THE UNIVERSITY OF NEW MEXICOHEALTHSCIENCESCENTERCOLLEGEOF PHARMACY

ALBUQUERQUE,NEW MEXICO

Correspondence Continuing Education Coursesfor

Nuclear Pharmacists and Nuclear MedicineProfessionals

VOLUME VHI, NUMBER 4

Clinicalin

and Pharmacoeconomic Considerationsthe Treatment of Bone Metastasis

By:

Jay A, Spicer,MSBarbaraWoods,RPh, MA*

andSara Ruppelt,PharrnD,RPh

Universityof KansasMedicalCenterDepartmentsof Pharmacyand Radiology

Kansas City, KSand

*University of KansasSchool of Pharmacy

Lawrence, KS

mThe IJniversity of New Mexico Health Sciences Center College of Pharmacy is approved by theAmerican Council on Phamlaccutical Education as a provider of continuing pharmaceuticaleducation, Program No. 039-000 -99-002-H04. 2.5 Contact Hours or .25 CEtJs

@

Coordinating Editor and Director of Pharmacy Continuing EducationWilliam B. Hladik 111, MS, RPh

College of Pharmacy

University of New Mexico Health Sciences Center

Managing EditorJulliana Newman, ELS

Wellman Publishing Inc.

Albuquerque, New Mexico

Editorial BoardGeorge H. Hinkle, MS, RPh, BCNP

William B. Hladik III, MS, RPhJeffrey P. Norenberg MS, RPh, BCNP

I.aura L. Boles l>onto, PhD, RPhTimothy M. Quinton, PharmD, MS, RPh, BCNP

Guest ReviewerDr. Rodney Hicks, M.B., B.S. (Hens), FRACP

Director of Nuclear MedicinePeter MacCallum Cancer Institute

12 Cathedral IJlaccEast Melbourne, Victoria 3002”

AUSI’RAL,IA

While the advice and information in this publication are believed to be true ~nd accurate at press time, the author(s),

editors, or the publisher cannot accept any legal res~nsibility for any errors or omissions that may be made. The

publisher makes no warranty, express or implied, with respect to the material contained herein.

Copyri@lt 2000University of New Mexico 1Icalth Sciences Center

Pharmacy Continuing EducationAlbuquerque, New Mexico

● CLINICAL AND PHARMACOECONOMIC CONSIDERATIONSIN THE TREATMENT OF BONE METASTASES

STATEMENT OF OBJECTIVES

The primary goal of this lesson is to present the reader with information on the differenttypes of therapy that are available for the treatment of bone pain due to metastatic diseaseand the cost effectiveness of each. Thts lesson will concentrate on various radiopharma-ceuticals, bisphosphonates, surgery, radiation therapy, and pharmaceuticals that areavailable for pain control. An analysis of the effectiveness, cost, and side effects of eachmodality will also be presented.

Upon successful completion of this material, the reader should he able to:

1.

2.

● 3,

4.

5.

6.

List the seven radiopharmaceuticals that are available as approved agents or are

currently in clinical trials for the palliation of bone pain due to metastasis.

List six other techniques that are available for the palliation of bone pain due to

metastasis.

Describe the effectiveness of all of the techniques listed for the control of bone

pain due to metastasis.

Describe the side effects of all of the techniques listed for the control of bone pain

due to metastasis.

Estimate the cost associated with each of the techniques listed for the control of

bone pain due to metastasis.

Compare the use and cost of each modality in the control of bone pain due to

metastasis.

COURSE OUTLINE

1. INTRODUCTION

11. WDIOPHARMACE~CALSFOR PALLIATION OF BONEPAINA. Strontium-89 Chloride

(Metastron)

B. Samarium-153 ethylene-diaminetetramethylenePhosphoric Acid(Quadramet)

c, Phosphorus-32 SodiumPhosphates

HI. EXTERNAL BEAMRADIATION THERAPYA. EffectivenessB. Side Effectsc. cost

IV. CHEMOTHERAPY ANDSURGERY

v. ANALGESICS-NSAIDS and0PL4TES

VI* BISPHOSPHONATES

VII. PHARMACOECONOMICANALYSIS

●

VIII. CONCLUSIOND. Rhenium- 186

hydroxyethylenediphosphonate

E. The Alumina-BasedTungsten- 188/Rhenium-188 Generator

F. Tin-1 17m (Stannic, 4+)Diethylenetriaminepenta-acetic Acid (Tin- 117m(4+) DTPA

●

●

2

CLINICAL ANDPHARMACOECONOMIC

CONSIDERATIONS IN THETREATMENT OF BONE

METASTASES

By:Jay A, Spicer, MS

Barbara Woods, RPh, MA,*and

Sara Ruppelt, PharmD, RPhUniversity of Kansas Medical Center

Depatiments of Pharmacy andRadiology

Kansas City, KSand

*University of KansasSchool of Pharmacy

Lawrence, KS

INTRODUCTION

●Control of pain caused by metastasis

of primary cancers is an importantclinical challenge. It has been estimatedthat 75% to 90% of patients withadvanced cancer experience chronicpain, 1 The prevalence of this problem iscostly not only in monetary terms butalso patient quality of life. As ourunderstanding of and clinical experiencewith the tre~tment of pain expands, itbecomes more difficult for clinicians toselect optimal therapy from the growingarray of treatments available. Optionscurrently available for the palliation ofpain due to metastatic spread of osseouscancer include radiopharmaceuticals,external beam radiotherapy,chemotherapy and surgery, analgesicsand bisphosphonates.

These therapies should beindividualized based on patient need andclinician experience. For

●therapy, it is necessary for theand the patient to consider

optimalclinicianclinical,

humanistic and economic issues,Historically, orIly clinical eficacy andtoxicity were incorporated into thetherapy selection process, but morerecently it has been recognized thatpatient quality of life needs and costrestraints must also be considered,Definition of optimal pain therapy iselusive because of the lack of outcomestudies directly comparing thepreviously listed treatment alternatives.Because of the lack of these studies,pharmacoeconomic comparisons ofavailable treatments are difficult. Thereare a few investigations,2’3 which attemptto compare the palliative characteristicsof radiopharmaceuticals versus externalbeam radiotherapy in their ability todecrease the use of analgesics andopiates. Even less information isavailable concerning the ability ofbisphosphonates to reduce patient useof pain medication.4 There are nostudies that compare the palliativeefficacy of bisphosphonates withradiopharmaceuticals.

Because of the lack ofcomparative information about treatmentalternatives, this lesson will provide areview of current literature on palliativeapproaches for painful metastatic bonedisease including a review ofeffectiveness, side effects, and cost. Byproviding this information, the readershould be able to consider economic aswell as clinical issues in their decision-making.

RADIOPHARMACEUTICALS FORPALLMTION OF BONE PAIN

This section is intended to provide anoverview of all of the agents that areapproved in either Phase 1, 11, or 111trials, or are in a research and

development phase. A review article onmany of these drugs by McEwan5

3

provides some excellent information.This continuing education lesson willupdate McEwan’s paper as well aspresent information on the pharma-coeconomic analysis of these agentscompared to other forms of painpalliation.

Strontium-89 Chloride (Metastron@)The use of ‘gStrontium Chloride

(89SrClz) for the treatment of metastaticbone disease and the pain associatedwith it dates back to the early 1940s, 6Strontium-89 has several characteristicsthat make it useful for the treatment ofbone pain caused by the spread ofcertain cancers. These characteristics aresummarized as follows. Strontium-89 isin the same chemical family as calcium,thus it will form strontiumhydroxyapetite crystals that areincorporated directly into the bonematrix+ Strontium-89 as strontiumchloride is produced on a nuclear reactor

by the following reaction: g~Sr(n0,y)89Sr.and decays with a physical half-life of50 days. The maximum energy of thebeta particle emitted is about 1.4 MeV.Since 89Sr has very poor imagingcharacteristics, it has been proven by theuse of ‘5Sr that strontium isotopesconcentrate in metastatic bone sites forlong periods of time, while they clearrapidly form normal tissue.7

In June of 1993 the FDA approved

Metastron@ for use as a palliative agentin the management of bone pain due tometastasis from either prostrate or breastcancer. Because of its ability toconcentrate in metastatic cancer of thebone for long periods of time, 89Sr hasbeen shown to be very effective atrelieving pain associated with metastasisfrom either breast or prostate cancer.s”10According to Robinson and associatesapproximately 50°/0 of the injected dose

of 89Sr concentrates in the bone. ~er 14days the ‘9Sr has cleared normal boneand all of the remaining drug is

associated with metastatic sites. SinceMetastron@ is concentrated in allmetastatic bone sites, it has been provento be as effective as hemibody radiationfor pain control, According to Quilty and

associates, 11 Metastron@ is much moreeffective at preventing the occurrence ofnew disease. More recent trials9’10 inEurope have shown that pain relief ofsome magnitude has been obtained in ashigh as 90% of the patients treated.These trials have not only showneffectiveness, but they confirm the drugcan be safely given repeatedly every 3months with only transient hematologicside effects.

A standardized procedural guidelinefor the treatment of bone pain with 89Srhas been available since 1996,12 Whenthese guidelines are followed closely. theadverse effects associated with thistherapy are minimal in most cases. Themost common adverse effect is the“flare” response. This response is due tosudden swelling of the tumor from theradiation and usually occurs within thefirst week to 10 days following treatmentand is commonly associated with lessextensive metastatic disease. The “flare”response can cause an increase in painfor the first week to 10 days and shouldnot be mistaken as a worsening of thedisease. Patients should be informed ofthis potential reaction. The second mostfrequent side effect is a transientlowering of marrow production. Thisside effect is most commonly seen at 3-4weeks post therapy with a rebound at 2-3months, Jf patients are on chemotherapyor other types of marrow depressingagents, then the platelet and white cellcounts should be monitored closely astransfusion may be necessary. The most

Io

4

severe risk factor is disseminatedintravascular coagulation (DIC), whichmay occur due to post therapythrombocytopenia. There have beenreports of death occurring from DICassociated with the use of beta emittingradiopharmaceuticals,’ 2 however, DIC isa recognized complication of advanced

r,restate cancer and its association withSr administration maybe coincidental.

