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ReviewBreastCare
Articlebersichtsarbeit
BreastCare2012;7:100107DOI:10.1159/000337634
Publishedonline:April24,2012

RadionuclideTherapyofBoneMetastases
ManfredFischeraWillmU.Kampenb
aPraxisfrRadiologieundNuklearmedizin,Kassel,bNuclearMedicineSpitalerhof,Hamburg,Germany
Keywords
SchlsselwrterBonemetastasesPainpalliation
Radionuclides
KnochenmetastasenSchmerztherapieRadionuklide
153Sm-EDTMP89Sr223Ra
153Sm-EDTMP89Sr223Ra
Summary
ZusammenfassungTheskeletonisapotentialmetastatic
targetofmany
ZahlreichemaligneTumorenmetastasierenindas
malignanttumors.Upto85%ofprostateandbreast
Skelett.Beibiszu85%derPatientenmiteinem
Prostata-cancerpatientsmaydevelopbonemetastasescausing
oderMammakarzinomfindensichKnochenmetastasen,
severepainsyndromesinmanyofthem.Inpatients
diebeivielenzueinerausgeprgtenSchmerzsympto-
sufferingfrommultilocular,mainlyosteoblasticlesions
matikfhren.BeiPatienten,dieaneinermultilokulren
andpainsyndrome,radionuclidetherapyisrecom-
KnochenmetastasierungundSchmerzenleiden,kann
mendedforpainpalliation.Low-energybeta-emitting
einepalliativeSchmerztherapiemitRadionukliden
radionuclides(153samarium-ethylenediaminetetrameth-
durchgefhrtwerden.NiedrigenergetischeBeta-Strahler
ylenephosphonate(EDTMP)and89strontium)deliverhigh
(153Samarium-Ethylendiamintetra(methylenphosphon-
radiationdosestobonemetastasesandmicrometasta-
sure)(EDTMP)und89Strontium)bewirkeneinehohe
sesinthebonemarrow,butonlynegligibledosestothe
StrahlendosisaufdieKnochenmetastasenunddieMik-
hematopoieticmarrow.Theresponserateregarding
rometastasenimKnochenmarkbeinurgeringerDosis
painsyndromeisabout75%;about25%ofthepatients
aufdasMarkselbst.DieAnsprechrateaufdieTherapie
mayevenbecomepainfree.Thetherapyisrepeatable,
betrgt7080%,etwa25%derPatientenwerden
dependingoncellcounts.Concomitanttreatmentwith
schmerzfrei.DieTherapiekanninAbhngigkeitvom
modernbisphosphonatesdoesnotinterferewiththe
Blutbildwiederholtwerden.EinegleichzeitigeTherapie
treatmenteffects.Clinicaltrialsusinganew,notyet
mitmodernenBisphosphonatenfhrtnichtzueinerWir-
approvednuclide(223radium)and/orcombinationsof
kungsnderung.KlinischeStudienmiteinemneuen,
chemotherapyandradionuclidesareaimingatamore
nochnichtzugelassenenNuklid(223Radium)oder
Kombi-curativeapproach.
nationstherapien mit Chemotherapeutika und Radio- nukliden zielen auf einen mehr kurativen Effekt und zei- gen
vielversprechendeErgebnisse.
Introduction
The incidence rate ofmanycommonprimarytumorsisstillrisingand,duetoprogressioninefficacioustreatment,manypatients
surviveforalongertime.
