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Review Article bersichtsarbeit

Breast Care 2012;7:100107 Published online: April 24, 2012DOI: 10.1159/000337634

Prof. Dr. med. Manfred FischerPraxis fr Radiologie und NuklearmedizinIm Bodden 60, 34125 Kassel, GermanyTel. +49 561-878987, Fax [email protected]

2012 S. Karger GmbH, Freiburg1661-3791/12/0072-0100$38.00/0

Accessible online at:www.karger.com/brc

Fax +49 761 4 52 07 [email protected]

Breast Care

Radionuclide Therapy of Bone MetastasesManfred Fischer a Willm U. Kampen b

aPraxis fr Radiologie und Nuklearmedizin, Kassel,bNuclear Medicine Spitalerhof, Hamburg, Germany

SchlsselwrterKnochenmetastasen Schmerztherapie Radionuklide 153

Sm-EDTMP 89

Sr 223

Ra

ZusammenfassungZahlreiche maligne Tumoren metastasieren in dasSkelett. Bei bis zu 85% der Patienten mit einem Prostata-oder Mammakarzinom finden sich Knochenmetastasen,die bei vielen zu einer ausgeprgten Schmerzsympto-matik fhren. Bei Patienten, die an einer multilokulrenKnochenmetastasierung und Schmerzen leiden, kanneine palliative Schmerztherapie mit Radionuklidendurchgefhrt werden. Niedrigenergetische Beta-Strahler(153 Samarium-Ethylendiamintetra(methylenphosphon-

sure) (EDTMP) und 89Strontium) bewirken eine hoheStrahlendosis auf die Knochenmetastasen und die Mik-rometastasen im Knochenmark bei nur geringer Dosisauf das Mark selbst. Die Ansprechrate auf die Therapiebetrgt 7080%, etwa 25% der Patienten werdenschmerzfrei. Die Therapie kann in Abhngigkeit vomBlutbild wiederholt werden. Eine gleichzeitige Therapiemit modernen Bisphosphonaten fhrt nicht zu einer Wir-kungsnderung. Klinische Studien mit einem neuen,noch nicht zugelassenen Nuklid ( 223 Radium) oder Kombi-nationstherapien mit Chemotherapeutika und Radio-nukliden zielen auf einen mehr kurativen Effekt und zei-gen vielversprechende Ergebnisse.

KeywordsBone metastases Pain palliation Radionuclides 153

Sm-EDTMP 89

Sr 223

Ra

SummaryThe skeleton is a potential metastatic target of manymalignant tumors. Up to 85% of prostate and breastcancer patients may develop bone metastases causingsevere pain syndromes in many of them. In patientssuffering from multilocular, mainly osteoblastic lesionsand pain syndrome, radionuclide therapy is recom-mended for pain palliation. Low-energy beta-emittingradionuclides ( 153 samarium-ethylenediaminetetrameth-ylenephosphonate (EDTMP) and 89strontium) deliver high

radiation doses to bone metastases and micrometasta-ses in the bone marrow, but only negligible doses to thehematopoietic marrow. The response rate regardingpain syndrome is about 75%; about 25% of the patientsmay even become pain free. The therapy is repeatable,depending on cell counts. Concomitant treatment withmodern bisphosphonates does not interfere with thetreatment effects. Clinical trials using a new, not yetapproved nuclide ( 223 radium) and/or combinations ofchemotherapy and radionuclides are aiming at a morecurative approach.

Introduction

The incidence rate of many common primary tumors is stillrising and, due to progression in efficacious treatment, manypatients survive for a longer time.

Because the skeleton is a potential metastatic target for themajority of malignant extracranial tumors [1], an increasingnumber of patients will suffer from painful bone metastases,

which can significantly impair the patients health. Post-

mortem studies indicate that approximately 80% of allpatients with prostate cancer and 75% of breast carcinomapatients develop bone metastases, which together account forapproximately 80% of all skeletal metastases [2]. By compari-son, bone metastases occur in approximately 2040% of pa-tients with lung or renal cancer [3] (table 1). World HealthOrganization (WHO) data suggest that approximately 4 mil-lion people worldwide experience daily pain due to malignantdisease; in half of these people, metastatic bone discomfort is

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Breast Care 2012;7:100107Radionuclide Therapy of Bone Metastases 101

discomfort [9]. The prognosis of patients with metastases con-fined to the skeleton is usually superior to that of patientswith soft-tissue metastases, in lungs, liver or lymph nodes, forexample [10], and therefore merits careful consideration.