Metastron@ is available fromNycomed Arnersham. The drug isshipped in 4 mCi/4rnL lots that expire 28days post calibration. The cost of thedrug ranges from $2500.00 to $2900.00per vial, depending on whether it ispurchased directly from NycomedAmersham in Chicago or if it is suppliedby a centralized nuclear pharmacy, Themost common dose given to the patientis 4 mCi, however a dose of 40-60uCi/kg can be given depending on theweight of the patient.

Samarium-153 Ethylenediamine-tetramethylene Phosphoric Acid(Quadramet@)

Samariium-153 Ethylenediamine-tetramethylene Phosphoric Acid (153Sm-

EDT~), or Quadramet@, is an FDAapproved drug indicated for use in painrelief in patients with confirmedosteoblastic metastatic bone lesions thatenhance on a radionuclide bone scan. ~sSamarium- 153 has a physical half-life of46 hours and emits both a gamma rayand multiple beta particles. The 103 keVgamma emission has an abundance of28% and can be imaged with anystandard gamma camera. Although itemits multiple beta particles, themaximum beta energy for 153Sm is 810keV, Production of the isoto e is

raccomplished by irradiation of a 1j SmOItarget with neutrons from a nuclearreactor. The equation for production is

132Sm(no,y)15sSm. The final product isproduced by reacting ‘53SmOI withC~a EDTMP in 0, lN HCI. The molarratio of 153Sm to EDTMP is 1:1, thusforming a very stable complex. Themechanism of uptake for ‘5qSm-EDTMPis very similar to the ‘gmTc phosphonatesused in diagnostic bone imaging. TheEDT~ portion of the molecule willbind to the hydroxyapetite crystal of thebone matrix by passive chemabsorption.This uptake is reversible thus allowingthe drug to passively difise from thebone matrix. According to the literature14an average of 52°A of the injected doseremains in the skeletal system at 6 hourswith the remainder being eliminated in

the urine, Quadramet@ is known toconcentrate in metastatic bone sites morethan in normal bone, thus delivering amuch higher radiation dose to tumorcells than to normal bone tissue.

Unlike Metastron@, the literaturedoes not contain information comparingQuadramet@ with other forms of painrelief such as radiation therapy, Becauseof a lack of comparison, one can onlyassume that ‘53Sm-EDTM is similar to8gSr in its ability to control bone painand prevent the spread of disease whencompared to radiation therapy and othermodalities, There are a number ofarticles’ 5-]g that have been publishedregarding dosage and dose/response to

Quadramet,@ which would seem toimply that it has the ability to controlpain as well as 8gSr. According to thesearticles, the response rate for paincontrol varies from 55°/0 when patientsreceive 0.5 mCi/kg body weight 14 to950A’6 in patients receiving up to1.5mCilkg body weight. The averagepercent of patients that receive somedegree of pain relief was about 80V0which is comparable to results obtainedwith ‘9Sr. Several of the above

5

references compared pain relief based onthe activity of Quadramet@ that wasgiven, Doses ranged from 0.5 mCi/kgbody weight up to 3,0 mCi/kg bodyweight. A dose of 153Sm-EDTMPequivalent to 1,0 mCi/kg body weightgenerally appeared to provide the bestpain relief with a smaller percentage ofpatients having hematologic side effects.

Although Quadramet@ andMetastron@ appear to have similarresponse rates, some differences areworth noting. First of all, Quadramet@ isapproved for use in a wider variety ofmetastatic bone tumors based onevidence of favorable response to thedrug. ]b”]g The demonstration thatmetastasis from tumors other than breastor prostate respond well to ‘53SmEDTMP may be due to the relativelyshort physical half-life of the 1‘3Sm. Amuch larger radiation dose in a veryshort eriod of time can be delivered

Ywith 15 Sm when compared to 89Sr whichmeans that highly metabolic tumors mayrespond better to the short lived nuclide,The second note of interest is that,according to both Seraftni17 andResche,ls patients with breast cancerstatistically responded better to

Quadramet@ than patients with othertypes of diseases including prostate

cancer, No reason for the increasedresponse was given, The final note ofinterest is that the average duration ofrelief of pain for ‘53Sm EDTMP is only6-8 weeks compared to 10 - 12 weeksfor 8gSr, This difference may be due tothe fact that the above published reports

on Quadramet@ treatment groupsinclude metastatic sites from manydifferent types of cancers rather than justbreast or prostate cancers. One canspeculate that tumors that metastasizemore aggressively may require treatmentmore frequently than others.

Although published guidelines’2 fortreatment of metastatic bone pain refer

only to Metastron@, the product insert ●for Quadramet@ contains guidelines forits use. The guidelines for the use of

either Quadramet@ or Metastron@ aresimilar, As is the case with “Sr, acommon side effect experienced bypatients receiving 15JSm EDT~ is a“flare” response. Most patients receivingQuadramet@ will experience a loweringof marrow production with the nadiroccurring at 2-3 weeks post injection.The rebound by the marrow will becomplete in 6-8 weeks as compared to 8-12 weeks for 89Sr.

Currently, the distribution of

Quadramet@ in the United States ishandled by Berlex Laboratories ofWayne, New Jersey. The drug can alsobe obtained through a central nuclearpharmacy. Samarium- 153 EDTMP isshipped frozen and expires 8 hours postthaw. The recommended treatment doseis 1 mCi/kg body weight. The cost ofQuadramet@ is $2200.00 for any mCiamount of drug that is ordered if it ispurchased directly from Berlex. The costmay vary if it is purchased through acentral nuclear pharmacy. Because of theexpense of the drug, if it is ordered andnot opened the drug may be returned toBerlex with no expense to your

institution,

●

Phosphorous-32 Sodium PhosphatesLike 87Sr, phosphorus-32 sodium

phosphate (s2P-NaH2P04) has been usedfor palliative bone pain relief since theearly 1940s,20 Phosphorus-32 was thefirst radionuclide to be approved by theFDA for use in the palliation of bonepain due to metastatic disease,Production of 32P is accomplished on anuclear reactor according to the equation32S(n0,y)32p, The physical half-life of the

6

radionuclide is 14 days. Phosporus-32

● decays by beta emission with amaximum energy of 1.71 MeV. Since32P has no gamma emissions, one cannotobtain images for biodistributionpurposes. Bone matrix consists mainlyas a combination of calcium,phosphorous and oxygen, so 32P isreadily incorporated into the bone.Unfortunately, phosphorous, being anessential element of the body is alsoincorporated into other organs as well asbone, The maximum uptake of 32P inbone does not occur until 3 daysfollowing injection, and at 2 weeksabout 33°/0 of the injected dose remainsin the bone with an additional 20°/0remaining in sofi tissue.2’ According tothe product insert, 32P is approved foruse in the treatment of polycythemiavera as well as palliation of bone paincaused by metastasis of certain types ofcancer. Interestingly, the type of primaw

● cancers or the fact that the rnetastasesmust be imageable on a diagnostic bonescan are not part of the indication for useof this drug. The lack of the aboveinformation in the product insert is mostlikely due to “grandfathering” of 32P foruse in palliation of pain due tometastasis of cancer to the bone.

The use of 32P sodium phosphate forthe treatment of pain caused bymetastasis to the bone is welldocumented in the literature. 21-26Historically, 32P has typically been usedin combination with surgery or someform of drug therapy21-25 and a placebocontrolled trial has never beenrepofled,21 A recent article2A compared‘2P directly with 8gSr for control of painfrom metastasis to the bone, Exactlywhy no one has studied ‘2P alone for itsability to control bone pain frommetastasis is unclear. According to the. .aforementioned literature, ~JP is very

effective at treating pain when usedeither in combination with surge~, withother drugs, or when used alone.According to Nair,26 32P was just aseffective as 89Sr for palliation of bonepain with a response rate of 88% for 32Pas compared to 93°/0 for 8gSr. Theseresults are slightly higher than thoseobtained by others,21 but Nair’s afliclewas based on a small patient population.

The guidelines for use of 32P as apalliation agent would be similar tothose for ‘9Sr as previously referenced.A more serious side effect of ‘2P use ishematologic depression. Like both

Metastron@ and Quadramet@, 32P hasbeen shown to cause a transient drop inWBC and platelet counts.21’2b Thischange is statistically more severe with32P than has been reported for otherradiopharmaceutical s2A and deservesspecial attention. A very closeobservation of platelet and WBC counts(weekly) is warranted. Not only is themarrow production lowered significantlywith 32P as compared to otherradiopharmaceuticals, but also the timerequired for rebound of the platelets and

WBC counts is longer. For Metastron@

and Quadramet@ the recovery time isabout 6-12 weeks as compared to as longas 6 months for 32P. Higher rates ofpatient transfusions have been reported2]using P than with otherradiopharmaceuticals, although thenecessity for these has been questioned.

Reports of dosing trials using 32Phave produced, at best, conflictinginformation. Maxfield27 reported in 1958that 32P should only be given in smallmultiple doses over a period of time inorder to avoid severe hematologicdepression of the bone marrow, By usingthis technique, doses of up to 20 mCi of32P could be administered without

causing more than transient effects on

7

the marrow production. These resultsconfirmed an earlier study by Albright.28More recently2° 26 it has been reportedthat a single injection dose of up to 12mCi can be given safely with onlytransient marrow effects. As is the casewith other bone pain palliation agents,an increase in dose does not seem tohave a significant effect on as pain relief.

The manufacturer of phosphorus-32sodium phosphate is MallinckrodtMedical in St, Louis, MO. It is sold in 5mCi lots at a cost of approximately$400.00, if purchased directly from themanufacturer. Expiration is 6 weeksfrom calibration. This cost is

considerably less than either Metastron@or Quadramet@ and is likely the reasonwhy there is still a great deal of interestin using 32P today.