Because the skeleton is a potential metastatic target for the majority of malignant extracranial tumors [1], an increasing
numberofpatientswillsufferfrompainfulbonemetastases,whichcansignificantlyimpairthepatientshealth.Post-
2012S.KargerGmbH,Freiburg
Prof.Dr.med.ManfredFischer1661-3791/12/0072-0100$38.00/0
PraxisfrRadiologieundNuklearmedizinImBodden60,34125Kassel,GermanyAccessibleonlineat:
Tel.+49561-878987,Fax-8075249www.karger.com/brc
finukskk@aol.commortemstudiesindicatethatapproximately80%ofallpatientswithprostatecancerand75%ofbreast
carcinomapatientsdevelopbonemetastases,whichtogetheraccountforapproximately80%ofallskeletalmetastases[2].By
compari-son,bonemetastasesoccurinapproximately2040%ofpa-tientswithlungorrenalcancer[3](table1).WorldHealth
Organization(WHO)datasuggestthatapproximately4mil-lionpeopleworldwideexperiencedailypainduetomalignant
disease;inhalfofthesepeople,metastaticbonediscomfortis

discomfortthedominantsourceofsymptoms[4].Themajorityofpa-
[9].Theprognosisofpatientswith
metastasescon-tientswithbonemetastasesdevelopseverepainastheirdis-
finedtotheskeletonisusuallysuperiortothatof
patientseaseprogresses,resultinginaconsiderablereductionintheir
withsoft-tissuemetastases,inlungs,liverorlymph
nodes,forqualityoflife.Amultidisciplinaryapproachtosymptompal-
example[10],andthereforemeritscarefulconsideration.
liationisrecommended,tailoringtreatmenttoindividual
Inadditiontoanalgesicdrugs(prescribedaccording
toneed,withtheaimofindividualizedtreatmentbeingtoadd
theWHOscheme)[4],localexternal-beamradiation
therapy,lifetotheyears,notyearstothelife.
andsurgicalinterventions,especiallyinlocallyrestricted
Theuptakeofbone-seekingradiotracersusedforradionu-
disease,severalradiopharmaceuticalshavebeen
developedclidetherapyofbonemetastasesdependsontheosteoblastic
forthesystemicpalliationofbonepainwithmore
multilocu-activityandthecalcificationofthetumortissue.Inthepast,
larskeletalinvolvement.themorphologyofbone
metastasesarisingfromprimaryprostatecancerwastypicallycharacterizedasmainlyosteo-blastic,whereasplasmocytomaand
renalcellcarcinomahave
RadionuclideTherapybeenassociatedwith
predominantlyosteolyticbonelesions.Mixedpatternsofosteoblasticandosteolyticmetastasesare
Thefirstapplicationofthebone-seeking
radiopharmaceuticalmorecommoninbreast,lung,colorectalandpancreatic
strontium-89[89Sr]-chloridewasdescribedbyPecherin
malignancies[5,6].Morerecently,whencomparingthe
1940/41[11],followedbythefirstreportofpain
palliationinamorphologyofbreastcancermetastasesbycomputedtomo-
patientwithbonemetastasesfrombreastcarcinoma
usinggraphyinthetimeperiod19962000versus20012005,a
phosphorous-32[32P]byFriedell[12].higher
prevalenceofosteosclerosiswasobservedinthelater
InEurope,strontium[89Sr]-chlorideisapprovedfor
boneperiod(19962000:osteolytic53.7%,osteosclerotic32.1%,
painpalliationinpatientswithbonemetastasesof
prostatemixedtype14.3%;20012005:osteolytic9.4%,osteosclerotic
cancer,whereassamarium
[153Sm]-ethylenediaminetetrameth-71.9%,mixedtype18.7%).Thismaybeduetotheapplication
ylenephosphonate(EDTMP)isapprovedforthe
treatmentofofsystematicadjuvantbisphosphonatetreatment[7].