In addition to analgesic drugs (prescribed according tothe WHO scheme) [4], local external-beam radiation therapy,

and surgical interventions, especially in locally restricteddisease, several radiopharmaceuticals have been developedfor the systemic palliation of bone pain with more multilocu-lar skeletal involvement.

Radionuclide Therapy

The first application of the bone-seeking radiopharmaceuticalstrontium-89 [89Sr]-chloride was described by Pecher in1940/41 [11], followed by the first report of pain palliation in apatient with bone metastases from breast carcinoma using

phosphorous-32 [32P] by Friedell [12].In Europe, strontium [89Sr]-chloride is approved for bone

pain palliation in patients with bone metastases of prostatecancer, whereas samarium [153Sm]-ethylenediaminetetrameth-ylenephosphonate (EDTMP) is approved for the treatment ofpain from all osteoblastic bone metastases. Phosphor [32P]-orthophosphate is used in several other countries.89Sr is acalcium analog and is incorporated into the newly formedhydroxyapatite of the bone matrix.153Sm is radiolabeled to abisphosphonate (EDTMP) and adsorbed onto the hydroxy-apatite surface of metabolically active bone by the samemechanism as technetium [99mTc]-labeled bisphosphonatesused for diagnostic bone scintigraphy.

Selective uptake depends on the degree of the metabolic(i.e. osteoblastic) response elicited in normal bone by thepresence of metastatic tissue. Increased bone turnover leadsto enhanced incorporation of bone-seeking radiopharmaceu-ticals at metastatic sites, by comparison with normal bone,and can therefore deliver a high, targeted local radiation dose.Skeletal uptake of the radiolabeled bisphosphonate153Sm-EDTMP is in the order of 48% of the administered activity

the dominant source of symptoms [4]. The majority of pa-tients with bone metastases develop severe pain as their dis-ease progresses, resulting in a considerable reduction in theirquality of life. A multidisciplinary approach to symptom pal-liation is recommended, tailoring treatment to individualneed, with the aim of individualized treatment being to add

life to the years, not years to the life.The uptake of bone-seeking radiotracers used for radionu-clide therapy of bone metastases depends on the osteoblasticactivity and the calcification of the tumor tissue. In the past,the morphology of bone metastases arising from primaryprostate cancer was typically characterized as mainly osteo-blastic, whereas plasmocytoma and renal cell carcinoma havebeen associated with predominantly osteolytic bone lesions.Mixed patterns of osteoblastic and osteolytic metastases aremore common in breast, lung, colorectal and pancreaticmalignancies [5, 6]. More recently, when comparing themorphology of breast cancer metastases by computed tomo-

graphy in the time period 19962000 versus 20012005, ahigher prevalence of osteosclerosis was observed in the laterperiod (19962000: osteolytic 53.7%, osteosclerotic 32.1%,mixed type 14.3%; 20012005: osteolytic 9.4%, osteosclerotic71.9%, mixed type 18.7%). This may be due to the applicationof systematic adjuvant bisphosphonate treatment [7].

Approximately 75% of patients with bone metastases com-plain of pain as their main symptom and the dominant reasonfor a decreased quality of life [8]. Appropriate pain manage-ment may be difficult, particularly in case of poorly localized

Table 1. Incidence of bone metastases reported in postmortem studies[54]Tumor Mean frequency, % Range, %Breast 73 4785Prostate 68 3385Thyroid 42 2885Kidney 35 3340Lung 36 3055Esophagus 6 57Gastrointestinal 5 311Rectum 11 813

Table 2. Physical characteristics of radiopharmaceuticals used for bone pain palliationRadionuclide Carrier Physical half-life,

daysbmax, MeV bmean, MeV Mean rangec

in tissue, mmg-Energy, keV (%)

89Sr chloride 50.5 1.46 0.583 6.7 153Sm EDTMP 1.95 0.8 0.224 3.4 103 (28)32Pa phosphate 14.28 1.71 0.695 7.9 188Reb HEDP 0.71 2.12 0.76 11.0 155 (1)117mSnb DTPA 13.6 no beta-emission 0.3 CE 15933Pb phosphate 25.34 0.249 0.85 0.05223Rab chloride 11.4 alpha-emitter (eff. energy 26.4 MeV) < 100mmaNot approved in Germany.bClinical trial only.cMean range in periosseous soft tissue.EDTMP = Ethylenediaminotetramethylenephosphonate, HEDP = hydroxyethylenediphosphonate, DTPA = diethylenetriaminopentaacetate,

CE = conversion electrons.

