NUCLEARNUCLEAR MEDICINEMEDICINE ININ NETSNETS

David Farlow Director Dept of , PET and Ultrasound Westmead Hospital, Sydney, Australia

Unicorn Foundation Neuroendocrine Education/Support Group Meeting North Shore Private Hospital, St Leonards 11 August 2010 WHATWHAT ISIS NUCLEARNUCLEAR MEDICINEMEDICINE ??

usesuses medicalmedical isotopesisotopes toto mapmap physiologyphysiology andand pathophysiologypathophysiology inin humanhuman bodybody alsoalso knownknown asas functionalfunctional oror molecularmolecular imagingimaging complementscomplements RadiologyRadiology whichwhich displaysdisplays anatomyanatomy 7070 yearyear historyhistory andand recentrecent rapidrapid growthgrowth duedue toto convergenceconvergence technologiestechnologies suchsuch asas PETPET --CT.CT. computed FDG positron emission tomography PET-CT ? dead or alive maps metabolism but where is the finding? RADIOPHARMACEUTICALRADIOPHARMACEUTICAL

= isotope + ligand

administered intravenously, orally, etc

localises in target organ, or target pathology

emits gamma rays or beta rays detected by or PET camera with or without CT MEDICALMEDICAL ISOTOPESISOTOPES isotopesisotopes areare unstableunstable  emissionsemissions electronselectrons (beta(beta radiation)radiation) usedused inin nuclearnuclear medicinemedicine therapytherapy positronspositrons (antimatter(antimatter electrons)electrons) annihilateannihilate toto produceproduce gammagamma raysrays forfor PETPET gammagamma rays:rays: photonsphotons likelike XX --raysrays butbut electron originateoriginate fromfrom nucleus,nucleus, notnot thethe shellshell neutron

proton MEDICALMEDICAL ISOTOPESISOTOPES

DiagnosticDiagnostic TherapeuticTherapeutic 99m 131  Tc  I 123 90  I  Y 201 177  Tl  Lu 67 153  Ga  Sm 111 89  In  Sr 131 188  I  Rh 68 32  Ga  P 18  F reactor and cyclotron produced radioactive isotopes; differing half lives and different electron, positron and gamma emissions RADIOPHARMACEUTICALSRADIOPHARMACEUTICALS

99m isotope is directed to  Tc HDP: for bone scan organ or target of interest 99m  Tc MIBI: cardiac via ligand via ligand perfusion scan scan name often derived 18  F FDG: PET tumour from ligand eg MIBI scan, F FDG: PET tumour or from target organ eg scan ( glu metabolism) lung scan  Ga68 Octreotate: neuro - endocrine tumour scan, assessing SS receptor uptake

Single Photon Emission = SPECT Computed Tomography

PLANAR I-131 MIBG therapy for metastatic tumour

SPECT-CT DATA PETPET --CTCT alsoalso imagesimages gammagamma raysrays arisingarising fromfrom positronpositron annihilationsannihilations shortshort halfhalf lifelife isotopesisotopes egeg CC11 ,, NN 13 ,, FF 18 mapmap basicbasic metabolicmetabolic pathwayspathways likelike glucoseglucose metabolismmetabolism (F(F 18 --FDG)FDG) nownow combinedcombined withwith CTCT (PET(PET --CT)CT) NUCLEARNUCLEAR MEDICINEMEDICINE THERAPYTHERAPY

TherapyTherapy isotopesisotopes emitemit betabeta radiation,radiation, withwith oror withoutwithout gammasgammas I-131 Y-90 Lu -177 SameSame principleprinciple asas diagnosticdiagnostic NucNuc MedMed ie target the isotope chemically to specific areas eg Lu -177 Octreotate (= Lutate ) NEURONEURO --ENDOCRINEENDOCRINE TUMOURSTUMOURS

widewide rangerange ofof tumourtumour typestypes carcinoid , phaeochomocytoma,meningioma , small cell lung cancer, medullary cancer, many others manymany areare wellwell differentiated,differentiated, andand slowslow growinggrowing widewide rangerange ofof treatmenttreatment optionsoptions surgery, somatostatin treatment, chemotherapy, radiotherapy, therapy NucNuc Med/PETMed/PET hashas diagnosticdiagnostic andand therapeutictherapeutic rolerole inin NETsNETs NUCLEARNUCLEAR MEDMED ININ NETNET