Rhenium-186 hydroxyethyleneDiphosphonate (1s6Re HEDP)

A review of the periodic chart of theelements indicates that rhenium is in thesame family as technetium, Since muchof the diagnostic imaging in nuclearmedicine uses ‘gn’Tc, it would bereasonable to assume that anyradiopharmaceutical labeled with 99mTccould also be labeled with rhenium.Such is the case with the bone-seekingagent lgbRe-HEDP, Rhenium-186 isproduced on a nuclear reactor from purerhenium met al by the reaction:]*5Re(noy)1‘bRe. Once the lsbRe isobtained, it is oxidized to perrhenate ionwhich is then reacted with a combinationof stannous chloride and Na2H2HEDP toform the desired product. This is thesame reaction as is used in the kitproduction of ‘g’’’THEDPDP. exce~t the}orrnationheating atto forceRhenium-

,of 1‘bRe-HED’P requires

100”C for 10 minutes in orderthe reaction to completion.86 emits both a beta particle

and a gamma ray. The beta particle has amaximum energy of 1.07 MeV and thegamma ray is emitted with an energy of137 keV and 9% abundance. Thephysical half-life of ‘sbRe is 90 hours.The mechanism of localization for 1‘hRe-HEDP should be the same as its 99mTccounterpart; in other words, thephosphate portions of the molecule arechemabsorbed into the hydroxyapetitecrystal structure of the bone matrix,Since this process is reversible, a portionof the 18dRe-HEDP will be constantlyreleased and excreted into the urine,

The FDA has yet to approve lgdRe-HEDP, which is still in Phase IIIevaluation. Mallinckrodt Medical in St.Louis, MO is the manufacturer of thedrug. Several studies have beenconducted over the last few yearsinvolving the use of 18LRe-HEDP,2g-s4Most of the published informationinvolving the use of 1‘bRe-HEDP in theUnited States is prior to 1993.29-32Muchof the early work using thisradiopharmaceutical is summarized byMaxon and associates.31 According tothis article, pain relief of somemagnitude was achieved in 77°/0 of thepatients treated, Most of the patientssuffered from primary cancers of eitherthe prostate or breast, with only 5patients having other primaries. Thedose used in Maxon’s studies was about35 mCi per patient with no variation,even when multiple doses were used,Interestingly, prior to the 1992 article,there are no dosing studies that wouldindicate what an appropriate dose mightbe. One of the first attempts at doseranging originated from the Netherlandsand was published by de Klerk33 in1994. In this article, 24 patients withprostate cancer were treatedof 18bRe-HEDP ranging from90 mCi, The results seemed

with doses35 mCi toto indicate

●

8

that the maximum tolerated dose wasapproximately 80 mCi, Two more recentarticles34’35 from The Netherlandsprovide follow up information on dosingusing lsLRe-HEDP. An article byQuirijnen and colleaguess4 providesmore information on dose ranges from35 mCi up to 95 mCi involving a total of43 patients. In the patient groupreceiving 35 mCi only 3370 wereconsidered to be responders. For asecond group of patients who received50-65 mCi doses, the response rate wassignificantly better at 78°/0, When dosesof 80-95 mCi were given to a thirdgroup, the response rate was 700A.Although the total number of patientsstudied-in the trial was less than ’50, theresults would appear to indicate thatdoses in the range of 50-65 mCi, whichis similar to those of 153Sm-EDTMP,gave the most pain relief with the fewestside effects. Higher doses are probably

●not warranted, as the palliation ‘effect isessentially the same as the 50-65 mCirange an-d the probability of unwantedside et~ects is increased. A second, morerecent, article by de Klerk35 involvingdose escalation states that in bonemetastasis from prostate cancer, themaximum tolerated dose was again 80mCi, however patients with metastaticdisease from breast cancer could onlytolerate doses of 65 mCi. A possiblereason for the difference was thatpatients with breast cancer have a lowermarrow production to begin with, due toprevious chemotherapy, thus onlysmaller doses are tolerated. As is thecase with the aforementioned agents,18GRe-HEDP causes a transient drop inthe marrow production. This usuallyoccurs at about 4-5 weeks post injectionwith rebound at 8 weeks.

An interesting note on ‘‘bRe-HEDPappears in an article by Limouris and

Skukla,3L Stomach uptake of I*bRe wasobserved during imaging. As is seenwith ‘9”’Tc labeled bone agents, theuptake was most likely due to perrhenateion much like the pertechnetate ionuptake observed on bone scans. It wastheorized that uptake was due toincreased calcium and phosphorus levelsand pH levels in the stomach,

Since 18bRe-HEDP has not receivedapproval from the FDA, there is noinformation available on purchasing,calibration or cost of the drug. A newstudy conducted in Europe involving a

;;:P,::;Y7of patients, has just beenThe results of this study

will determine if Mallinckrodt willpursue an NDA for ‘8cRe-HEDP.

The Alumina-Based Tungsten-1 88/Rhenium-188 Generator

Nuclear medicine has a long historyof using radioactive generators, mainlyfor supplying diagnostic radionuclides toend users, In recent years, there has beenconsiderable work from the group at OakRidge National Laboratories (ORNL)involving the development of agenerator for

,8~v:;:h;a~~:;;radionuclide, ,of applications,3s One of the possibleapplications of this radionuclide is thepreparation of radiopharmaceuticals foruse in palliation of bone pain due toosseous metastasis of primary cancers.

The generator produces lssRe in thechemical form of perrhenate which isanalogous to the chemical form in which‘gmTc is eluted from a generator, Sincewe know that ‘9mTc in the form ofpertechnetate will react with a variety of“cold” reagents to produce variousradiopharmaceuticals, similar technol-ogy may apply to the production of 1E8Redrugs. Recently, there have been threearticles that describe the preparation,

9

quality control, and use of various 1‘rel-abeled agents.38-40

The group at ORNL describe thegenerator and some of its more usefulcharacteristics,40 The parentradionuciide, ‘g8W, has a relatively longphysical half-life of 69 days. This couldmean that the generator may bepurchased every few months, thusmaking a considerable impact on theprice of the end product, Rhenium-188has a physical half-life of 16.9 hours. Itemits a beta particle that has a maximumbeta energy of 2.2 MeV and a gammaray that has an energy of 155 keV ( 15°/0abundance) which can be imaged. Thegenerator uses an ion exchange columnto concentrate and then elute the 188ReOJion, The elution solvent is normal salineso the product is ready for use inlabeling procedures when eluted fromthe generator.

The article from ORNL as well asothers describe the preparation of threedifferent radiopharmaceuticals that canbe prepared with 188Re.3R-40 Thepreparation of l*8Re-HEDP is describedin two of the articles.38’3g Each articledescribes the preparation of the dreg,quality control results, and thebiodistribution pattern. The paper byMaxon and associates3g is one of the firstreports on the use of 188Re-HEDP inhuman trials in the United States. In thisstudy, eight men with prostate cancerand metastasis to the bone proven with99’”TC bone scans were given varyingdoses of 188Re-EHDP. Five of the eightpatients received a dose ofapproximately 35 mCi with the otherthree receiving doses of approximately50 mCi, At least one patient whoreceived 50 mCi of the drug experiencea “flare” response, with some

hematopoietic toxicity being reported in50V0 of the patients, and the palliationresponse rate was determined to be 63°/0.Overall, it was determined that the*88Re-HEDP results were similar tothose obtained by 18LRe-HEDP. Asecond group from Europe have studiedthe use of pentavalent 1*8Re-dimercaptosuccinic acid (18sRe(V)-DMSA) for the treatment of osseousmetastasis pain.40 The uptake of thedrug was compared with the uptake of9gmTc-HDP (oxidronate) on bone scansand it was shown that the ‘88Re(V)-DMSA only concentrated significantlyin the metastatic sites in bone and not innormal bone, The same article alsostated that ~88Re(V)-DMSA could beprepared by using perrhenate from theaforementioned generator and a DMSAkit that is commercially available inEurope for the preparation of 99mTc -DMSA. A total of six patients weregiven *88Re(V)-DMSA and images wereobtained at 3 and 24 hours post injection.The results were very encouragingbecause hematopoietic toxicity may benegligible when compared to otheragents, but not enough data is availablefor accurate dosimetry calculations. Onepotential problem with this drug is theuptake by the kidneys, as they mayreceive a relatively large radiation dose,A third drug that has been prepared islg8Re-Octreotide, but it is not used forpalliation of bone pain.38

Since neither of the described drugsis available for widespread use, there islittle information available on theeffectiveness, side effects, and cost. Thepotential for the reduction of costsassociated with bone palliation agentsmay be a factor in the development ofthis generator.

●

●

●

10

Tin-1 17m (Stannic, 4+) Diethylene-

● triaminepentaacetic Acid(Tin-1 17m (4+) DTPA)

The development of ‘l7mSn(+4)-

DTPA was undertaken by BrookhavenNational Laboratory (BNL) in anattempt to develop a palliative agent forosseous bone metastasis that would haveideal characteristics for therapy withvery little, if any, side effects, While noradiopharmaceutical is ideal, this agenthas many desirable characteristics. Tin-117m has a physical half-life of 14 daysand it decays by both a conversionelectron with an energy of 127-129 keVand a gamma ray with an energy of 152

keV (86% abundance). As is the casewith other nuclides described previously,117*”Snis produced in a nuclear reactor.

The following equation describes theprocess:

‘17Sn(n0,y)117mSn

The tin is produced as an oxide, and thenconverted to the pure metal by heatingprior to irradiation. Once the target isirradiated, it is a rather involved processto produce the I17msn(+4)-DTpA from it.

41 The specific activity can vary greatlydepending on the production facility,however it does not seem to affect theuptake of the radiopharmaceutical, Theone thing that sets this drug apart fromthe other therapeutic bone palliationagents, is that conversion electrons areemitted rather than beta particles. Eventhough they are both electrons, theirorigin is different, The narrow range ofenergy exhibited by conversion electronsmay make it easier to control theradiation dose given, particularly to themarrow.

In a pilot study,41 a total of fifieenpatients with four different primarycancers that had metastasized to the bone

were divided into two, :rups. Group 1

(7 patients) received k Sn(+4)-DTPA

in doses that ranged from 33-84 ~Ci perkilogram of body weight. Group 2 (8patients) received doses that ranged from131-156 pCi /kg of body weight. InGroup 1, 4 of 7 patients had partial tocomplete pain relief and 7 of 8 patientsin Group 2 had comparable relief of painsymptoms. Within the two groups, onlyone patient had a decrease in WBCcounts and no significant decrease inplatelet counts was observed in anypatient.

