB,TaylorKD,TofiqS,VenkataramanG.Somatostatin receptor subtypeexpressioninhumanthyroidandthyroidcarcinomacell lines.J Clin Endocrinol Metab.1997;82:1857-62.

25. Forssell-AronssonEB,NilssonO,BejegardSA,etal.111In-DTPA-D-Phe1-octreotidebindingandsomatostatinreceptorsubtypesinthyroidtumors.J Nucl Med.2000;41:636-42.

26. BalonHR,GoldsmithSJ,SiegelBA,etal.ProcedureGuidelineforSomatostatinReceptorScintigraphywith111In-Pentetreotide.J Nucl Med.2001;42:1134-1138.

27. GabrielM,DecristoforoC,MainaT, et al. 99mTc-N4-[Tyr3]OctreotateVersus99mTc-EDDA/HYNIC-[Tyr3]Octreotide:anintrapatientcomparisonoftwonovelTechnetium-99mlabeledtracersforsomatostatinreceptorscintigraphy.Cancer Biother Radiopharm.2004;19:73-9.

28. WildD,SchmittJS,GinjM,etal.DOTANOC,ahigh-affinityligandofsomatostatinreceptorsubtypes2,3and5forlabellingwithvariousradiometals.Eur J Nucl Med Mol Imaging.2003;30:1338-47.

29. GabrielM,FroehlichF,DecristoforoC,etal.99mTc-EDDA/HYNIC-TOCand(18)F-FDGinthyroidcancerpatientswithnegative(131)Iwhole-bodyscans.Eur J Nucl Med Mol Imaging.2004;31:330-41.

30. GabrielM,DecristoforoC,DonnemillerE,etal.Anintrapatientcomparisonof99mTc-EDDA/HYNIC-TOCwith 111In-DTPA-octreotidefordiagnosisofsomatostatinreceptor-expressingtumors.J Nucl Med.2003;44:708-16.

31. RodriguesM,Traub-WeidingerT,LeimerM,etal.Valueof111In-DOTA-lanreotideand111In-DOTA-D-Phe1-Tyr3-octreotideindifferentiatedthyroidcancer:resultsofinvitrobindingstudiesandinvivocomparisonwith18F-FDGPET.Eur J Nucl Med Mol Imaging.2005;32:1144-1151.

32. ZlockDW,GreenspanFS,ClarkOH,HigginsCB.Octreotidetherapyinadvancedthyroidcancer.Thyroid.1994;4:427-31.

33. RobbinsRJ,HillRH,WangW,MacapinlacHH,LarsonSM.Inhibitionofmetabolicactivityinpapillarythyroidcarcinomabyasomatostatinanalogue.Thyroid.2000;10:177-83.

34. BrunsC,Lewis I,BrinerU,Meno-TetangG,WeckbeckerG.SOM230:anovelsomatostatinpeptidomimeticwithbroadsomatotropinreleaseinhibitingfactor(SRIF)receptorbindingandauniqueantisecretoryprofile.Eur J Endocrinol.2002;146:707-16.

35. ValkemaR,De JongM,BakkerWH, et al. Phase I studyofpeptide receptorradionuclidetherapywith[In-DTPA]octreotide:theRotterdamexperience.Semin Nucl Med.2002;32:110-22.

208

�36. AnthonyLB,WolteringEA,EspenanGD,CroninMD,MaloneyTJ,McCarthyKE.Indium-111-pentetreotideprolongssurvivalingastroenteropancreaticmalignancies.Semin Nucl Med.2002;32:123-32.

37. BuscombeJR,CaplinME,HilsonAJ.Long-termefficacyofhigh-activity 111in-pentetreotidetherapyinpatientswithdisseminatedneuroendocrinetumors.J Nucl Med2003;44:1-6.

38. KrenningEP,deJongM,KooijPP,etal.Radiolabelledsomatostatinanalogue(s)forpeptidereceptorscintigraphyandradionuclidetherapy.Ann Oncol.1999;10Suppl2:S23-9.

39. SmithMC,LiuJ,ChenT,etal.OctreoTher:ongoingearlyclinicaldevelopmentofasomatostatin-receptor-targetedradionuclideantineoplastictherapy.Digestion.2000;62(Suppl1):69-72.