OctreotideOctreotide scansscans In -111 scan (SPECT -CT) Ga -68 Octreotate scan (PET -CT_ otherother scansscans egeg bonebone scanscan LuLu --177177 OctreotateOctreotate therapytherapy otherother therapytherapy I-131 MIBG therapy SirSphere therapy MAKINGMAKING AA RADIOPHARMAECUTICALRADIOPHARMAECUTICAL isotopeisotope ++ linklink ++ OctreotideOctreotide GaGa --6868 ++ DOTADOTA ++ TOCTOC InIn --111111 ++ DTPADTPA ++ OctreotideOctreotide aim:aim: linklink andand isotopeisotope shouldshould notnot interfereinterfere withwith bindingbinding ofof octreotideoctreotide compoundcompound halfhalf --lifelife ofof isotopeisotope shouldshould approximatelyapproximately matchmatch uptakeuptake andand bindingbinding characteristicscharacteristics ofof OctreotideOctreotide compoundcompound DONDON ’’TT GETGET BOGGEDBOGGED ININ DETAILDETAIL

Peptide Receptor : Forrer et al. Best Practice & Research Clinical Endocrinology & Metabolism. 21; 111–129, 2007 OCTREOTIDEOCTREOTIDE FAMILYFAMILY differentdifferent typestypes ofof OctreotideOctreotide differentdifferent receptorreceptor bindingbinding differentdifferent labellinglabelling capabilitiescapabilities octreotide octreotate OctreotateOctreotate mostmost commonlycommonly usedused inin PETPET andand therapy,therapy, whilewhile OctreotideOctreotide mostmost commonlycommonly usedused inin SPECT.SPECT. mixedmixed formulationsformulations maymay evolveevolve inin future,future, forfor differentdifferent tumourtumour subsub --typestypes RADIOACTIVERADIOACTIVE ISOTOPESISOTOPES

IndiumIndium 111.111. MostlyMostly aa diagnosticdiagnostic agent,agent, butbut somesome previousprevious therapytherapy use.use. AugerAuger electronselectrons havehave shortshort tissuetissue pathpath (up(up toto 1010 microns)microns) YY--90:90: highhigh energyenergy electrons,electrons, withwith tissuetissue penetrationpenetration ofof upup toto 12mm.12mm. NoNo gammasgammas soso lessless radiationradiation concernsconcerns forfor bystandersbystanders LuLu --177:177: midmid energyenergy electrons,electrons, tissuetissue penetrationpenetration ofof upup toto 2mm.2mm. SomeSome gammasgammas forfor imaging.imaging. OCTREOTIDEOCTREOTIDE DIAGNOSTICDIAGNOSTIC SCANSSCANS InIn --111111 OctreotideOctreotide scanscan withwith SPECTSPECT --CTCT isis currentcurrent standard,standard, withwith goodgood availabilityavailability inin mostmost NuclearNuclear MedMed DeptsDepts GaGa --6868 OctreotateOctreotate PETPET --CTCT isis superior:superior: WestmeadWestmead isis onlyonly providerprovider inin NSW.NSW. ReferralsReferrals acceptedaccepted fromfrom allall Oncologists.Oncologists. OtherOther statesstates havehave oneone centrecentre eacheach performingperforming Ga68Ga68 --OctreotateOctreotate scans.scans. RNSHRNSH wantswants toto offeroffer thisthis serviceservice too.too.

OTHEROTHER NUCLEARNUCLEAR MEDMED TECHNIQUESTECHNIQUES SirSphereSirSphere therapytherapy

 usedused toto treattreat liverliver metastasesmetastases

 YY--9090 labelledlabelled microspheresmicrospheres toto emboliseembolise andand givegive locallocal highhigh dosedose radiotherapyradiotherapy

 usedused whenwhen mostmost ofof thethe diseasedisease isis withinwithin thethe liverliver

 WestmeadWestmead HospitalHospital andand StSt VincentVincent ’’ss PrivatePrivate

 expensiveexpensive ($8K($8K forfor SirSpheresSirSpheres plusplus costscosts ofof angiogramangiogram xx 2,2, etc)etc) OTHEROTHER IMAGINGIMAGING

CTCT scanningscanning MRIMRI ultrasoundultrasound plainplain xx --raysrays angiographyangiography interventionalinterventional proceduresprocedures egeg lineline placementplacement PET:PET: FF --DopaDopa ,, FF --tryptophantryptophan :: nono therapytherapy analogueanalogue allall provideprovide essentialessential anatomicanatomic informationinformation andand alloalloww proceduresprocedures toto bebe reliablyreliably performedperformed LuLu --177177 OctreotateOctreotate mostmost commoncommon peptidepeptide receptorreceptor therapytherapy isotopeisotope usedused inin AustraliaAustralia andand EuropeEurope littlelittle usedused inin USUS duedue toto locallocal regulationsregulations LuLu --177177 reactorreactor produced;produced; importedimported fromfrom HollandHolland LucasLucas HeightsHeights reactorreactor justjust startingstarting toto produceproduce smallsmall amountsamounts (first(first testtest shipments)shipments)

saline flush to check for leaks tropisetron to block nausea + vomiting LUTATELUTATE THERAPYTHERAPY