Since the initial pilot study, severalother studies have been completed.42’4fiKrishnamutthy and associates42 studiedthe pharmacokinetics of *17mSn(4+)-DTPA as well as dose response, Patientsreceived three dosages of 180pCi/kg,229 ~Ci/kg, and 285 pCi/kg,respectively. The results indicated thatgreater than 77% of the injected doseremained in the bone for up to 14 dayspost injection and pain relief was seen atall three dosing levels. Fourteen patientswere studied that had lung, breast, orprostate cancer with metastatic diseaseto the bone. All three dose ranges gavepartial to complete relief of pain inapproximately 85% of the patientstreated, and no observable marrowtoxicity was noted. In a larger study of40 patients, Srivastava and associates43found similar results. In this doseescalation study, patients were givendoses ranging from 70-286 pCi/kg bodyweight. Again, no significant change ineither platelet or WBC counts wasobserved at any dose level and 75°/0 ofthe patients received some to completepain relief ln another study by

Srivastava and associates44” 47 patientswere studied using five different doseranges. The results of this report werevery similar to the earlier studies with no

11

correlation between dose ranges andpain relief The overall pain relief ratewas 75°/0.

Currently 117mSn(4+)-DTPA isundergoing phase III clinical trials withdoses ranging from 10 to 20 mCi. Thisdouble blind study, sponsored by DiatideInc. of Londonderry, NH, compares1‘7mSn(4+)-DTPA with Metastron@.Since this drug is not FDA approved,there is no information available aboutthe cost. Based on the productionprocedures, it most likely will be in thesame price range as those agents that arecurrently approved.

EXTERNAL BEAM RADIATIONTHERAPY

The use of external beam radiationtherapy (EBRT) to treat cancer was firstexplored in 1944.47 since that timeEBRT has become the “gold standard”in the use of radiation to treat manytypes of cancers. According to theliterature, as much as 40-50% of allEBRT is used for the palliation ofpain.48y4gUsing EBRT for the palliationof pain due to a single site metastaticcancer to the bone has a success rate of70-90% with 40-50% of the patientsreporting complete relief,48’51 Whenmultiple metastatic sites are present andhalf-body radiotherapy is used, thepalliation success rate is about 70% butonly about 20V0 of the patients reportedcomplete relief. The success rates usinghemi-body radiotherapy for multiplemetastatic sites are comparable to thoseof radiopharmaceuticals, but there is nocomparison between EBRT andradiopharmaceuticals for singlemetastatic sites,

There is still a great deal ofcontroversy surrounding the use ofEBRT for the palliation of pain due tometastatic disease. This controversy

centers on the issue of using severalsmaller doses of radiation over a 1-2week period versus using a single largerdose of radiation. The results of bothtechniques are equivocal according toreports in the literature,50 while otherstudies claim one technique is moreeffective than the other. 51 Controversyarises regarding cost as well as theamount of time it takes to completetherapy, depending on what course isrecommended.

The side effects associated withhemi-body radiotherapy can be severe,The most common side effects arenausea and vomiting which can bepartially controlled by the use ofantiemetics before and during thetreatment, Other serious side effectsinclude marrow depression, mucositis,and radiation pneumonitis, with the latterbeing potentially fatal if not treatedimmediately.

The costs associated with EBRT canbe considerable. It is obvious that asingle hemi-body radiotherapy treatmentshould be less expensive and ceflainlyless time consuming than a course ofradiation involving fractionated dosesover a 1-2 week period. Since the sideeffects must usually be treated, this toowill add to the cost of the treatment,Overall, the cost of the radiotherapyitself can vary depending on theinstitution and the type of radiotherapythat is used. Estimated cost can rangefrom $2,oOO to $15,000, excluding anycosts associated with side effects.

CHEMOTHERAPY AND SURGERYChemotherapy and surgery are both

usefil in controlling bone pain frommetastasis, Both treatments maydiminish pain by decreasing the effectsof mechanical pressure. In addition,chemotherapeutic agents may affect the

12

population of granulocytes, lymph-ocytes, and monocytes (both within andsurrounding a tumor), and may diminishpain by blocking cytokine release fromthese cells. 51 Because investigators haveobserved that pain control is notdependent upon the antitumor effects ofcytotoxic therapy, it has also beenhypothesized that cytotoxic drugs mayinfluence pain by altering bothperipheral and central neurotransmittersystems.5~

Baum and associates list fiveessential functions of surgery in cancerpalliation,sz among which is control ofpain, Surgery is used to relieveobstruction to hollow viscera and debulka primary tumor, thereby enhancing theeffectiveness of radiotherapy andchemotherapy. Surgery may also preventfuture pain by preventing the tumorinfiltration of nerve roots, especially

around the brachial and sacral plexus.The use of surgery is particularlyeffective where pain is due tomechanical factors or unstable fractures,

ANALGESICS-NSAIDS ANDOPIATES

Nonsteroidal anti-inflammatorydrugs (NSAIDS) are the mainstay in thetreatment of bone pain, and the WorldHealth Organization recommends thatphysicians use NSAIDS as the first stepin the analgesic ladder.5J Bone painresults from the local secretion ofprostaglandins, and NSAIDS inhibitprostaglandin synthesis by decreasingthe activity of the enzyme, cyclo-oxygenase. Specifically, NSAIDS inducea reduction in the edema, whichstretches the periosteum and reduces theprosta Iandin-induced

%4pain sensiti-

zation, Effectiveness is usually bestagainst pain of low to moderate intensit

2or as an adjunct for more severe pain.

3

NSAIDS have demonstrated a ceilingeffect, defined as a dosage at which amaximum analgesic response isobserved, beyond which only furtheranti-inflammatory effects or increasedtoxicity occur. 54 Both the effective andtoxic dose are unknown in the cancerpatient suffering from bone pain. Thereis a variety of NSAIDS available as overthe counter or prescription medications.No conclusive data exists showingwhich NSAID is more effective, and thechoice of a particular drug should bebased on the frequency of dosingrequired, adverse effects, patient history,and cost. The results of controlledclinical trials of NSAIDS in cancerpatients with bone pain have not beenreported separately from pain notoriginating in the skeleton; therefore it isdificult to make any specificconclusions on overall effectiveness forthis indication.

Adverse effects of NSAIDS aregenerally related to the inhibition ofcyclo-oxygenase.5q The most commonand problematic is their propensity tocause gastrointestinal ulceration. In thestomach, prostaglandins act to increasethe production of protective mucosa anddecrease acid secretion, 53 Due to theinhibition of prostaglandin synthesisseen with NSAIDS, the patient is atgreater risk for the development of anulcer. The American College ofGastroenterology has developedguidelines to prevent and treat ulcerscaused by N SAIDS, and has establishedcategories to determine which patientsare at a higher risk. Prophylactic therapyis recommended for patients who are athigh-risk for the development of anulcer.

NSAIDS can also adversely affectplatelet and renal finction. In normal

patients, prostaglandins play a small role

13

in regulating renal blood flow, However,in patients with chronic renal failure,prostaglandins become more important,and a reduction in glornerular filtrationrate may result.

Most, if not all, NSAIDS arehighly protein bound (90-99%) and mayinteract with other highly protein bounddrugs, such as warfarin, oralhypoglycemic, and methotrexate,Dosages should be readjustedcombination therapy is necessary,

While most NSAIDSinexpensive, one needs to considercost s associated with theirMedications used for prophylactic

when

areother

use,ulcer

therapy, such as misoprostol,omeprazole, or lansoprazole, can bequite expensive, and need to beconsidered when choosing theappropriate treatment for bone pain.

If pain persists or increases, theWorld Health Organization recommendsthe addition of a weak or strong opioid.ssThis group of analgesics includes allnatural and synthetic compounds whichinteract with the morphine receptors inthe CNS and elsewhere,53 Combinationtherapy with NSAIDS and an opioid isappropriate since they have differentmechanisms of action and act at differentlevels of the neurological pathways ofpain.s~ Opioids, such as morphine, bindto opiate receptors in the CNS, causinginhibition of ascending pain pathways,therefore altering the perception of andresponse to pain, There is a general CNSdepression that results.

Patients will respond to individualopioids differently. Dose-limitingadverse effects may occur with oneopioid, while another may provideadequate pain control and no unwantedeffects. 53 It is important to understandthat switching from one opioid toanother may provide a solution for the

patient unable to tolerate a specificmedication. Adverse effects includesedation, constipation, and nausea andvomiting, and it is these adverse effectsthat determine the upper limit of opioiddosage. Tolerance to adverse effectsusually develops more quickly thantolerance to the analgesic effect, andslow titration of opioids may provideadequate pain control within a few daysfor most patients. 53

Problems arise in the presence ofsignificant incident pain and the titrationof opioid dosage becomes verydifficult .54 Some patients may requirevery little baseline opioid doses,however when a movement inducessevere pain, adequate drug serumconcentrations are not obtained quicklyenough.’~ The pain then wears off veryquickly, however the drug continues toact for several hours. It is during thisinterval that possible opioid toxicitycould occur. It may be necessary toincrease the baseline opioid dosage andcounteract dose-limiting sedation withthe use of psychostimulant drugs, suchas methylphenidate.

It is important to recognize thatincluded in the costs associated with themedications used for the palliation ofbone pain, are the costs of treating theunwanted side effects. A pharmaco-economic evaluation needs to take intoconsideration the dose-limiting adverseeffects and include any costs associatedwith their treatment.