40. O’DonoghueJA,BardiesM,WheldonTE.Relationshipsbetweentumorsizeandcurabilityforuniformlytargetedtherapywithbeta-emittingradionuclides.J Nucl Med.1995;36:1902-9.

41. ReubiJC,WaserB,FoekensJA,KlijnJG,LambertsSW,LaissueJ.Somatostatinreceptorincidenceanddistributioninbreastcancerusingreceptorautoradiography:relationshiptoEGFreceptors.Int J Cancer.1990;46:416-20.

42. ReubiJC,ScharJC,WaserB,etal.AffinityprofilesforhumansomatostatinreceptorsubtypesSST1-SST5ofsomatostatinradiotracersselectedforscintigraphicandradiotherapeuticuse.Eur J Nucl Med.2000;27:273-82.

43. deJongM,ValkemaR,JamarF,etal.Somatostatinreceptor-targetedradionuclidetherapyoftumors:preclinicalandclinicalfindings.Semin Nucl Med.2002;32:133-40.

44. VirgoliniI,BrittonK,BuscombeJ,MoncayoR,PaganelliG,RivaP.In-andY-DOTA-lanreotide:resultsandimplicationsoftheMAURITIUStrial.Semin Nucl Med.2002;32:148-55.

45. WaldherrC,PlessM,MaeckeHR,etal.Tumorresponseandclinicalbenefit inneuroendocrinetumorsafter7.4GBq90Y-DOTATOC.J Nucl Med.2002;43:610-6.

46. KwekkeboomDJ,TeunissenJJ,BakkerWH,etal.RadiolabeledSomatostatinAnalog[177Lu-DOTA0,Tyr3]OctreotateinPatientsWithEndocrineGastroenteropancreaticTumors.J Clin Oncol.2005;23:2754-62.

47. TeunissenJJM,KwekkeboomDJ,KooijPPM,BakkerWH,KrenningEP.PeptideReceptorRadionuclideTherapyforNon-Radioiodine-AvidDifferentiatedThyroidCarcinoma.J Nucl Med.2005;46:107S-114.

48. WaldherrC,SchumacherT,PlessM,et al.Radiopeptide transmitted internalirradiationofnon-iodophilthyroidcancerandconventionallyuntreatablemedullarythyroidcancerusing[90Y]-DOTA-D-Phe1-Tyr3-octreotide:apilotstudy.Nucl Med Commun.2001;22:673-8.

49. ChinolM,BodeiL,CremonesiM,PaganelliG.Receptor-mediatedradiotherapywithY-DOTA-D-Phe1-Tyr3-octreotide:theexperienceoftheEuropeanInstituteofOncologyGroup.Semin Nucl Med.2002;32:141-7.

50. StokkelMP,VerkooijenRB,BouwsmaH,SmitJW.Sixmonthfollow-upafter111In-DTPA-octreotidetherapyinpatientswithprogressiveradioiodinenon-responsivethyroidcancer:apilotstudy.Nucl Med Commun.2004;25:683-90.

51. ReubiJC,MackeHR,KrenningEP.Candidatesforpeptidereceptorradiotherapytodayandinthefuture.J Nucl Med.2005;46Suppl1:67S-75S.

52. ValkemaR,FrobergAC,BakkerW,etal.Peptidereceptorradionuclidetherapy(PRRT)withLu-177-DOTANOCandpeptidereceptorscintigrapy(PRS)withIn-111-DOTANOCandGa-68-DOTANOC,J Nucl Med.2005;46Suppl2,151P

Stag

ing

and

trea

tmen

t o�� d

i����er

entia

ted

thyr

oid

carc

inom

a w

ith

radi

olab

eled

som

atos

tati

n an

alog

s

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

cuss

ion

7

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

214

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

Sum

mar

y an

d ge

nera

l dis

cuss

ion

7

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

216

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,

Sum

mar

y an

d ge

nera

l dis

cuss

ion

7

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

218

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

Sum

mar

y an

d ge

nera

l dis

cuss

ion

7

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.