painfromallosteoblasticbonemetastases.Phosphor[32P]-
Approximately75%ofpatientswithbonemetastasescom-
orthophosphateisusedinseveralothercountries.89Sris
aplainofpainastheirmainsymptomandthedominantreason
calciumanalogandisincorporatedintothenewly
formedforadecreasedqualityoflife[8].Appropriatepainmanage-
hydroxyapatiteofthebonematrix.153Smis
radiolabeledtoamentmaybedifficult,particularlyincaseofpoorlylocalized
bisphosphonate(EDTMP)andadsorbedontothehydroxy-apatitesurfaceofmetabolicallyactivebonebythesamemechanism
astechnetium[99mTc]-labeledbisphosphonatesTable1.Incidenceofbonemetastasesreportedinpostmortemstudies
usedfordiagnosticbonescintigraphy.[54]
Selectiveuptakedependsonthedegreeofthe
metabolicTumorMeanfrequency,%Range,%
(i.e.osteoblastic)responseelicitedinnormalbonebythe
Breast73Prostate68Thyroid42478533852885
presenceofmetastatictissue.Increasedboneturnoverleadstoenhancedincorporationofbone-seekingradiopharmaceu-Kidney
353340
ticalsatmetastaticsites,bycomparisonwithnormal
bone,Lung36Esophagus6Gastrointestinal53055
57311
andcanthereforedeliverahigh,targetedlocalradiationdose.Skeletaluptakeoftheradiolabeledbisphosphonate153Sm-
Rectum11813
EDTMPisintheorderof48%oftheadministeredactivity
Table2.Physicalcharacteristicsofradiopharmaceuticalsusedforbonepainpalliation
RadionuclideCarrierPhysicalhalf-life,
days

max
,MeV
mean
,MeVMeanrangec
intissue,mm
-Energy,keV(%)
89Srchloride50.51.460.5836.7153SmEDTMP1.950.80.2243.4103(28)32Paphosphate14.281.710.6957.9188Reb
HEDP0.712.120.7611.0155(1)117mSnbDTPA13.6nobeta-emission0.3CE15933Pbphosphate25.340.2490.850.05
223Rabchloride11.4alpha-emitter(eff.energy26.4MeV)<100m
aNotapprovedinGermany.bClinicaltrialonly.cMeanrangeinperiosseoussofttissue.EDTMP=
Ethylenediaminotetramethylenephosphonate,HEDP=hydroxyethylenediphosphonate,DTPA=diethylenetriaminopentaacetate,
CE=conversionelectrons.
BreastCare2012;7:100107RadionuclideTherapyofBoneMetastases101

per[13].Theeffectivehalflifeof89Srinbonemetastasesisgreater
kilogrambodyweight[22].Followingintravenous
ad-than50days,comparedwith14daysinnormalbone[14]
ministration,skeletaluptakepeakswithin1hof
injection,(table2).
withnosubsequentredistribution.PhaseIandIIstudies
32Passodiumphosphateisnolongerapprovedinmany
confirmlowtemporarymyelosuppressionapproximately
countriesbecauseofdocumentedmyelotoxocityassociated
4weeksposttreatment,butthisrarelyexceedsWHO
gradeI/withtherapeuticadministration.Morerecently,aclinicaltrial
IIevenathighactivities(200kBq/kg)inheavily
pretreatedcomparing89Srand32Pinpatientssufferingfrombonemetas-
patients[23].Lessthan1%of292patientsdeveloped
gradetasesreportedslightlyhighertoxicityinthe32Pgroupbut
IVhematologicaltoxicity;gradeIIItoxicityfor
hemoglobincomparableefficacyintermsofpainpalliation[15].Further
wasexperiencedby4.8%,andforplatelets,neutrophiles
andresearchwillbenecessarytoconfirmtheseresultsparticularly
whitebloodcellsby<3%.Thepreliminaryresultsofa
inheavilypretreatedpatientswhomayhavelimitedbone
double-blind,randomized,placebo-controlledphaseIII
trialmarrowreserves.
(ALSYMPCA)withitsprimaryendpointofsurvivalshow
Clinicaltrialsareinprogressevaluatingthetherapeutic
lowtoxicityandameansurvivalof14monthsforthera-
potentialofotherradionuclidesforbonepainpalliation.
dium-223groupcomparedto11.2monthsforthe
placeboTheseinclude:tin[117mSn]-diethylenetriaminopentaacetate
group.Themediantimeofnewskeletaleventswas13.6
(DTPA),sodium[33P]-phosphate,rhenium[188Re]-hydroxye-
versus8.4months.thylidenediphosphonate(HEDP),
lutetium[177Lu]-EDTMP,
Themechanismandradiobiologyofpainreduction
usingandradium[223Ra]-chloride.