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102 Breast Care 2012;7:100107 Fischer/Kampen

per kilogram bodyweight [22]. Following intravenous ad-ministration, skeletal uptake peaks within 1 h of injection,with no subsequent redistribution. Phase I and II studiesconfirm low temporary myelosuppression approximately4 weeks post treatment, but this rarely exceeds WHO grade I/II even at high activities (200 kBq/kg) in heavily pretreated

patients [23]. Less than 1% of 292 patients developed gradeIV hematological toxicity; grade III toxicity for hemoglobinwas experienced by 4.8%, and for platelets, neutrophiles andwhite blood cells by < 3%. The preliminary results of adouble-blind, randomized, placebo-controlled phase III trial(ALSYMPCA) with its primary endpoint of survival showlow toxicity and a mean survival of 14 months for the ra-dium-223 group compared to 11.2 months for the placebogroup. The median time of new skeletal events was 13.6versus 8.4 months.

The mechanism and radiobiology of pain reduction usingunsealed source therapy is not yet fully understood. A direct

radiation effect on neuronal tissue seems unlikely due to thewell-known high radiation resistance of peripheral neurons.It is more conceivable that radiation to cells and tissuessurrounding the metastasis promotes cell signaling changes,resulting in modulation of both pain reception and transmis-sion. Possible target cells are likely to include macrophages,mast cells, thrombocytes, lymphocytes, and endothelial cells,which influence secretion of pain mediators such as ATP,histamine, prostaglandin E (PGE), interleukin (IL)-1 and -2,leukotrienes, and substance P. Animal experiments [24] haveshown that 223Ra inhibits the differentiation of osteoclasts,and probably thereby also the progression of mainly osteo-lytic breast cancer bone metastases.

Indications, Contraindications and Procedureof Pain Palliation Treatment

Surgical stabilization and/or external-beam radiation are thetreatments of choice for the management of solitary, painfulbone metastases, bones at high risk of pathological fracture,and in patients with impending spinal cord compression.

Systemic radionuclide therapy is indicated to manage

multifocal metastatic bone pain following failure of conven-tional analgesics and to palliate recurrent pain within a previ-ously irradiated site. It is likewise indicated if the side effectsof high-dose analgesics become intolerable and significantlycompromise the quality of life, even if pain control isadequate.

Strontium [89Sr]-chloride is approved for pain palliation inpatients with bone metastases from prostate cancer; samarium[153Sm]-EDTMP may also be used in patients suffering fromosteoblastic metastases of other tumor types. The activity of153Sm-EDTMP is adjusted for the patients body weight(37 MBq/kg), whereas89Sr-chloride is prescribed as standard-ized activity (150 MBq).

[13]. The effective half life of89Sr in bone metastases is greaterthan 50 days, compared with 14 days in normal bone [14](table 2).

32P as sodium phosphate is no longer approved in manycountries because of documented myelotoxocity associatedwith therapeutic administration. More recently, a clinical trial

comparing89

Sr and32

P in patients suffering from bone metas-tases reported slightly higher toxicity in the32P group butcomparable efficacy in terms of pain palliation [15]. Furtherresearch will be necessary to confirm these results particularlyin heavily pretreated patients who may have limited bonemarrow reserves.

Clinical trials are in progress evaluating the therapeuticpotential of other radionuclides for bone pain palliation.These include: tin [117mSn]-diethylenetriaminopentaacetate(DTPA), sodium [33P]-phosphate, rhenium [188Re]-hydroxye-thylidenediphosphonate (HEDP), lutetium [177Lu]-EDTMP,and radium [223Ra]-chloride.

In addition to clinical variables such as skeletal metastaticburden, disease distribution, and prior treatment, myelosup-pression resulting from systemic bone-seeking radiopharma-ceutical therapy reflects the effective half-life, particle energyand particle range of the radionuclide used. The use of low-energy beta-emitting radionuclides would be expected to de-liver a high absorbed dose to the bone surface, but a negligi-ble dose to the hematopoietic bone marrow [16]. Theoreticaldose calculations predict a 36-fold advantage in terms ofmyelotoxicity risk if33P were substituted for32P, for example[17]. The same is true for conversion electons of117mSn oralpha-emitters like223Ra.

To reduce the myelotoxicity, the therapeutic potential ofconversion electron-emitting radiolabels such as117mSn-DTPAhas been reported. Conversion electrons ejected during thedecay of this nuclide have a 1.75.5 times lower energy thanbeta-particles conventionally used for systemic treatment forpain palliation [18]. But the limiting factor of this compoundused in a phase I/II clinical study was not the radiation doseto the marrow but the high amount of DTPA in the currentformulation, in a 20-fold molar excess over tin [19]. Morerecently, a new 1:1 chelate was synthesized [20].