220

REFERENCES

1. KrenningEP,BakkerWH,BreemanWA,KoperJW,KooijPP,AusemaL,LamerisJS,Reubi JC, Lamberts SWLocalisationof endocrine-related tumourswithradioiodinatedanalogueofsomatostatin.Lancet. 1989;1:242-244.

2. KrenningEP,BakkerWH,KooijPP,BreemanWA,OeiHY,deJongM,ReubiJC,VisserTJ,BrunsC,KwekkeboomDJ,etal.Somatostatinreceptorscintigraphywithindium-111-DTPA-D-Phe-1-octreotideinman:metabolism,dosimetryandcomparisonwithiodine-123-Tyr-3-octreotide.J Nucl Med. 1992;33:652-658.

3. JohnM,MeyerhofW,RichterD,WaserB,SchaerJC,ScherublH,Boese-LandgrafJ,NeuhausP,ZiskeC,MollingK,RieckenEO,ReubiJC,WiedenmannBPositivesomatostatinreceptorscintigraphycorrelateswiththepresenceofsomatostatinreceptorsubtype2.Gut. 1996;38:33-39.

4. KrenningEP,KooijPP,BakkerWH,BreemanWA,PostemaPT,KwekkeboomDJ,OeiHY,deJongM,VisserTJ,ReijsAE,etal.Radiotherapywitharadiolabeledsomatostatinanalogue,[111In-DTPA-D-Phe1]-octreotide.Acasehistory.Ann N Y Acad Sci.1994;733:496-506.

5. AnthonyLB,WolteringEA,EspenanGD,CroninMD,MaloneyTJ,McCarthyKEIndium-111-pentetreotideprolongssurvivalingastroenteropancreaticmalignancies.Semin Nucl Med.2002;32:123-132.

6. Buscombe JR,CaplinME,HilsonAJLong-termefficacyofhigh-activity 111in-pentetreotidetherapyinpatientswithdisseminatedneuroendocrinetumors.J Nucl Med. 2003;44:1-6.

7. ValkemaR,DeJongM,BakkerWH,BreemanWA,KooijPP,LugtenburgPJ,DeJongFH,ChristiansenA,KamBL,DeHerderWW,StridsbergM,LindemansJ,EnsingG,KrenningEPPhaseIstudyofpeptidereceptorradionuclidetherapywith[In-DTPA]octreotide:theRotterdamexperience.Semin Nucl Med. 2002;32:110-122.

8. WichersM,BenzE,PalmedoH,BiersackHJ,GrunwaldF,KlingmullerDTesticularfunctionafterradioiodinetherapyforthyroidcarcinoma.Eur J Nucl Med.2000;27:503-507.

9. BruheimK,SvartbergJ,CarlsenE,DuelandS,HaugE,SkovlundE,TveitKM,GurenMGRadiotherapyforRectalCancerIsAssociatedWithReducedSerumTestosteroneandIncreasedFSHandLH. Int J Radiat Oncol Biol Phys.2008;70:722-727.

10. KwekkeboomDJ,deJongFH,vanHemertAM,VandenbrouckeJP,ValkenburgHA,LambertsSWSerumgonadotropinsandalpha-subunitdeclineinagingnormalpostmenopausalwomen.J Clin Endocrinol Metab.1990;70:944-950.

11. DocterR,KrenningEP,deJongM,HennemannGThesickeuthyroidsyndrome:changes inthyroidhormoneserumparametersandhormonemetabolism.Clin Endocrinol (Oxf).1993;39:499-518.

12. ForrerF,UusijarviH,WaldherrC,CremonesiM,BernhardtP,Mueller-BrandJ,MaeckeHRAcomparisonof111In-DOTATOCand111In-DOTATATE:biodistributionanddosimetryinthesamepatientswithmetastaticneuroendocrinetumours.Eur J Nucl Med Mol Imaging. 2004;31:1257-1262.

13. ReubiJC,SchärJ-C,WaserB,WengerS,HeppelerA,SchmittJS,MäckeHRAffinityprofilesforhumansomatostatinreceptorsubtypesSST1-SST5ofsomatostatinradiotracersselectedforscintigraphicandradiotherapeuticuse.Eur J Nucl Med Mol Imaging.2000;27:273-282.