unsealedsourcetherapyisnotyetfullyunderstood.Adirect
Inadditiontoclinicalvariablessuchasskeletalmetastatic
radiationeffectonneuronaltissueseemsunlikelydueto
theburden,diseasedistribution,andpriortreatment,myelosup-
well-knownhighradiationresistanceofperipheral
neurons.pressionresultingfromsystemicbone-seekingradiopharma-
Itismoreconceivablethatradiationtocellsandtissues
ceuticaltherapyreflectstheeffectivehalf-life,particleenergy
surroundingthemetastasispromotescellsignaling
changes,andparticlerangeoftheradionuclideused.Theuseoflow-
resultinginmodulationofbothpainreceptionand
transmis-energybeta-emittingradionuclideswouldbeexpectedtode-
sion.Possibletargetcellsarelikelytoinclude
macrophages,liverahighabsorbeddosetothebonesurface,butanegligi-
mastcells,thrombocytes,lymphocytes,andendothelial
cells,bledosetothehematopoieticbonemarrow[16].Theoretical
whichinfluencesecretionofpainmediatorssuchas
ATP,dosecalculationspredicta36-foldadvantageintermsof
histamine,prostaglandinE(PGE),interleukin(IL)-1and
-2,myelotoxicityriskif33Pweresubstitutedfor32P,forexample
leukotrienes,andsubstanceP.Animalexperiments[24]
have[17].Thesameistrueforconversionelectonsof117mSnor
shownthat223Rainhibitsthedifferentiationof
osteoclasts,alpha-emitterslike223Ra.
andprobablytherebyalsotheprogressionofmainlyosteo-
Toreducethemyelotoxicity,thetherapeuticpotentialof
lyticbreastcancerbonemetastases.conversion
electron-emittingradiolabelssuchas117mSn-DTPAhasbeenreported.Conversionelectronsejectedduringthedecayofthis
nuclidehavea1.75.5timeslowerenergythan
Indications,ContraindicationsandProcedure
beta-particlesconventionallyusedforsystemictreatmentfor
ofPainPalliationTreatmentpainpalliation[18].Butthe
limitingfactorofthiscompoundusedinaphaseI/IIclinicalstudywasnottheradiationdose
Surgicalstabilizationand/orexternal-beamradiationare
thetothemarrowbutthehighamountofDTPAinthecurrent
treatmentsofchoiceforthemanagementofsolitary,
painfulformulation,ina20-foldmolarexcessovertin[19].More
bonemetastases,bonesathighriskofpathological
fracture,recently,anew1:1chelatewassynthesized[20].
andinpatientswithimpendingspinalcordcompression.
Estimatesoftheabsorbedradiationdosedeliveredto
Systemicradionuclidetherapyisindicatedtomanage
osteoblasticbonemetastasesvarywidely,rangingfrom661
multifocalmetastaticbonepainfollowingfailureof
conven-cGy/MBqfor89Sr,100014,000cGyfromastandardtreat-
tionalanalgesicsandtopalliaterecurrentpainwithina
previ-mentactivityof1295MBq186Re-HEDP(thisradiopharma-
ouslyirradiatedsite.Itislikewiseindicatediftheside
effectsceuticalwasrecentlywithdrawnfromthemarket),anda
ofhigh-doseanalgesicsbecomeintolerableand
significantlymeandoseof87Gyfrom2590MBq153Sm-EDTMP.Adose
compromisethequalityoflife,evenifpaincontrolisof
54mGy/MBqwasreportedusing117mSn-DTPA,withthe
adequate.boneuptakerangingfrom34to83%ofthe
injectedactivity
Strontium[89Sr]-chlorideisapprovedforpain
palliationin[21].
patientswithbonemetastasesfromprostatecancer;
samariumThebone-seekingalpha-particleemitterradium-223is
[153Sm]-EDTMPmayalsobeusedinpatientssuffering
frompredictedtodeliverahighabsorbedradiationdosetothe
osteoblasticmetastasesofothertumortypes.The
activityofbonesurface,withsparingofthebonemarrowcompartment.