Estimates of the absorbed radiation dose delivered to

osteoblastic bone metastases vary widely, ranging from 661cGy/MBq for 89Sr, 100014,000 cGy from a standard treat-ment activity of 1295 MBq186Re-HEDP (this radiopharma-ceutical was recently withdrawn from the market), and amean dose of 87 Gy from 2590 MBq153Sm-EDTMP. A doseof 54 mGy/MBq was reported using117mSn-DTPA, with thebone uptake ranging from 34 to 83% of the injected activity[21].

The bone-seeking alpha-particle emitter radium-223 ispredicted to deliver a high absorbed radiation dose to thebone surface, with sparing of the bone marrow compartment.From data of animal experiments, a total skeletal dose of 553790 Gy was calculated after administration of 3750 kBq223Ra

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A prerequisite for radionuclide treatment of metastaticbone pain is the demonstration of multifocal abnormal skele-tal uptake on conventional99mTc phosphate bone scintigra-phy, corresponding to known pain sites [58]. Patients shouldhave reasonable bone marrow reserves, as evidenced by(near) normal blood counts. The gamma-emission of Sm-153

is useful for early post-therapy imaging to confirm selectivetracer uptake and appropriate targeting.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 using89Sr, patients should have alife expectancy of at least 3 months. Absolute contraindica-tions to radionuclide therapy include pregnancy, breast-feed-ing and severe bone marrow depression, for beta-emittersindicated by platelets < 60,000/ml or leucopenia < 2400/ml [25].Acute spinal cord compression, disseminated intravascularcoagulation, and impaired renal function (urea > 12 mmol/l orcreatinine > 150 mmol/l) are regarded as additional contrain-

dications in German, European and American guidelines forpain palliation treatment using Sm-153-EDTMP or Sr-89.

Patients with urinary incontinence should be catheterizedprior to treatment, to mitigate the risk of radioactive urinecontamination. Specialist referral is advised where bones areconsidered at risk of pathological fracture. To allow time forbone marrow recovery and avoid unpredictable cumulativetoxicity, unsealed source treatment should be delayed for68 weeks after completion of chemotherapy. It is recom-mended that further chemotherapy be deferred for at least812 weeks, depending on the radiopharmaceutical used. A23-month delay is recommended after large-field radiationtherapy.

Concomitant treatment with modern bisphosphonates,which are characterized by very low effective levels, doesnot interfere with the uptake of bone-seeking radionuclides[23, 26, 59]. This is in contrast to former concerns regardingthe classical drugs clodronate or etidronate. Focal abnormaluptake should, however, be confirmed in every patient by pre-therapeutic bone imaging and correlated with the localizationof the pain.

Following appropriate oral hydration, the bone-seekingradiopharmaceutical is administered intravenously via a pe-

ripheral cannula, usually in an outpatient setting, dependingon local legislation. Prior to discharge, the uptake and distri-bution of the activity of153Sm-EDTMP can be documented bywhole-body scanning 524 h post injection. Renal excretion ofthe unbound fraction of the radionuclide is very rapid, i.e.71% within 3 days [27] compared with 53% of the unbound153Sm-EDTMP excreted via the kidneys within 68 h afterinjection [28].

Blood counts, especially thrombocytes and white bloodcells, must be monitored weekly to track expected, temporarybone marrow suppression. Marrow recovery is usual within8 weeks of153Sm-EDTMP administration and within 12 weeksof 89Sr treatment, with the speed and completeness of hemato-

poietic regeneration being determined by the underlying bonemarrow reserves. With appropriate patient selection and care-ful monitoring, clinically significant or protracted bone mar-row suppression requiring red cell or platelet transfusion israre. Palliative pain therapy may be repeated to treat recur-rent symptoms, a minimum of 812 weeks after previous153

Sm-EDTMP administration or 34 months after therapywith89Sr. Hematotoxicity caused by223Ra is much less becauseof the rapid uptake in bone (> 75 of the administered activityis cleared from the blood and plasma within 15 min afterinjection) and the very short range of alpha-particles [29].

Clinical Results

Of the patients with metastatic prostate or breast cancer,7080% report symptom benefit following treatment withbone-seeking radiopharmaceuticals (figs. 1 and 2). Pain relief

typically occurs within 1 week of intravenous153Sm-EDTMPadministration and usually lasts for about 812 weeks, al-though prolonged responses of up to 12 months have beenreported [23]. The advantage of89Sr is a longer mean responseduration of approximately 4 to 6 months, but this benefit mustbe weighed against the delayed onset of symptom palliation of1428 days after radiopharmaceutical administration [30] andthe increased risk of myelosuppression.