BISPHOSPHONATESAn exciting recent adjunct for

treatment of bone metastasis is systemictherapy with a bisphosphonate. Table 1lists the agents in this drug class thathave been used for, or show potentialuse for this indication. Initiallydeveloped by the chemical industry to be

14

*

used for binding calcium in industrialprocesses, bisphosphonates have beenused as water-so~eners, tested aspotential additives to toothpaste toprevent the build-up of dental calculus,and evaluated for use in the treatment ofcoronary atherosclerosis. ss’ ‘6 Since the1960s, the predominant clinical value ofbisphosphonates has been in thetreatment of disorders that involveabnormalities of bone mineralmetabolism. These include hyper-calcemia of malignancy, osteoporosis,Paget’s disease, and myeloma,Numerous recent studies havedocumented their value in treating bone

pain, promoting bone healing, andpreventing skeletal complications whenused in conjunction with anticancertreatments. ss.s~

The structure of bisphosphonatesresembles that of pyrophosphates butdiffers in that it cont~ins- a backbone ofphosphorous-carbon-phosphorous ratherthan phosphorous-oxygen-phosphorous(Figure 1). A variety of bisphosphonateshave been synthesized by modi~ing thechemical substituents located on thecarbon backbone.sg This has resulted insecond and third-generation agents with1,000 to 10,000 times greater potencyand greater selectivity for bone,

Figure 1,~- RI O-

o= P” L-h=o

Bisphosphonates act to inhibit boneresorption through their direct andindirect action on osteoclast activity,56although the specific mechanism ofdecreasing pain is not entirelyunderstood, Bisphosphonatesconcentrate at sites of active boneremodel ing60 where they bind tohydroxyapetite crystals, the form ofcalcium phosphate present in bone salts,and inhibit their growth and dissolution.There is also evidence that the drugs areinternalized by osteoclasts and interferewith differentiation and specificbiochemical processes.j~ Recent studieshave shown bisphosphonates to induceosteoclast and tumor cell apoptosis61 >62and make it diticuh for osteoclasts torecognize exposed unmineralized bonesurface .57 Usedbisphosphonatesrelieve bone pain

as single agents,have been shown toassociated with breast,

IIR2 O-

prostatic, and other miscellaneousprimary cancers. As adjuncts toanticancer therapy, they can preventskeletal complications, slow down themetastatic process, and improve patientquality of life.59’60

Not all bisphosphonates are equallyeffective in treating morbidity associatedwith bone metastasis, One of the firstbisphosphonates available wasetidronate, approved for marketing in1987, While useful in the treatment ofPaget’s disease, the use of etidronate intreating metatstatic bone pain has beenlimited by its inhibition of normal bonemineralization, 57 Very few studies havebeen done to evaluate its use for bonepain, and newer more potent agents havealready been marketed. Alendronate is anewcomer to the market, approved bythe FDA in 1995. One small,uncontrolled preliminary study was

15

conducted outside the U, S. and showedoral and parenteral alendronate to havepromise in reducing pain in atients with

Rmetastatic prostate cancer. However,currently the product is available in theU.S. in oral form only for the indicationof osteoporosis.

The bisphosphonates most exten-sively studied and commonly used intreatment of bone metastasis areclodronate and pamidronate. Clodronateis a second-generation bisphosphonatethat, unlike etidronate, does not inhibitmineralization of normal bone,Clodronate is available in both oral andinjectable forms in Canada and Europe,but not yet in the United States, Severalpublished studies have supported its usein osteolytic bone metastasis associatedwith breast cancer, myeloma andprostatic cancer. Long term treatmentwith clodronate in patients withmetastasis from breast and prostatecancer has reduced severity of bonepain, vertebral fractures, and analgesicrequirements. ~”>~sDiel and colleaguesb4conducted a prospective, randomized,non-placebo-controlled study in 302patients with primary breast cancer andtumor cells in the bone marrow. Patientsreceived 1600mg of oral clodronatedaily for two years in addition tostandard therapy or standard therapywithout clodronate. There was asignificant reduction in the incidence ofboth osseous and visceral metastasis inthe clodronate group.ti4

There is no consensus on the optimaldose and schedule of administration forclodronate treatment of bone metastasis,Although the oral route is moreconvenient than intravenous injection,variable patient response necessitatesindividual treatment. The common oraldose is 1600 m per day (range 1600 to

#3200 mg)GO’G~’4 or 300mg per day

intravenously for a varied duration,AdamiL3 suggests 300mg of Clodronateper day for 5 days followed byadditional single IV infusion inresponding patients administered at therecurrence of pain. Clodronate should bediluted and administered intravenouslyover at least 2 hours or by mouth with afill glass of water, at least 1 to 2 hoursbefore or after food,

Pamidronate disodium wasapproved for marketing in the UnitedStates in 1995 for the treatment ofnormocalcemic patients with myelomabone disease and in 1996 for treatmentof patients with osteolytic lesions ofmetastatic breast cancer. Pamidronatetherapy has also been associated withclinical benefits for skeletal metastasis.One studybs randomized 382 womenwith metastatic breast cancer and lyticbone lesions into pamidronate or placebogroups. The pamidronate group received90mg of drug intravenously every 3 to 4weeks as adjunct to standardchemotherapy. Patients were evaluatedevery month for 2 years for skeletalcomplications, At the end of the studyperiod, the pamidronate group requiredsignificantly less radiation or surgery totreat bone complications. Despite nodemonstrated difference in survivalbetween the two groups, investigatorsconcluded that pamidronate used as asupplement to chemotherapy is moreeffective than chemotherapy alone inpreventing skeletal complications inbreast cancer patients. Additional studiessupport these clinical benefits in patientstreated for metastatic prostaticcarcinomab3 and cancer from otherprimaries.GG

The recommended dose in patientswith osteolytic bone metastasis is 90mgadministered as a 4-hour infisionmonthly, Treatment with high, single-

16

●dose pamidronate (120mg in 1 liter ofnormal saline) has also been suggestedas effective. Purohit and associates~hconducted a small, open phase II studyto assess this treatment regimen on painand quality of life, The study showed ahigh frequency of symptomatic responsewith minor side effects, Retreatment wasalso successful but only in patients whohad demonstrated symptomatic responseto the. first treatment,

Pamidronate is marketed by Ciba asAredia@ in vials of 30mg and 90mg. Itis currently available for intravenousadministration only. The dose should bediluted in 500ml of 0.45V0 or 0.9% NaClor 5°/0 Dextrose injection and infusedover 4 hours.

All bisphosphonates have very poorintestinal absorption when given orally,therefore some investigators haveadvocated parenteral therapy as thepreferential route.bs’bb Patients may notshow maximal clinical response tobisphosphonate treatment for up to 4-7days.h~

Treatment with bisphosphonates isassociated with mild adverse reactions.Oral bisphosphonates have very poororal absorption and medications, foods,and dietary supplements that containcalcium and other minerals may interferewith their absorption. Oraladministration is most commonlyassociated with upper GI symptoms thatinclude nausea, vomiting, diarrhea, andconstipation. To minimize these adversereactions, patients should be advised totake oral medication on an emptystomach I to 2 hours prior to a meal andstand or sit upright for at least 30minutes following the dose, Intravenousadministration is also associated withgenerally mild adverse reactions. Noclinically significant side effects due toclodronate therapy were noted in a

57recent review. Treatment withpamidronate has also been reported to begenerally well tolerated, but reports ofocular complications,LX anemia, hypo-calcemia, hyperphosphatemia, transientfever, myalgias, arthralgias, andinfluenza-like symptoms have beenpublished. b5’GG

Although bisphosphonate treatmentwith current agents has been shown toreduce skeletal morbidity, there is noevidence that bisphosphonate therapycan alter metastatic disease progressionor significantly change patientmortality.G5 Several new agents arecurrently in investigational trials toevaluate their role in reducing themorbidity associated wit h bonemetastasis. These include ibandronate,zoledronate, and olpadronate. 61,69,70

Bisphosphonate treatment is

expensive. The cost will vary as dictatedby individual needs, drugs utilized,purchasing source, preparation time,duration of therapy, treatment of adversereactions, personnel time, and expensesassociated with inpatient or outpatientservices. The cost of a single-month90mg pamidronate treatment will exceed$500 when considering averagewholesale drug price alone. Althoughthere is little doubt about the value ofadjunct bisphosphonate treatment forpainful bone metastasis, questionsremain to be answered concerning itscost-effectiveness,

“ Can expensive treatment withbisphosphonates be compensatedwith savings from reducedtreatment of fractures,metastasis, and pain?

“ What are the savings associatedwith improved quality of life forpatients suffering from painfulbone metastasis?

17

Table 1. Bisphosphonates Available for Potential Use in the Palliation of Bone Pain

Generic

Clodronate*disodium

Pamidronatedisodium

Etidronatedisodium

Alendronatesodium

Tiludronate

Risedronate

* Not availab

Brand(Manufacturer)

Ostac (BoehringerMannheim)

Aredia (Novartis)

Didronel (Proctor& Gamble; MGIPharma)

Fosamax (Merck)

Skelid (SanofiWinthrop)

Actonel (Proctor& Gamble)

Availablestrengths androutes ofadministration30mg/mlinjection for slowiv, infusion;400 mg capsules30mg, 90mgpowder forinjection

200 & 400mgtablets;300mg/ampule(6ml amp)

5 mg, 1Omg,

40mg tablets

240mg tablets(equivalent to200mg tiludronicacid)30mg tablets

ApprovedIndication

Not approved inthe U.S,

Neoplasm withhypercalemia;Paget’s Disease;Bone metastasis

Neoplasm withhypercalcemia;Paget’s;Hetertropicossification

Osteoporosis,postmenopausal;Paget’s disease

Paget’s disease

Paget’s disease

in the [ln~ted States; +Redbook 1999

AWP Cost perDose+

Not applicable

30mg- $231.1190mg -$652.22

200mg -$2.29400mg -$4.58ampule -$67,00

5 & 10mg - $1.9040mg -$4,80

240mg -$7.52

30mg -$12.88

PHARMACOECONOMICCONSIDERATIONS OF THERAPY

As the clinical alternatives for thetreatment of metastatic bone painexpanded during the last decade,concerns about the escalating costs andutilization of health care also increased.Currently, the United States has the mostexpensive health care system in the

expensive and cost containment issuesare important. Clinicians, payers,patients, and politicians are all interestedin selecting treatment which is mostlikely to confer the greatest value orworth in terms of clinical, humanistic(quality of life) and economic outcomes.Traditionally, clinical outcomes haveprovided the basis for the majority of

world -- one that is growing faster than treatment selection decisions. However,the rest of the economy .71 ‘Selection of there is evidence that clinicians have anoptimal therapy is very difficult for increased concern about financial issues.clinicians when new therapy is Studies have shown that economic issues

18

●

● ✌

●

can impact the setting in which care isprovided72 and also influence pres-cribing preferences over considerationsof life extension or drug side effects.73Outcomes research seeks to identify,measure, and evaluate the results ofhealth care services. Kozma andassociates74 proposed a multi-dimensional model that provides acomprehensive framework for assessingoutcomes by integrating clinical as well

economic and quality of life~~umanistic) considerations. The authorstermed this model, ECHO, an acronymthat represents economic, clinical, andhumanistic outcomes.