153Sm-EDTMPisadjustedforthepatientsbodyweight
Fromdataofanimalexperiments,atotalskeletaldoseof553
(37MBq/kg),whereas89Sr-chlorideisprescribedas
standard-790Gywascalculatedafteradministrationof3750kBq223Ra
izedactivity(150MBq).
102BreastCare2012;7:100107Fischer/Kampen

A prerequisite forradionuclidetreatmentofmetastaticbonepainisthedemonstrationofmultifocalabnormalskele-taluptakeon
conventional 99mTc phosphate bone scintigra- phy, corresponding to known pain sites [58]. Patients should have reasonable
bone marrow reserves, as evidenced by (near) normal blood counts. The gamma-emission of Sm-153 is useful for early
post-therapyimagingtoconfirmselectivetraceruptakeandappropriatetargeting.
Due to the delay between treatment administration and onset of pain relief, which may take 1 week in case of [153Sm]-
EDTMP and up to 4 weeks using 89Sr, patients should have alifeexpectancyofatleast3months.Absolutecontraindica-tions
to radionuclide therapy include pregnancy, breast-feed- ing and severe bone marrow depression, for beta-emitters indicated by
platelets < 60,000/l or leucopenia < 2400/l [25]. Acute spinal cord compression, disseminated intravascular coagulation,and
impaired renal function (urea > 12 mmol/l or creatinine >150mmol/l)areregardedasadditionalcontrain-dicationsinGerman,
EuropeanandAmericanguidelinesforpainpalliationtreatmentusingSm-153-EDTMPorSr-89.
Patients with urinary incontinence should be catheterized prior to treatment, to mitigate the risk of radioactive urine
contamination. Specialist referral is advised where bones are considered at risk of pathologicalfracture.Toallowtimeforbone
marrow recovery and avoid unpredictable cumulative toxicity, unsealed source treatment should bedelayedfor68weeksafter
completion of chemotherapy. It is recom- mended that further chemotherapy be deferred for at least812weeks,dependingon
theradiopharmaceuticalused.A23-monthdelayisrecommendedafterlarge-fieldradiationtherapy.
Concomitant treatment with modern bisphosphonates, which arecharacterizedbyveryloweffectivelevels,doesnotinterfere
with the uptake of bone-seeking radionuclides [23, 26, 59]. This is in contrast to former concerns regarding the classicaldrugs
clodronate oretidronate.Focalabnormaluptakeshould,however,beconfirmedineverypatientbypre-therapeuticboneimaging
andcorrelatedwiththelocalizationofthepain.
Following appropriate oral hydration, the bone-seeking radiopharmaceutical is administered intravenously via a pe- ripheral
cannula, usually in an outpatient setting, depending on local legislation. Prior to discharge, the uptake and distri- bution of the
activity of 153Sm-EDTMP can be documented by whole-body scanning 524 h post injection. Renal excretion oftheunbound
fraction of the radionuclide is very rapid, i.e. 71% within 3 days [27] compared with 53% of the unbound 153Sm-EDTMP
excretedviathekidneyswithin68hafterinjection[28].
Blood counts, especially thrombocytes and white blood cells, must be monitored weekly to track expected, temporary bone
marrow suppression. Marrow recovery is usual within 8 weeks of 153Sm-EDTMP administration and within 12weeksof89Sr
treatment,withthespeedandcompletenessofhemato-
poietic regeneration being determined by the underlying bone marrow reserves. With appropriate patientselectionandcare-ful
monitoring, clinically significant or protracted bone mar- row suppression requiring red cell or platelet transfusion is rare.
Palliative pain therapy may be repeated to treatrecur-rentsymptoms,aminimumof812weeksafterprevious153Sm-EDTMP
administration or 34 months after therapy with89Sr.Hematotoxicitycausedby223Raismuchlessbecauseoftherapiduptake
in bone (> 75 of the administered activity is cleared fromthebloodandplasmawithin15minafterinjection)andtheveryshort
rangeofalpha-particles[29].