14. deJongM,BakkerWH,KrenningEP,BreemanWA,vanderPluijmME,BernardBF,VisserTJ,JermannE,BeheM,PowellP,MackeHRYttrium-90andindium-111labelling,receptorbindingandbiodistributionof[DOTA0,d-Phe1,Tyr3]octreotide,apromisingsomatostatinanalogueforradionuclidetherapy.Eur J Nucl Med.1997;24:368-371.

Sum

mar

y an

d ge

nera

l dis

cuss

ion

7

15. JonardP,JamarF,WalrandS,LabarD,MathieuI,SmithC,KvolsL,KrenningE,PauwelsSEffectofpeptideamountonbiodistributionof86Y-DOTA-Tyr3-octreotide(SMT487). J Nucl Med. 2000;41:260P.

16. BernhardtP,OddstigJ,KolbyL,NilssonO,AhlmanH,Forssell-AronssonEEffectsofTreatmentwith177Lu-DOTA-Tyr3-OctreotateonUptakeofSubsequentInjectioninCarcinoid-BearingNudeMice.Cancer Biother Radiopharm. 2007;22:644-653.

17. BreemanWAP,KwekkeboomDJ,KooijPPM,BakkerWH,HoflandLJ,VisserTJ,EnsingGJ,LambertsSWJ,KrenningEPEffectofDoseandSpecificActivityonTissueDistributionofIndium-111-PentetreotideinRats. J Nucl Med.1995;36:623-627.

18. BernhardtP,KolbyL, JohansonV,NilssonO,AhlmanH,Forssell-AronssonEBiodistributionof 111In-DTPA-D-Phe1-octreotide in tumor-bearingnudemice:influenceofamountinjectedandrouteofadministration.Nucl Med Biol.2003;30:253-260.

19. RollemanEJ,ValkemaR,de JongM,KooijPP,KrenningEPSafeandeffectiveinhibitionofrenaluptakeofradiolabelledoctreotidebyacombinationoflysineandarginine.Eur J Nucl Med Mol Imaging.2003;30:9-15.

20. BodeiL,CremonesiM,GranaC,RoccaP,BartolomeiM,ChinolM,PaganelliGReceptorradionuclidetherapywith90Y-[DOTA]0-Tyr3-octreotide(90Y-DOTATOC)inneuroendocrinetumours.Eur J Nucl Med Mol Imaging. 2004;31:1038-1046.

21. WildD,SchmittJS,GinjM,MackeHR,BernardBF,KrenningE,DeJongM,WengerS,ReubiJCDOTA-NOC,ahigh-affinityligandofsomatostatinreceptorsubtypes2,3and5forlabellingwithvariousradiometals.Eur J Nucl Med Mol Imaging. 2003;30:1338-1347.

22. AinKB,TaylorKD,TofiqS,VenkataramanGSomatostatin receptor subtypeexpressioninhumanthyroidandthyroidcarcinomacell lines.J Clin Endocrinol Metab.1997;82:1857-1862.

23. KwekkeboomDJ,Mueller-BrandJ,PaganelliG,AnthonyLB,PauwelsS,KvolsLK,O’DorisioTM,ValkemaR,BodeiL,ChinolM,MaeckeHR,KrenningEPOverviewofresultsofpeptidereceptorradionuclidetherapywith3radiolabeledsomatostatinanalogs.J Nucl Med.2005;46Suppl1:62S-66S.

8 Samenvatting en algemene discussie

224

�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

Sam

enva

ttin

g en

alg

emen

e di

scus

sie

8

(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.

226

�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

Sam

enva

ttin

g en

alg

emen

e di

scus

sie

8

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

228

�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.

Sam

enva

ttin

g en

alg

emen

e di

scus

sie

8

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

230

�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

Sam

enva

ttin

g en

alg

emen

e di

scus

sie

8

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

232

�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

Sam

enva

ttin

g en

alg

emen

e di

scus

sie

8

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

234

�wordenveelvuldigontdekt.DezereceptorenzijninprincipeallemaaleenpotentiëeldoelwitvoorradioactiefgelabeldepeptidenendusookvoorPRRT.Het isdanooknietondenkbaardatPRRTindetoekomstookinanderedeelgebiedenvandeoncologieeenbelangrijketherapeutischeoptiezalzijn.