By definition, “pharmacoeconomics”is a division of outcomes research thatinvolves the economic “description andanalysis of the costs of drug therapy tohealth care systems and society. “75Pharmacoeconomic research methodsprovide explicit, systematic ways to

●compare treatment alternatives thatconsider costs and outcomes. One suchtreatment alternative may even includenot providing active treatment, becausean ill patient will likely continue toconsume health care resources even if

not receiving treatment. Those costs mayeven exceed the costs associated withactive treatment .76 Pharmacoeconomicsis a tool that helps payers, clinicians, andsociety decide which treatment is mostlikely to provide the best patientoutcome for the cost.

At present, there are four differentpharmacoeconomic research methods inuse. These include cost-minimizationanalysis (CMA), cost-benefit analysis(CBA), cost-effectiveness analysis(CEA), and cost-utility analysis (CUA).The basic similarities and differencesbetween the methods are summarized inTable 2, All four methods measure thecost s of healthcare programs orinterventions that are being compared interms of dollars. However, the methodsdiffer in the way in which outcomes orconsequences of the programs, orinterventions are measured and reported.Which method an investigator decides touse depends upon the informationdesired. Of the four methods listedabove, cost-effectiveness analysis isprobably the most frequently usedtechnique currently reported in medicalliterature.

●

19

Table 2. Types of Full Pharmacoeconomic Methods*

costMinimizationAnalysis

Cost BenefitAnalysis

costEffectivenessAnalysis

Cost UtilityAnalysis

Costs associatedwith programs orinte~entions aremeasured andreportedin . . .Dollars

Dollars

Dollars

Dollars

Outcomes resultingfrom programs orinterventions are. . . .

Demonstrated by theinvestigator to beequivalent.

Measured and reported indollars

Measured and reported ina single “natural” unit”(e.g. number of cures,number of symptom-freedays)

Measured and reported inQuality-adjust life years(QALYs) or similarmeasure that incorporatespatients’ perspective.

* Adaptedfrom Draugalis,m Bootman,JL, Larson,LN, McGhan,WF.PhurConcepts. 1989. The UpjohnCompany.

Results of analysis arereported as . . .

~heleast costly program orIntervention.

Benefit to cost ratio,Net benefit, and/orReturn on investment

Cost effectiveness ratioand/or Incremental cost-effectiveness ratio

Incremental cost utility ratio

Icoeconomics, Current

Among the first steps in conducting therapies for cancer pain. Costs are

an economic evaluation is identificationof the costs and outcomes associatedwith a treatment or drug regimen.Economic issues regarding the treatmentof bone pain are complex, makingidentification of costs difficult.Portenoyl has reported that economicevaluation has been limited by the lackof systematic outcomes research andagreement as to what constitutes optimaltreatment for cancer pain. Portenoy hasidentified and attempted to justify some

of the issues and costs associated with

associated with primary therapy (i. e.,surgety, chemotherapy, radiotherapy),analgesic and adjuvant drug use(NSAIDS, opiates, antidepressants,radiopharmaceuticals, bisphosphonates,etc.), drug administration costs (oral,intravenous, intraspinal, subcutaneousroutes), treatment of side effects, site ofcare (hospital, outpatient, home), nursingcare, and physician fees. The not-so-obvious costs include indirect andintangible expenses such as

reimbursement biases, loss of work,

●

o

●

20

suffering, home and childcare, and mostimportantly, loss of quality of life.

Very few published studies comparetreatment options for palliation of bonepain either by cost or by cost andoutcomes. Therapy that minimizesskeletal morbidity and maximizes patientquality of life is assumed to be costeffective, however, high financial costsassociated with new therapy often act asdisincentives to their widespread use,77Thorough pharmacoeconomic analysesare needed to provide clinicians withmore complete and comparativeinformation concerning costs andbenefits of treatment alternatives.

Three published studies haveevaluated cost and outcome issuesrelated to the use of radiotherapytreatment for metastatic bone pain.McEwan and associates233 conducted asmall (n = 14) retrospective cost analysisto estimate the impact of Metastron(strontium-89 chloride) on themanagement costs of advanced prostatecancer patients, The results supportevidence that Metastron use has apositive cost to benefit contribution tothe management costs of these patients.Direct costs (including analgesic costs)and tertiary inpatient requirements werereduced. They also noted significantimprovement in patient well-beingwhich was not costed. Schmeler andBastin7R evaluated the outcomes ofhospice-eligible prostatic cancer patientstreated with intravenous strontium-89(8gSr). Their purpose was to determinewhat patient criteria should be used tojustify the risks and costs of ‘9Srtreatment in contrast to traditionalopiate, NSAIDS, and external beamtherapy. Patients were categorized andevaluated by Karnosfsky PerformanceStatus Scale (KPS), pain response,toxicity, and actuarial survival. The

authors concluded that only patients witha pre-treatment KPS score of 60 orgreater should be considered for 89Srtreatment and these patients should haveadequate long-term survival to justifythe risks and costs. A pilot cost-minimization analysis was conducted byMarklis and associates to identify andcompare the costs of brief-coursepalliative radiotherapy to published costsof narcotic analgesic therapy in treatingpainful metastasis.79 Patients included inthe study had metastasis from a varietyof cancer types and KPS scores of 70 orgreater. The results suggest that the costof brief-course, palliative radiotherapy,when used as an integral component of atreatment regimen, can be justified incircumstances where it reduces intensivenarcotic use.

There are also very few studiesthat evaluate the cost to benefit use ofadjuvant treatment with bisphosphon-ates. Clodronate therapy is suggested tohave significant potential to lower thecost associated with managing metastaticdisease of breast cancer. The conclusionis based on a retrospective analysis ofdirect hospital-based costs. The data alsoinferred, but did not quantify, theintangible cost benefit resulting fromimproved patient quality of life resultingfrom fewer fractures and decreased painand immobility.’0 In a randomized study,oral pamidronate therapy was reported toimprove selected aspects of patientquality of life by significantly decreasingbone pain and mobility impairment inpatients with advanced breast cancer.glThe economic value of these benefitswas not measured.

It has been estimated that severalfactors, including an aging populationand increasing cancer incidence, willincrease the need for palliative care forcancer patients in the fiture. 82 When

21

coupling the high expense of newtherapy with growing limitations orIhealth care spending, evaluation of thefinancial impact of all therapies will benecessa~ to justify their widespread use.It will also become increasinglyimportant for health care professionals tothoughtfully and systematically integrateeconomic and humanistic factors intotheir clinical decision-making.

CONCLUSIONBone metastasis and associated

skeletal pain are frequent complicationsin patients with neoplastic disease, and

their treatment is highly variable, This

lesson has reviewed the range ofavailable treatments for the palliation ofpain. Since pain contributes to patients’poor quality of life during the end stagesof their illness, it is important forclinicians to prescribe adequatetreatment for its palliation, Despite theavailability and array of therapies, themanagement of pain ofien remainsinadequate for many patients.83 Poorpain management of metastatic cancerhas been associated with patient gender,race, and treatment setting.

As this lesson illustrates, costsassociated with each therapy are highlyvariable and dependent upon clinicalresponse of the patient and the institutionor site of patient care. It is thisvariabilityy, in conjunction with fewpublished outcome studies concerningoptimal pain palliation, that make usefilcomparison of therapies a difficult taskfor the clinician.

The diff~culty in identifying andmeasuring appropriate costs of eachtreatment is also a barrier to conductingpharmacoeconornic studies. These

studies must not only consider the directcost of the treatments, but also indirectcosts and intangibles such as loss of

quality of life and suffering. Therapies

that appear to be expensive due to a highdirect cost may actually be lessexpensive when the savings fromindirect costs and intangibles areconsidered. Consider, for example, theuse of radiopharrnaceutical therapy vsEBRT or half-body radiotherapy.Radiopharmaceuticals require a one-time injection, which can last from 3-12months with rare side effects that requiremedical attention while EBRT or half-body radiotherapy may require multipletreatments daily for 1-2 weeks and ofienhave side effects that require medicalattention. Further trials comparingbisphosphonate treatment as adjunct toother options may support the cost-effectiveness of bisphosphonate use.

REFERENCES

1. Portenoy RK. Issues in theeconomic analysis of therapies for cancerpain, OncoloU. 1995; 9(1 l)(suppl): 71-78.

2. McEwan AJB, AmyotteMcgowan, DG, and associatesretrospective analysis of theeffectiveness of treatment

Metastron@(89Sr-chloride) in patients

GA,A

costwithwith

prostate cancer metastatic to bone. iVucl h4edComm. 1994; 15:499-504,

3. McEwan AJB, Amyotte GA,McGowan DG, and associates Aretrospective analysis of the costeffectiveness of treatment with Metastron inPatients with prostate cancer metastatic tobone. Eur Urol. 1994; 26 (suppl 1): 26-31.

4. Bierrnann, WA Cantor RI, FellinFM, and associates An evaluation of thepotential cost reductions resulting from theusc of clodronate in the treatment ofmctastatic carcinoma of the breast to bone.Bone, 1991; 12(suppl 1): S37-S42

22

5. McEwan AJB, Unsealed sourcetherapy of painful bone metastasis: Anupdate. Sem Nucl A4ed, 1997; 27(2): 165-182.

6. Pecher C. Biological investigationswith radioactive calcium and strontiumProc Soc Exp Biol Med. 1941;46:86-91.

7. Robinson RG, Blake GM, PrestonDF, and associates Strontium-89: Treatmentresults and kinetics in patients with painfulmetastatic prostate and breast cancer inbone. RadioGraphics, 1989;9(2): 271-281.

8. Robinson RG, Preston DF,Schiefelbein M, and associates Strontium 89therapy for the palliation of pain due toosseous metastasis, .JAMA.August 2, 1995;274 (5): 420-424.

9. Pens F, Herranz ~ Garcia A, andassociates Strontium-89 for palliation ofpain from bone metastasis in patients withprostate and breast cancer, Eur J Nucl Med.1997:24 (10): 1210-1214.