ClinicalResults
Of the patients with metastatic prostate orbreastcancer,7080%reportsymptombenefitfollowingtreatmentwithbone-seeking
radiopharmaceuticals (figs. 1 and 2). Pain relief typically occurs within 1 week of intravenous 153Sm-EDTMP administration
and usually lasts for about 812 weeks, al- though prolonged responses of up to 12 months have been reported [23]. The
advantage of 89Sr is a longer mean response duration of approximately 4 to 6months,butthisbenefitmustbeweighedagainst
the delayed onset of symptom palliation of 1428 days after radiopharmaceutical administration [30] and the increased risk of
myelosuppression.
Fig. 1. A 76-year-old male patient with prostate cancer. Whole-body bone scan 2 h after intravenous injection of 698 MBq
99mTc-DPD Multiple osteoblastic metastases are seen from both the anterior (a) and posterior (b) projection. Post-therapy
whole-body scan (c, d) 24 h after application of the second treatment with 153Sm-EDTMP. The cumulative activity of both
treatments was 6.7 GBq. The scan showsmildprogressionofthebonylesions.ThePSAlevelincreasedupto1,210ng/ml,from
thestagingscanto5monthsafterthesecondtreatment.Thepatientispainfreesincethefirsttherapy.
BreastCare2012;7:100107RadionuclideTherapyofBoneMetastases103
abcd

No reliable responsepredictorshavebeenestablished[31,32].Prostate-specificantigen(PSA)declineinprostatecancerpatients
treated using radionuclide therapy does not correlate with pain palliation. In a small study of 50 patients treated with 89Sr for
metastatic castration-resistant prostate cancer (CRPC), a decrease or stabilization of the PSA levels after treatment (28% of
patients, n =14)wasassociatedwithasig-nificantmeansurvivalimprovementfrom275to641daysandprolongedtimetopain
progression (67 to 142 days) [33]. In a review of data published in evidence-based trials, Serafini [34] summarized reported
response rates, in terms of pain pallia- tion, of different radionuclides (table 3). These results were confirmed or completed by
othergroups[35,36].
Table3.Clinicalresponserateonsystemicradionuclidetherapy
NuclidePrimarytumorResponse,%Reference
89Sr n.r. 7090 [34] 153Sm n.r. 7080 [55] 186Rebreastcancer50[56]186Rebreastcancer92[34]89Srbreastcancer36[57]
186Reprostatecancer83[56]
n.r.=Notreported.
Perspectives
There is growing interest in extending the role of bone-seek-ingradiopharmaceuticalsbeyondpainpalliationtowardstreatment
delivered with tumoricidal intent.Thepotentialadvantageofearlytreatmentinpatientswithasymptomaticmetastasestoachieve
durable disease control is well recog- nized [37]. Response duration is longer in patients treated early in the natural history of
their disease than in subjects with advanced metastases [32]. This observation may be at- tributable to the effect of long-range
beta-radiation on bone marrow micrometastases. Such micrometastases were de- tected by polymerase chain reaction (PCR)in
the bone mar- row of patients with prostate cancer who were staged N0 by clinical investigation and imaging procedures[38].
Other tumoricidal options include activity escalation, repeated radionuclide administration and multi-modality regimens de-
signed to exploit potential synergies between radionuclide treatment and external-beam radiotherapy or chemotherapy.
Preliminary activity-ranging studies using 153Sm-EDTMP sug- gested improved response rates, superior response quality and
prolonged survival in patientstreatedusinghighadministeredactivities[39,40].Thedisadvantageoffurtheractivityescala-tion
was dose-limiting myelosuppression. A subsequent phase I study demonstrated PSA reduction in CRPC patients treated with
high-activity186Re-HEDPandperipheralstemcellsupport[41].
