THE UNIVERSITY OF NEW MEXICO HEALTH SCIENCES CENTER COLLEGE OF PHARMACY ALBUQUERQUE, NEW MEXrCO . The University of New Mexico Correspondence Continuing Education Courses for Nuclear Pharmacists and Nuclear Medicine Professionals VOLUMEVII,NUMBER4 A Review of Selected Radiopharmaceuticals Approved by the FDA During 1996-1997 by: Brigette McGhee, MS, PharmD, RPh, BCNP Kristina Wittstrom, RPh, BCNP Sam C. Augustine, PharmD, RPh, BCNP The TJnlvcr?.ityof New Mexico Health Sciences Center Crdlcgc of Pharmacy ISapproved by the Amer]can Council on Pharmaceutical Education as a prcividvr of continuing pharmaceutical education Program No 039-00(-98-M 1-HM 2.5 Contact HOW or .25 CEU’S
Transcript
THE UNIVERSITY OF NEW MEXICOHEALTH SCIENCES CENTER
COLLEGE OF PHARMACYALBUQUERQUE, NEW MEXrCO
.
The University of New Mexico
Correspondence Continuing Education Coursesfor
Nuclear Pharmacists and Nuclear MedicineProfessionals
VOLUMEVII,NUMBER4
A Review of Selected RadiopharmaceuticalsApproved by the FDA During 1996-1997
The TJnlvcr?.ityof New Mexico Health Sciences Center Crdlcgc of Pharmacy ISapproved by the Amer]can Council on Pharmaceutical Education
as a prcividvr of continuing pharmaceutical education Program No 039-00(-98-M 1-HM 2.5 Contact HOW or .25 CEU’S
Coordinating Editor and Director of Phormacy Continuing Education
William B. Hladik III, MS, RPhCollege of Pharmacy
University of Ncw Mexico Health Sciences Center
Managing EditorJulliana Newman, ELS
Wellmart Publishing, Inc.
Associate Editor and fioduction Specialist
Sharon I. Magers Ramirez, Administrative Assistant IICollege of Pharmacy
University of New Mexico Health Sciences Center
Editorial Board
George H. Hinkle, MS, RPh, BCNP
William B. Hladik 111,MS, RPhJeffrey P. Norenberg, MS, RPh, BCNP
Laura L, Boles Ponto, PhD, RPhTimothy M, Quinton, PharmD, MS, RPh, BCNP
Guest ReviewerKennti T. Cheng, PhD, BCNP
While the advice and information in this publication are believed to be true and accurate at press time, neifier the author(s) nor the editor nor the publisheroan accept any legal respmsibility for any =om or omissions that maybe made. The publisher m~es no warranty, express or implied, with ruspect to the
matcriai contained herein.
copyright 1998Univmity of New Mexico Health Sciences Center
Phatmacy Continuing EducationAlbuquerque, New Mexico
A REVIEW OF SELECTED RADIOPHARMACEUTICALS APPROVED BY THEFDA DURTNG 1996-1997
STATEMENT OF OBJECTIVES
The purpose of this lesson is to provide a general review of radiopharmaceutical productsapproved by the FDA in 1996 and 1997 Specifically, this unit will review the following
Upon completion of this continuing education unit, the reader should he able to:
1. Recall the normal adult dosage for each of the products discussed. List the clinicalindications for each of the products discussed.
2. Describe the basic pharmacokinetics, elimination and biodistribution for each of theproducts discussed.
3. Describe the basic imaging protocol for each of the agents discussed.4. List the critical or dose-limiting organ for each of the agents discussed.5. Recall the compounding and quality control procedure for each of the agents
discussed.6. Describe factors that contribute to the development of the HAMA response following
monoclinal antibody administration.7. Discuss the basic principles of radiolabeling monoclinal antibody-based
radiopharmaceuticals.
COURSE OUTLINE
I. ~TRODUCTION
II. MONOCLINAL ANTIBODIESA. Production MethodsB. HAMA Responsec. Designer AntibodiesD, Antibody Fragments vs. Intact AntibodiesE. Antibody MassF, Radiolabeling Considerations
111. PROSTASCINT@A. Indications and Disease State InformationB. Pharmacology, Biodistribution and Dosimetryc, Compounding and Quality AssuranceD. Dosage and AdministrationE. Imaging Considerations
Iv.
v.
VI.
VII.
CEA-SCAN@A. Indications and Disease State InformationB. Pharmacology, Biodistribution and Dosimetryc. Compounding and Quality AssuranceD, Dosage and AdministrationE. Imaging Considerations
VERLUMA@A. Indications and Disease State InformationB. Pharmacology, Biodistribution and Dosimetryc. Compounding and Quality AssuranceD. Dosage and AdministrationE. Imaging Considerations
mLUMATMA. Indications and Disease State InformationB. Pharmacology, Biodistribution and Dosimetryc. Compounding and Quality AssuranceD, Dosage and AdministrationE. Imaging Considerations
QUADRAMET@
2
A. Indications and Disease State Information
B. Pharmacology, Biodistribution and Dosimetry
c. Handling ConsiderationsD. Dosage and AdministrationE. Patient Considerations
e A REVIEW OF SELECTED RADIOPHARMACEUTICALS APPROVED BY THEFDA DURTNG 1996-1997
by:
Brigette McGhee, MS, PharmD, BCNP,Kristina Wittstrom, R.Ph, BCNP, and
Samuel Augustine, RPh, PharmD, BCNP
INTRODUCTION
The purpose of this continuingeducation unit is to review theradiopharmaceutical products approvedfor use by the FDA in 1996 and 1997.Specifically, this unit will review thefollowing products: nofetumomabmerpentan (Verluma@), capromab(Prostascint@), arcitumomab (CEA-Scan@), Tc99m-sestamibi (MlralumaTM),
oand samarium- 153 lexidronam(Quadramet@). For each product, abrief discussion of the pharmacology,chemistry, pharmacokinetics, preparationparameters, dosimetry and clinicalapplications will follow. As this articlerepresents a hedge-podge of products,specific disease states and epidemiologicdata will be only briefly discussed.Given that several of theradiopharmaceutical products released in1996-97 are monoclinal antibodies, theauthors feel it necessary to present anoverview of this class of agents prior todiscussing specifics about eachmonoclinal product.