Sam

enva

ttin

g en

alg

emen

e di

scus

sie

8

REFERENCES

1. KrenningEP,BakkerWH,BreemanWA,KoperJW,KooijPP,AusemaL,LamerisJS,Reubi JC, Lamberts SWLocalisationof endocrine-related tumourswithradioiodinatedanalogueofsomatostatin.Lancet. 1989;1:242-244.

2. KrenningEP,BakkerWH,KooijPP,BreemanWA,OeiHY,deJongM,ReubiJC,VisserTJ,BrunsC,KwekkeboomDJ,etal.Somatostatinreceptorscintigraphywithindium-111-DTPA-D-Phe-1-octreotideinman:metabolism,dosimetryandcomparisonwithiodine-123-Tyr-3-octreotide.J Nucl Med. 1992;33:652-658.

3. JohnM,MeyerhofW,RichterD,WaserB,SchaerJC,ScherublH,Boese-LandgrafJ,NeuhausP,ZiskeC,MollingK,RieckenEO,ReubiJC,WiedenmannBPositivesomatostatinreceptorscintigraphycorrelateswiththepresenceofsomatostatinreceptorsubtype2.Gut. 1996;38:33-39.

4. KrenningEP,KooijPP,BakkerWH,BreemanWA,PostemaPT,KwekkeboomDJ,OeiHY,deJongM,VisserTJ,ReijsAE,etal.Radiotherapywitharadiolabeledsomatostatinanalogue,[111In-DTPA-D-Phe1]-octreotide.Acasehistory.Ann N Y Acad Sci.1994;733:496-506.

5. AnthonyLB,WolteringEA,EspenanGD,CroninMD,MaloneyTJ,McCarthyKEIndium-111-pentetreotideprolongssurvivalingastroenteropancreaticmalignancies.Semin Nucl Med.2002;32:123-132.

6. Buscombe JR,CaplinME,HilsonAJLong-termefficacyofhigh-activity 111in-pentetreotidetherapyinpatientswithdisseminatedneuroendocrinetumors.J Nucl Med. 2003;44:1-6.

7. ValkemaR,DeJongM,BakkerWH,BreemanWA,KooijPP,LugtenburgPJ,DeJongFH,ChristiansenA,KamBL,DeHerderWW,StridsbergM,LindemansJ,EnsingG,KrenningEPPhaseIstudyofpeptidereceptorradionuclidetherapywith[In-DTPA]octreotide:theRotterdamexperience.Semin Nucl Med. 2002;32:110-122.

8. WichersM,BenzE,PalmedoH,BiersackHJ,GrunwaldF,KlingmullerDTesticularfunctionafterradioiodinetherapyforthyroidcarcinoma.Eur J Nucl Med.2000;27:503-507.

9. BruheimK,SvartbergJ,CarlsenE,DuelandS,HaugE,SkovlundE,TveitKM,GurenMGRadiotherapyforRectalCancerIsAssociatedWithReducedSerumTestosteroneandIncreasedFSHandLH. Int J Radiat Oncol Biol Phys.2008;70:722-727.

10. KwekkeboomDJ,deJongFH,vanHemertAM,VandenbrouckeJP,ValkenburgHA,LambertsSWSerumgonadotropinsandalpha-subunitdeclineinagingnormalpostmenopausalwomen.J Clin Endocrinol Metab.1990;70:944-950.

11. DocterR,KrenningEP,deJongM,HennemannGThesickeuthyroidsyndrome:changes inthyroidhormoneserumparametersandhormonemetabolism.Clin Endocrinol (Oxf).1993;39:499-518.

12. ForrerF,UusijarviH,WaldherrC,CremonesiM,BernhardtP,Mueller-BrandJ,MaeckeHRAcomparisonof111In-DOTATOCand111In-DOTATATE:biodistributionanddosimetryinthesamepatientswithmetastaticneuroendocrinetumours.Eur J Nucl Med Mol Imaging. 2004;31:1257-1262.