Sequential post Lutate therapy whole body scans over 16 weeks

Reduction in size and activity of carcinoid metastases LutateLutate TherapyTherapy IndicationsIndications

NETNET wellwell differentiated;differentiated; KiKi --6767 indexindex << 1010 (proliferative(proliferative rate)rate) disseminateddisseminated andand notnot surgicallysurgically amenableamenable progressiveprogressive diseasedisease (symptoms,(symptoms, CT,CT, markersmarkers egeg chromograninchromogranin A)A) TREATMENTTREATMENT PHILOSOPHYPHILOSOPHY curecure notnot achievedachieved withwith disseminateddisseminated diseasedisease byby monomono --therapytherapy combinecombine LutateLutate withwith biotherapybiotherapy // chemotherapychemotherapy

 egeg capecitabinecapecitabine ,, temozolamidetemozolamide ,, everolimuseverolimus dose:dose: 7.87.8 GBqGBq xx 44 cyclescycles @@ 88 weekweek intervalsintervals expectexpect gradualgradual responseresponse PATIENTPATIENT PREPPREP dayday OncologyOncology wardward admissionadmission lightlight breakfastbreakfast 22G22G cannulacannula oraloral benzodiazepinebenzodiazepine premedpremed becausebecause itit isis aa longlong dayday (can(can ’’tt drivedrive home).home). 44 hourhour aminoamino acidacid infusioninfusion forfor renoreno -- protectionprotection INFUSIONINFUSION

LutateLutate infusedinfused overover 1010 mins,mins, 3.5ml3.5ml ofof injectateinjectate mademade upup toto 10ml10ml withwith normalnormal salinesaline 4040 mlml salinesaline flushflush infusioninfusion viavia pumppump vialvial behindbehind shieldshield onon trolleytrolley viavia samesame cannulacannula asas aminoamino acidacid infusioninfusion DISCHARGEDISCHARGE CRITERIACRITERIA averageaverage dischargedischarge cancan occuroccur atat 3.463.46 hourshours (dose(dose raterate == 2525 microSvmicroSv // hrhr atat 11 m)m) 100%100% cancan gogo homehome atat 66 hourshours coffeecoffee andand sandwichessandwiches asas soonsoon asas thethe patientpatient wisheswishes familyfamily membermember cancan staystay withwith patientpatient forfor dayday SIDESIDE EFFECTSEFFECTS immediateimmediate

 nausea and vomiting (requires IV tropisetron )

 due to AA and peptide (5m tropisetron for AA infusion, then up to 7mg for Lutate infusion at 20 -30 ml

 arm swelling (AA infusion) delayeddelayed

 side effects of chemo and radionuclide therapy only

 some marrow impairment (transient marrow suppression)

 no renal impairment similarsimilar resultsresults toto largelarge publishedpublished studiesstudies internationallyinternationally

PERTHPERTH LUTATELUTATE OUTCOMESOUTCOMES

3333 patientspatients withwith biopsybiopsy provenproven metastaticmetastatic NET,NET, progressiveprogressive despitedespite regularregular therapy,therapy, unresectableunresectable .. meanmean ageage 6060 yearsyears (32(32 --8282 y)y) 44 cyclescycles ofof LutateLutate givengiven objectiveobjective responsesresponses 24% partial response 70% stable disease 6% progressive disease 11 andand 22 yearyear survivalsurvival rates:rates: 91%91% andand 88%88% NSWNSW SITUATIONSITUATION mostmost hospitalshospitals provideprovide InIn --111111 OctreotideOctreotide SPECTSPECT --CTCT serviceservice WestmeadWestmead providesprovides GaGa --6868 OctreotateOctreotate PETPET --CTCT scansscans (and(and F18F18 --FDGFDG scansscans forfor NET)NET) nono NSWNSW sitesite providesprovides LutateLutate therapytherapy radionuclideradionuclide therapytherapy businessbusiness casecase submittedsubmitted toto NSWNSW HealthHealth (for(for LutateLutate funding,funding, plusplus otherother therapies).therapies). LUTATELUTATE THERAPYTHERAPY fundingfunding requiredrequired forfor LutateLutate serviceservice ($1($1 --3m3m perper annum).annum). WestmeadWestmead isis aa suitablesuitable sitesite forfor suchsuch aa therapytherapy service,service, butbut otherother hospitalshospitals alsoalso suitablesuitable ?? oneone oror twotwo sitessites inin NSWNSW CostCost == $20$20 --30K30K perper patient.patient. ExpensiveExpensive butbut similarsimilar inin costcost toto sandostatinsandostatin andand costcost offsetsoffsets commoncommon