10. Kasalicky J, and Krajska V. Theeffect of repeated strontium-89 therapy onbone pain palliation in patients with skeletalcancer metastasis. Eur J Nz~cl Med. 1998;25(10): 1362-1367.

11. Quilty PM, Kirk D, Bolger JJ, and

associates A comparison of the palliativeeffects of strontium-89 and external beamradiotherapy in mctastatic prostate cancer.Kadiother Oncol. 1994;3 1:33-40.

12, Silberstein E and Taylor A Jr.Procedure guideline for Bone PainTreatment: 1.0. J Nucl Med.1996; 37(5):881-884.

13. Quadramct@ Product InformationSheet. Dupont RadiopharmaceuticalDivision. The Dupont MerckPharmaceutical Company 331 Treble CoveRoad. North Billcrica. MA 01862.1997.

14. Bayouth .IE, Macey DJ, Kasi LP,and associates Dosimct~ and toxicity ofSamarium-1 53-EDTMP administered forbone pain due to skeletal metastasis, J NuclMed. 1994; 35(1): 63-69.

15. Silberstein EB. Editorial: Dosageand response in racliopharmaccutical therapyof painful osswus metastasis. ,J Nucl Med.1996; 37(2): 249-252.

16. Albcrts AS, Smit BJ, Louw WKA,and associates Dose response relationshipand multiple dose efficacy and toxicity ofsamarium- 153-EDTMP in mctastatic cancerto bone. Radiotherapy and Oncolo~. 1997;43:175-179.

17. Serafmi AN, Houston SJ, Resche 1,and associates Palliation of pain associatedwith metastatic bone cancer using

samarium- 153 lexidronam: A double-blindplacego-controlled clinical trial. J Clin~nCO~Ofl. 1998; 16(4): 1574-1581.

18. Resche I, Chatal JF, Pecking A, andassociates A dose-controlled study of ‘53Sm-ethylenediaminetertamethylenephosphonate(EDTMP) in the treatment of patients withpainful bone metastasis. Eur J Cancer.1997; 35(10): 1583-1591.

19. Tian J, Zhang J, Hou Q, andassociates Multiccntre trial on the cficacyand toxicity of single-dose samarim- 153-ethylene diamine tetramethylenephosphonate as a palliative treatment forpainful skeletal mctastases in China. E *JNUCIMed. 1999; 26(l): 2-7.

20. Kaplan E. Historical development of32P in bone therapy. In: I’heropy in NzicleorMedicine. Spencer RP Ed, Grune andStratton: Ncw York pp 237-249.

21. Silberstein EB, Elgazzar AH, andKapilivsky A, Phosphorus-32radiophatmaceuticals for the treatment ofpainful osseous metastasis. Sem Nucl Med.1992; 22(l): 17-27.

23

22, Friedell HL, and Storaasli JP. Theusc of radioactive phosphorus in thetreatment of carcinoma of the breast withwidespread metastasis to the bone. Am JRoent Rad Ther 1950; 64:559-575.

23. Storaasli JP, King RL, Krieger H,and associates Palliation of osseousmetastasis from breast carcinoma withradioactive phosphorus alone and incombination with adrenalectomy.Radiolo~. 1961; 76:422-430.

24, Tong ECK. Parathormone and 32Ptherapy in prostatic cancer with bonemetastasis. Rudiolo~, 1971; 98(2): 343-351.

25. Chcung, A and Driedger AA.Evaluation of radioactive phosphorus in thepalliation of metastatic bone lesions fromcarcinoma of the breast and prostate,Radiolo~. 1980; 134(l): 209-212.

26. Nair N. Relative efftcacy of 32Pand‘9Sr in palliation of skeletal mctastases, JNUC]Med. 1999; 40(2): 256-261,

27. Maxficld JR, Maxfield JGS, andMax field WS. The use of radioactivephosphorous and testosterone in metastaticbone lesions from breast and prostate. South.lMed, 1958; 51:320-328.

28. Albright F and Reifenstein E.Parathyroid glands and metabolic bonedisease. Baltimore, MD: William andWilkins; 1948.

29. Maxon HR, Deutsch EA, ThomasSR, and associates Re-186 (Sri) HEDP fortreatment of multiple metastatic foci inbone: Human biodistribution and dosimetricstudies, Radiolo~. 1988; 166(2): 501-507.

30. Maxon HR, Schroder LE, ThomasSR, and associates Re- 186 (Sri) HEDP fortreatment of painful osseous metastasis:Initial clinical experience in 20 patients withhormone-resistant prostate cancer.Radiolo~. 1990; 176(1): 155-159.

31. Maxon HR III, Thomas SR,Hertzberg VS, and associates Rhenium-186hydroxyethylidene diphosphonatc for thetreatment of painful osseous metastasis. ,$em

Nuclh4ed. 1992; 22(l): 33-40.

32. De Klerk JMH, Van Kijk A, VanHet Schip AD, and associatesPharmamkinetics of rhenium-186 afteradministration of rhenium- 186-HEDP topatients with bone mctastases. .J Nucl Med.1992; 33(5): 646-651,

33. De Klerk JMH, Zonnenberg BA,Van Het Schip AD, and associates Doseescalation study of rhenium- 186hydroxyethylidcne diphosphonate in patientswith metastatic prostate cancer. Eur J NuclMed. 1994; 21(10): 1114-1120.

34. Quirijnen JMSP, Han SH,Zonnenberg BA, and associates Efficacy ofrhenium-186-ctidronate in prostate cancerpatients with metastatic bone pain. J NuclMed. 1996; 37(9):1511-1515.

35. De Klerk JMH, Zonnenberg BA,Blijham GH, and associates Treatment ofmetastatic bone pain using the bone seekingradiopharrnaceutical Re-186-HEDP,Anticancer Res, 1997; 17:1773-1778.

36. Limouris GS, and Skukla SK.

Gastric Uptake during Re- 186 HEDP bonescintigraphy. Anticancer Res, 1997; 17:1779-1782.

37. Wolfangle, RG. PersonalCommunication.

38. Knapp FF Jr, Beets AL, Guhlke S,and associates Availability of Rhenium-188from the alumina-based Tungstcn-188/Rhenium- 188 generator for preparationof Rhenium-1 88-labeledradiopharmaceuticals for cancer treatment.Anticancer Aes. 1997:17:1783-1796.

39, Maxon HR 111, Schroder LE,Washburn LC, and associates Rhenium-188(Sn)HEDP for treatment of osscous

●

24

metastasis. .1 Nucl Med. 1998; 39(4): 659-663.

40. Blower PJ, Lam ASK, O’DohertyMJ, and associates Pcntavalent rhenium-188dimercaptosuccinic acid for targetedradiotherapyy: synthesis and preliminaryanimal and human studies. Eur J Nucl Med.1998; 25(6): 613-621.

41. Atkins HL, Mausner LF, SrivastavaSC, and associates Tin-1 17m(4+)-DTPA forpalliation of pain from ossmus metastasis:A pilot study, JNuc1 Med. 1995; 36(5): 725-729.

42. Krishmanurthy GT, Swailcm FM,Srivastava SC, and associates Tin-117m(4+)DTPA: Pharmacokinetics andimaging characteristics in patients withmctastatic bone pain. .J Nucl Med. 1997;38(2): 230-237.

43. Srivastava S,, Atkins H,Krishnamurthy I, and associates Treatmentof metastatic bone pain with tin-117mDTPA. The First Scandinavian Symposiumin Radiation Oncology. Rosendal, Norway.1997; May 24-28.

44. Srivastava SC, Atkins HL,Krishnamurthy GT, and associatesTreatment of mctastatic bone pain with tin-117m stannic diethylen~riamincpe~;=ceticacid; A phase 1/11 clinical study ‘ ClinCancer Res. 1998; 4:61-68.

45. Swailem FM, Krishnamurthy GT,Srivastava SC, and associates lN-~VOtissue uptake and retention of Sn-117m(4+)DTPA in a human subject withmctastatic bone pain and in normal mice.Nucl Med Biol, 1998; 25(3): 279-287.

46, Boucher LG, Belch WE, GodduSM, and associates Selection ofradionuclides for palliation of bone painfrom metastatic osscous lesions. J Nucl Med1998; 39(5): 84p.

47. Burch HA. Osseous metastasis fromgraded mcers of the breast with particularreference to rwntgen treatment. Am JRoentgenol. Radium Ther. 1944; 52:1-23.

48. Janjan, NA. Radiation for bonemetastasis. Cancer Supp. 1997; 80: 1628-1645.

49. H~gler D. Radiotherapy forpalliation o symptoms in incurable cancer.Curr Probl Cancer. 1997; May/June: 134-183.

50. Gaze MN, Kelly CG, Kerr G~ andassociates Pain relief and quality of lifefollowing radiotherapy for bone metastasis:a randomised trial of two fractionationschedules. Radiother and Oncol. 1997; 45:109-116.

51. MacDonald N. Principles governingthe usc of cancer chemotherapy in palliativemedicine, in Doyle D, Hans GWC,MacDonald N (eds): Oxford Testbook ofPalliative Medicine. Oxford: Oxford, UK,1993, 105-115.

52. Baum M, Breach NM, Shepherd JH,

and associates Surgical palliation, in DoyleD, Hans GWC, MacDonald N (eds): OxfordIextbook of Palliative Medicine. Oxford:Oxford, UK, 1993, 129-140.

53. Thurlima, B, de Stoutz, N.,

Causes and treatment of bone pain ofmalignant origin, Drugs, 51 (3)(1996) 383-398.

54. Mcrcandante, S., Malignant bonepain: pathophysiology and treatment, Pain.1997; 69:1-18.

55. Bankhead C. U.S. Department ofHealth and Human Services.Bisphosphonates spearhead new approach totreating bone metastasis. J Natl Cancer inst.1997;89:115-116.