13. ReubiJC,SchärJ-C,WaserB,WengerS,HeppelerA,SchmittJS,MäckeHRAffinityprofilesforhumansomatostatinreceptorsubtypesSST1-SST5ofsomatostatinradiotracersselectedforscintigraphicandradiotherapeuticuse.Eur J Nucl Med Mol Imaging.2000;27:273-282.

14. deJongM,BakkerWH,KrenningEP,BreemanWA,vanderPluijmME,BernardBF,VisserTJ,JermannE,BeheM,PowellP,MackeHRYttrium-90andindium-111labelling,receptorbindingandbiodistributionof[DOTA0,d-Phe1,Tyr3]octreotide,apromisingsomatostatinanalogueforradionuclidetherapy.Eur J Nucl Med.1997;24:368-371.

236

15. JonardP,JamarF,WalrandS,LabarD,MathieuI,SmithC,KvolsL,KrenningE,PauwelsSEffectofpeptideamountonbiodistributionof86Y-DOTA-Tyr3-octreotide(SMT487). J Nucl Med. 2000;41:260P.

16. BernhardtP,OddstigJ,KolbyL,NilssonO,AhlmanH,Forssell-AronssonEEffectsofTreatmentwith177Lu-DOTA-Tyr3-OctreotateonUptakeofSubsequentInjectioninCarcinoid-BearingNudeMice.Cancer Biother Radiopharm. 2007;22:644-653.

17. BreemanWAP,KwekkeboomDJ,KooijPPM,BakkerWH,HoflandLJ,VisserTJ,EnsingGJ,LambertsSWJ,KrenningEPEffectofDoseandSpecificActivityonTissueDistributionofIndium-111-PentetreotideinRats. J Nucl Med.1995;36:623-627.

18. BernhardtP,KolbyL, JohansonV,NilssonO,AhlmanH,Forssell-AronssonEBiodistributionof 111In-DTPA-D-Phe1-octreotide in tumor-bearingnudemice:influenceofamountinjectedandrouteofadministration.Nucl Med Biol.2003;30:253-260.

19. RollemanEJ,ValkemaR,de JongM,KooijPP,KrenningEPSafeandeffectiveinhibitionofrenaluptakeofradiolabelledoctreotidebyacombinationoflysineandarginine.Eur J Nucl Med Mol Imaging.2003;30:9-15.

20. BodeiL,CremonesiM,GranaC,RoccaP,BartolomeiM,ChinolM,PaganelliGReceptorradionuclidetherapywith90Y-[DOTA]0-Tyr3-octreotide(90Y-DOTATOC)inneuroendocrinetumours.Eur J Nucl Med Mol Imaging. 2004;31:1038-1046.

21. WildD,SchmittJS,GinjM,MackeHR,BernardBF,KrenningE,DeJongM,WengerS,ReubiJCDOTA-NOC,ahigh-affinityligandofsomatostatinreceptorsubtypes2,3and5forlabellingwithvariousradiometals.Eur J Nucl Med Mol Imaging. 2003;30:1338-1347.

22. AinKB,TaylorKD,TofiqS,VenkataramanGSomatostatin receptor subtypeexpressioninhumanthyroidandthyroidcarcinomacell lines.J Clin Endocrinol Metab.1997;82:1857-1862.

23. KwekkeboomDJ,Mueller-BrandJ,PaganelliG,AnthonyLB,PauwelsS,KvolsLK,O’DorisioTM,ValkemaR,BodeiL,ChinolM,MaeckeHR,KrenningEPOverviewofresultsofpeptidereceptorradionuclidetherapywith3radiolabeledsomatostatinanalogs.J Nucl Med.2005;46Suppl1:62S-66S.

� �

Sam

enva

ttin

g en

alg

emen

e di

scus

sie

8

�

Abbreviations

240

Abb

revi

atio

ns

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

242

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

revi

atio

ns

�

Dankwoord

246

Dan

kwoo

rd

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

248

Dan

kwoo

rd

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

252

Cur

ricul

um V

itae

�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

256

List

o�� p

ublic

atio

ns

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