The efficacy of repeated radionuclide therapy was reported in aphaseIItrialcomparingtheresponserateinCRPCpa-tients
with bone metastases after 1 or 2 administrations of 188Re-HEDP within 8 weeks (table 4). Pain palliation was sig- nificantly
higher and associated with > 50% PSA reduction in 39% of the patients in the double-dose group compared with 7% in the
single-dose group. The mean survival increased from 7 to 13 months [42]inthedouble-dosecohort.Amorerecentlypublished
retrospective analysis of these data ofthesamegroupshowed,inatotalnumberof60patientssufferingfrombonemetastasesof
hormone-refractory prostate cancer, an improvement of the mean survival from 4.5 to 15.66 months, in the subgroup with
multiple (3 and more) succes- sive administrations of 188Re-HEDP [43]. Similar results were published by Turner and
Claringbold [44] administering, in a phase II trial, either a single or repeated activityof153Sm-EDTMP.Themeansurvivalin
therepeated-therapygroupwas9monthsversus4monthsinthesingle-activitygroup.
Fig. 2. A 68-year-old female patient with breast cancer. Whole-body bone scan 3 h after intravenous injection of 656 MBq
99mTc-DPD, in anterior (a) and posterior view (b). Last post-therapy whole-body scan (c,d)23hafterintravenousinjectionof
3.2 GBq 153Sm-EDTMP. Mild progressive disease after a cumulative activity of 17.0 GBq 153Sm-EDT- MP; cancer antigen
(Ca) 153 was increased from 65.5 U/ml (staging scan) to 175 U/ml 15 months later. (e) Computedtomographyofthepel-vis
after thethird153Sm-EDTMPandcontinuousbisphosphonatetherapy,showingcalcificationofalarge,mainlylyticlesionofthe
pelvis(arrow).
104BreastCare2012;7:100107Fischer/Kampen
abc
e
d

Table4.Studieswithevidenceofimprovedsurvivalafterradionuclidetherapy
StudydesignCancertypeMediansurvival,weeksASurvival,weeksRef.
223Ra versus placebo HRPC 92.9/49.4 + 43.5 [52] 153Sm-EDTMP single versus repeated HRPC, BC, others 16/54 + 38 [44]
188Re-HEDPsingleversusrepeatedHRPC18/64+46[43]
HRPc=Hormone-refractoryprostatecancer,BC=breastcarcinoma.
Also pain control was significantly better in the repeated- therapy group (24 versus 8 weeks). These data were con- firmed by
other publications [45]. Interestingly,theresponseofmetastasesalreadyexistingpriortothefirsttherapywassignificantlybetter
than the response of those appearing during repeated therapy [45]. In a separate study, 6 of 40 pa- tientswithmetastaticbreast
cancer treated with 89Sr for painful skeletal metastases received repeated 89Sr administra- tions. Higher overall responserates
(83% versus 60%) were recorded in the re-treatment subset by comparison with pa- tients who had received asingletreatment
[35]. Prolonged response duration (3.08 0.48 versus 5.33 2.36 months) was reported in breast cancer patients receiving
multiple 89Sr ad- ministrations compared with patients who had received a single treatment [6]. These data have not been
confirmed in larger randomized studies. Following palliative external-beam radiotherapy to a dominant pain site, the
administration of systemic radio nuclide as consolidation treatment was shown to delay the development of new bone pain in
patientswithmetastaticCRPC[46,47].