25

56. Coleman RE, Purohit OP, VinholesJJ. The future of bisphosphonates in cancer.ACTA Oncologic. 1996;35 Suppl.5:23-9.

57. Diener KM, Bisphosphonates forcontrolling pain from mctastatic honedisease. Am J Health-Syst Pharm.1996; 53:1917-1927,

58. Rogers MJ, Watts, DJ, RussellRGR. Overview of bisphosphonatcs.Canc~r. 1997;Sup: 1652-1660.

59. Lourwood, DC. The pharmacologyand therapeutic utility of bisphosphonates.Pharmacotherapy. 1998; 18(4):779-789.

60. Kanis JA and McCloskey EV.Clodronate. Cancer. 1997 Supp,: 1691-1695.

61. Ziegler J. U.S. Department ofHealth and Human Services. Research onbone metastasis quickens its pace, J. NatlCancer Insl. 1997; 89:84-843,

62. Mundy GR and Yoneda T.Bisphosphonatcs as anticancer drugs. NewEngland Journal of Medicine. 1998;

63. Adami S. Bisphosphonatcs inprostate carcinoma, Cancer. 1997;Sup: 1674-1679,

64. Diel IJ, Solomayer EF, Costa SD,and associates Reduction in new metastasisin breast cancer with adjuvant clodronatetreatment. New England J of Medicine.1998; 339(6 );357-363.

65, Hortobagyi G, Theriault RL, LiptonA, and associates Long-term prevention ofskeletal complications of metastatic breastcancer with pamidronate. J ClinicalOncolo~. 1998; 16(6) June:2038-2044,

66. Purohit OP, Anthony C, RadstoneCR, and associates Highdosc intravenouspamidronate for metastatic bone pain. Br. J[~ancer. 1994; 70:554-558.

67. Kanis JA. Wtionale for the usc ofbisphosphonates in breast cancer, Ac[a-Oncol. 1996; 35( Suppl 5):61-67.

68, Bloomfield DJ. Shouldbisphosphonates be part of the standardtherapy of patients with multiple myelomaor bonernetastasesfrom other cancers? An

evidence-based review. J Clin Oncol.1998; 16(3): 1218-1225.

69, Bdy JJ. Clinical research update.Cancer. 1997;1699-1701.

70. Pelger RC, Hamdy NAT,Zwinderman AH, and associates Effects ofthe bisphosphonate olpadronate in patientswith carcinoma of the prostate metastatic tothe skeleton. Bone. 1998; 22(4):403-408.

71. Iglehart JK. The American healthcare system - Expenditure. New England JofA4edicine, 1999; 340(1):70-76.

72. Laetz T and Silberman G.Reimbursement policies constrain thepractice of oncology. JAMA. 1991;266(2 1):2996-2999.

73. Marchar DB, McCrory DC andBennett DL. Treatment considerations forpersons with metastatic prostate cancer:Survival versus out-of-pocket costsu~O~O~, 1997; 49(2):2 18-224.

74. Kozma CM, Reeder CE, SchulzRM. Economic, clinical, and humanisticoutcomes: A planning model forpharrnacoeconom ic research. ClinTherapeut. 1993; 15:1121-1 132.

75. Draugalis JR, Bootman JL, LarsonLN, McGhan WF. C~4rrent Concepts:

Pharmacoeconomics. 1989, The UpjohnCompany,

76. Gdwin PJ. Economic factors incancer palliation-methodologic consider-ations. Cancer Treatment Reviews. 1993;19(suppl A):97-102. I

● i

26

77. Clarke SEM. Radionuclide therapyin oncology. Cancer Treatment Reviews.1994; 20:51-71.

78. Schmeler K and Bastin K.

Strontium-89 for symptomatic metastaticprostate cancer to bone: Recommendationsfor hospice patients. Hospice Journal,1996; 11(2):1-10.

79. Macklis RM, Cornelli H, and LasherJ. Brief courses of palliative radiotherapy formetastatic bone pain. A pilot cost-minimization comparison with narcoticanalgesics. Am J Clin Oncol,1998; 21(6):617-622.

80. Biermann, WA, Cantor, RI, Fellin,FM, and associates An evaluation of thepotential cost reductions resulting from theusc of clodronate in the treatment ofmetastatic carcinoma of the breast to bone.Bone. 1991; 12(suppl 1):S37-S42.

81. van Holten-Veratvoort, ATM,

●Zcwinderman, AH, Aaronson, NK, andassociates The effect of supportivepamidronatc treatment on aspects of qualityof life of patients with advanced breastcancer. Elir J Concer. 1991 ;27(5):544-549.

82. Silbeman G. Cancer palliation:Economic and societal implications. Cancer

Treatment Reviews, 1993; 19(supp1 A):97-102.

83, Cleeland CS, Gonin R, Hatfield AK,and associates Pain and its treatment inoutpatients with mctastatic cancer. N Engl JMed. 1994;330(9):592-596.

QUESTIONS

●

1, Which of the followingradiopharmaceuticals is not FDA approvedfor the palliation of pain due to osseousmetastatic disease?a. ‘‘7mSn(+4)-DTPAb. 89SrCl ~c. 1f3Sm-EDTMP

d. 32 P-Sodiunl Phosphate

2< Which of the followingradionuclidcs may be usefil in the palliationof pain due to osseous metastatic diseaseand is generator produced?a. ‘8CRCb. 188Rec. 153Smd, 117mSn

3. Highly metabolic metastatic bonetumors will respond better to which of thefollowing FDA approvedradiophamaceuticals ?a. 89SrClzb. ‘8cRe-HEDP

c. ‘‘7rnSn(4+)-DTPAd. 1~3Sm-EDTMP

4. Complete relief of pain symptoms inpatients with multiple metastatic bone sitesfor both half-body radiotherapy andradiophamaceuticals occurs in aboutof all patients treated+a. 10%b, 5070

c. 20%d. 40%

5. The first radiopharmaceutical to beFDA approved for the palliation of pain ducto osseous metastasis was?

a. Mctastron@b, 32P-Sodium Phosphate

c. Quadramet@d. 153Sm-EDTMP

6, Which of the following FDAradiopharmaceuticals for bone painpalliation is approved for only metastasisfrom either breast or prostate cancer?

a. Quadramet@b. 32P-Sodium Phosphate

c. Metastron@d. 18GRE-HEDP

7. Of the FDA approved palliationradiopharmaccuticals which can be imagedusing a gamma camera?

a. Metastron@

b. Quadramet@

27

c+ 32P-Sodium Phosphated. Both b and C.

8. The recommended dose forEDTMP is?a. 1.0 mCi/Kg body weightb. 0.5 mCi/Kg body weightc. 1,5 mCi/Kg body weightd. 2,0 mCi/Kg body weight

9. Generally, the most seriouseffects occur with the use of ?

a. Metastron@b. Quadramet@

32P-Sodium Phosphate: Half-body radiotherapy

10. A potential agent for use in

153Sm-

side

palliation of bone pain that appears to onlytake up in m~static bone sites and notnormal bone tissue is?a. ‘8dRe-HEDPb. 18*Rc-HEDP

lggRe-DMSA: 18RRe-Octeotide

11. Which of the followingradionuclides emits a conversion electron?a. 117mSnb. 15sSm

18bRe:: “Sr

12. Which type of primary cancer withm-stases to the bone appears to respondbest to radiophamaceutical drugs?a. Prostateb. Breastc. Lungd. Colon

13. The approximate beta maximumgiven off by 89Sr is’?a. 1,7 MeVb. .2’7MeV

1,4 Mcv:: .80 MeV

14. Which of the following factorsshould be considered by both the clinician

and the patient when deciding on an optimaltherapy?a. Economicb. Humanisticc. Clinicald. All of the above

15. Chemotherapy has beenhypothesized to palliate pain associated withadvanced can=r by all of the followingmechanisms EXCEPT by:a. Decreasing mechanical pressure bydecreasing tumor size.b. Binding to receptors in the CNScausing inhibition of ascending painpathways.c. Dccrcasing cytokine production bylymphocytes and granulocytes.d. Altering peripheral and centralneurotransmitiers ystems.

16. In addition to pain palliation,bisphophonates are commonly used forwhich of the following disorders?a. Hypercalcemia of malignancyb. Osteoporosis

Paget’s Disease: All of the above.

17, Potency and selectivity ofbisphosphonates are altered by:a Modi@ing the chemical groups onphosphorous.b. Substituting the carbon with a heavymetal ion.c, Modifying the chemical groupslocated on the carbon backbone.d. None of the above,

18. Bisphosphonates are thought to actby which of the following mechanisms?a. Inhibit bone resorption by action onosteoclast activity.b. Interfere with osteoclastdifferentiation.c. Induce osteoclast apoptosis.d. All of the above.

19, Which of the following of thebisphosphonatcs is associated withinhibition of normal bone mineralization?

o

0

●

28

a. Alendronate

9 b. Etidronatec. Pamidronated. Zoledronate

20. The World Health Organi=tionrecommends that practitioners initiate whichtreatment as the first step of the analgesicladder?a. Opiatesb. Corticosteroidsc. Bisphosphonatesd. NSAIDS

21. Combination therapy with NSAIDSand opiates is appropriate because:a. Each class of drugs works by adifferent mechanism of action.

b. Each class work at differentneurological pathways of pain.c. Both class of drugs are veryinexpensive.d. a and b only

o 22, All of the following side effects mayoccur with the use of opiates EXCEPT:a. Sedationb, Constipationc, Thrombocytopeniad. Vomiting

23. To minimize the gastrointestinalside effects associated with bisphosphonateuse, the patient should be directed to:a. Take the dose with a fill glass ofmilk.b. Take the dose with a full glass ofwater 1-2 hours prior to a meal and remainupright for 30 minutes following the dose.c. Take the dose with the morningmeal.d. None of the above.

24. The recommended dosage of

pamidronate for skeletal complicationsassociated with metastatic bone cancer is:a. 60mg by mouth daily.b. 90mg intravenously once a month.c. 120mg intravcnousl y once a week,

d. 120 mg by mouth once a week

25. Which of the following state-meritsare true concerning economic evaluations ofthe treatment of meta-static bone pain?a, Pharmacoeconomic analysesprovide explicit, systematic evaluations ofcosts and outcomes of treatment alternatives.b. Many economics studies have beenperformed comparing costs and outcomes ofcurrent therapy for pain palliation.c. Pharmacoeconomics can be a useful

tool to enable clinicians to integrateeconomic and humanistic outcomes in theirclinical decision-making.d. a and c

9

●

●