Fig. 1. A 76-year-old male patient with prostate cancer. Whole-bodybone scan 2 h after intravenous injection of 698 MBq99mTc-DPD Multipleosteoblastic metastases are seen from both the anterior (a ) and posterior(b ) projection. Post-therapy whole-body scan (c , d ) 24 h after applicationof the second treatment with153Sm-EDTMP. The cumulative activity ofboth treatments was 6.7 GBq. The scan shows mild progression of thebony lesions. The PSA level increased up to 1,210 ng/ml, from the stagingscan to 5 months after the second treatment. The patient is pain free sincethe first therapy.

a b c d

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Perspectives

There is growing interest in extending the role of bone-seek-ing radiopharmaceuticals beyond pain palliation towardstreatment delivered with tumoricidal intent. The potentialadvantage of early treatment in patients with asymptomaticmetastases to achieve durable disease control is well recog-nized [37]. Response duration is longer in patients treatedearly 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 bonemarrow 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 byclinical investigation and imaging procedures [38]. Othertumoricidal options include activity escalation, repeatedradionuclide administration and multi-modality regimens de-signed to exploit potential synergies between radionuclidetreatment and external-beam radiotherapy or chemotherapy.Preliminary activity-ranging studies using153Sm-EDTMP sug-gested improved response rates, superior response quality andprolonged survival in patients treated using high administeredactivities [39, 40]. The disadvantage of further activity escala-tion was dose-limiting myelosuppression. A subsequent phaseI study demonstrated PSA reduction in CRPC patientstreated with high-activity186Re-HEDP and peripheral stemcell support [41].

The efficacy of repeated radionuclide therapy was reportedin a phase II trial comparing the response rate in CRPC pa-tients with bone metastases after 1 or 2 administrations of188Re-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 with7% in the single-dose group. The mean survival increasedfrom 7 to 13 months [42] in the double-dose cohort. A morerecently published retrospective analysis of these data of thesame group showed, in a total number of 60 patients sufferingfrom bone metastases of hormone-refractory prostate cancer,an improvement of the mean survival from 4.5 to 15.66months, in the subgroup with multiple (3 and more) succes-sive administrations of188Re-HEDP [43]. Similar results werepublished by Turner and Claringbold [44] administering, in aphase II trial, either a single or repeated activity of153Sm-EDTMP. The mean survival in the repeated-therapy group

was 9 months versus 4 months in the single-activity group.

Fig. 2. A 68-year-old female patient with breast cancer. Whole-bodybone scan 3 h after intravenous injection of 656 MBq99mTc-DPD, inanterior (a ) and posterior view (b ). Last post-therapy whole-body scan(c , d ) 23 h after intravenous injection of 3.2 GBq153Sm-EDTMP. Mildprogressive disease after a cumulative activity of 17.0 GBq153Sm-EDT-MP; cancer antigen (Ca) 153 was increased from 65.5 U/ml (stagingscan) to 175 U/ml 15 months later. (e ) Computed tomography of the pel-vis after the third153Sm-EDTMP and continuous bisphosphonate therapy,showing calcification of a large, mainly lytic lesion of the pelvis (arrow).

Table 3. Clinical response rate on systemic radionuclide therapyNuclide Primary tumor Response, % Reference89Sr n.r. 7090 [34]153Sm n.r. 7080 [55]186Re breast cancer 50 [56]186Re breast cancer 92 [34]89Sr breast cancer 36 [57]186Re prostate cancer 83 [56]

n.r. = Not reported.

No reliable response predictors have been established [31,32]. Prostate-specific antigen (PSA) decline in prostate cancerpatients treated using radionuclide therapy does not correlatewith pain palliation. In a small study of 50 patients treatedwith 89Sr for metastatic castration-resistant prostate cancer(CRPC), a decrease or stabilization of the PSA levels after

treatment (28% of patients, n = 14) was associated with a sig-nificant mean survival improvement from 275 to 641 days andprolonged time to pain progression (67 to 142 days) [33]. In areview 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 wereconfirmed or completed by other groups [35, 36].

a b c

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Disclosure Statement

M.F. is advisor to CISbio Germany, member of the IBA group. There isno conflict of interest for W.U.K.

enzymatic activity of the prostate-specific membrane antigen(PSMA). In patients, a high specificity of this tracer for pros-tate cancer tumor cells was observed. A trial is in progresstreating patients with metastases from prostate cancer using131I-MIP-1072 [53].

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