There is growing evidence to support the addition of cyto- toxic chemotherapy to radionuclide treatment in patients with
predominantly osteoblastic bone metastases (chemosensitiza- tion). In cell cultures, the co-incubation of radionuclides with
cisplatin showed a synergistic effect with strong correlation between radiation dose and cisplatin concentration [48]. These
results were confirmed by two randomized clinical tri- als in men with CRPC. Significant prolongation of mean sur- vival,
improved qualityanddurationofpainreduction,anddelayedpaininclinicallysilentmetastaseswereobservedinpatientstreated
using 89Sr/cisplatin compared with 89Sr/pla- cebo. There was no significant difference in hematological toxicity between the
two groups [49, 50].Tuetal.randomizedCRPCpatientspretreatedwithinductiondoxorubicinandvinblastinetoreceivefurther
doxorubicin as monotherapy or doxorubicin with 89Sr. A greater than 80% PSA reductionwasobservedin72%ofthesubjects
whohadreceiveddoxo-rubicinwith89Srcomparedwith36%ofthosewhohadre-ceiveddoxorubicinalone.Themeansurvival
increased from 17 months inthemonotherapyarmto28monthsinthecombinedtreatmentgroup[51].Earlyresultsindicatethat
high-linear energy transfer (LET) therapeutic alpha-particle- emitting radionuclides exert a tumoricidal effect in skeletal
metastases. A randomized, placebo-controlled phase II study using fractionated 223Ra in metastatic CRPC patients demon-
stratedsignificantreductionsinbonealkalinephosphatase,delayedtimetoPSAprogression(26versus8weeks),and
prolonged median overall survival (65.3 versus 46.4 weeks) in the active treatment arm by comparison with the controlgroup.
Thehematologicaltoxicitywassimilarinbothgroups[52].
SummaryandFutureAspects
Radionuclide treatment for metastatic bone pain palliation is a safe andeffectiveoptionforpatientswithmultifocalosteoblastic
metastases. Symptom benefit is reported in 70 80% of patients with metastatic breast and prostate cancer, although lower
response rates are observed in patients with otherprimarytumors[1,35].Approximately20%ofpatientsbecomepainfreeafter
radionuclide therapy. The majority of patients are able to reduce or withdraw opioid analgesics, but most continue on
non-steroidal anti-inflammatory medica- tion. Economic analyses demonstrate that targeted radio- nuclide therapy is a
cost-effective alternative to repeated ex- ternal-beam irradiation inpatientswithmultifocalskeletalmetastases.Forbeta-aswell
as for alpha-emitters there are convincingdatathat,besidesthepainpalliationeffect,evenaprolongationofthemeansurvivalis
obvious. The therapeutic potential of new radiopharmaceuticals for bone pain pallia- tion is under investigation. The high
absorbed dose delivered by alpha-emitting radionuclides, for example, is predicted to achieve a direct antitumoreffectinbone.
Limited hematologi- cal toxicity resultingfromtheshortparticlerangeofbothalphaandconversionelectronemittersmayallow
easierinte-grationwithothertreatmentswithoutthepenaltyofcumula-tivemyelotoxicity.
Several multi-modality bisphosphonate, chemotherapy and radiopharmaceutical regimenshavebeeninvestigated.Theresults
consistently suggest superior symptomcontrolandprolongedsurvivalusingcombinedtreatmentratherthaneitherchemotherapy
or radiopharmaceuticals alone.PhaseIIstudiescombiningeither223Raor153SmwithdocetaxelinCRPCareinprogress.Inthe
long term, these radiopharma- ceuticals might also offer opportunities for fractionated ther- apy to achieve both sustained
symptombenefitandsustainedskeletaldiseasecontrol.
A totally different approach is the use of radiolabeled monoclonal antibodies as presentedrecentlyfordiagnosticimagingof
prostate cancer metastases: (S)-2-(3-((S)-1-carboxy- 5-((4-123I-iodobenzyl)amino)pentyl)ureido)pentanedioic acid
(123I-MIP-1072).Thissmall-moleculeglutamateureahetero-dimerinhibitstheN-acetylated-linkedacidicdipeptidase
BreastCare2012;7:100107RadionuclideTherapyofBoneMetastases105

enzymaticactivityoftheprostate-specificmembraneantigen
DisclosureStatement(PSMA).Inpatients,ahigh
specificityofthistracerforpros-tatecancertumorcellswasobserved.Atrialisinprogress
M.F.isadvisortoCISbioGermany,memberoftheIBA
group.Thereistreatingpatientswithmetastasesfromprostatecancerusing
noconflictofinterestforW.U.K.
131I-MIP-1072[53].
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