The reader is also encouraged to reflectupon the fact that each of the productsdiscussed has clinical application in theoncological patient, whether as adiagnostic adjunct in combination withother imaging modalities, or as palliativetherapy. The use of nuclear medicineimaging in staging, evaluation, follow-up
or treatment in certain cancer patientsrepresents an area of growth for theindustry. Given that in 1996, theAmerican Cancer Society estimated that1.3 million people would be diagnosedwith cancer, there is great interest in thepotential role of nuclear medicine inoncology. 1
MONOCLINAL ANTIBODESA review of monoclinal antibody
production and radiolabeling is presentedin the text that follows. A comparison ofantibody fragments and intact antibodiesis also discussed. This section isintended to provide a framework underwhich to group the specific monoclonal-based radiopharmaceutical products.
Monoclinal production 2’3Large-quantity production of
monoclinal antibodies became a fairlystraightforward process as the hybridomatechnique was refined. To review this
technique, a specific antigen is injected
into a mouse, stimulating antibodyproduction by B-lymphocytes, These B-Iymphocytes are harvested from theanimal’s spleen and incubated withmyeloma cells in culture.
The resultant hybridoma is capable ofproducing large quantities of antibody
and may be maintained over a long timeperiod (immortal cell line). Thehybridomas are carefully screened to
3 I
determine which particular cell line hasthe most desirable uptake, binding and
Figure 1. Monoclinal antibody
LightChain
HAMA (Human anti-mouse antibody)Response 2’4’5It is the use of the murine-based
technique described above which mayinitiate the HAMA (human anti-mouse
antibody) response to foreign protein.Improper storage, rough handling duringlabeling or specific patient disease statesmay increase the likelihood of theHAMA, as well. Initiation of theHAMA response is undesirable becauseof its effect on subsequent diagnostictests or radiolabeled antibody scans.HAMA formation may interfere withdiagnostic tests that employ murine-based immunoassay techniques, such astumor markers like PSA, CEA orCA1 25. For this reason, it is advisable towait seven days post injection of a
cross-reactivity profile. The structure ofa monoclinal antibody is illustrated obelow in Figure 1.
VariableDomains
ConstantDomains
monoclinal imaging agent to draw blood
levels for immunoassay. Additionally,
induction of a HAMA response from a
previous exposure to a murine-product
may adversely affect the biodistribution
of the injected labeled antibody, If the
injected antibody is complexed to
HAMA, the complex clears from the
body more quickly and is routed to theRE system instead of traveling to thearea of interest. Many institutions
routinely draw HAMA titer prior to
injection of a monoclinal-based product,
and repeat the titer when serial studies
are planned.
“Designer” Antibodies 2In an attempt to avoid generating the
HAMA response by decreasing
4
immunogenicity, alternate monoclinal
production methods may be utilized. A
fully human antibody may be genetically
engineered, as may be a “chimeric”
(partial human/ partial rnurine) product.
Both are less likely to elicit HAMA.
These genetically engineered antibodies
are more expensive than those obtainedfrom mass-produced hybridomas, butcan be altered to optimize affinity for thetarget and decrease cross-reactivity withnormal tissue or other types of cancer.
Whole Antibodies vs. Fragments 2’JThe variable regions of the antibody
largely govern the specificity of themonoclinal for a particular target. TheFc portion (constant domain of theantibody) remains relatively constantamong species and is thought to beprimarily responsible for the HAMAresponse, The Fc portion is responsiblefor effecter function like antibodydependent cell cytotoxicity andcomplement fixation. Whole antibodiesmay be broken into fragments usingproteolytic enzymes, like papain orpepsin. Antibody fragments may bereferred to as Fab’ or F(ab’)z, referringto one “arm” of the “Y” or both arms ofthe “Y,” respectively. These fragmentsretain the antigen binding portion, butlose the immunogenic Fc portion. Thus,the molecular weight of an intactantibody is on the order of 150,000Daltons (Da), while that of a Fab’fragment is about 50,000 Da.
In addition to the advantage ofdecreasing the likelihood of HAMAformation, the use of fragments results inother desirable characteristics.Fragments clear the blood pool veryrapidly, while intact antibodies difise tothe target site more slowly and have amuch longer serum half-life. The serumhalf-life of intact antibodies is on the
order of 24-30 hours, whereas thefragments have a serum half-life of about90 minutes allowing for early imaging.Additionally, fragments tend to yielhighertumor to background ratio, improvingimage quality. Intact antibodies have alower tumor to blood ratio because oftheir slower diffusion and clearance, butmay achieve higher absolute tumor levelsbecause of their higher specificity for theantigen.
Ultimately, the choice of fragmentversus intact antibody is governed by theuptake characteristics of the targetantigen, as well as the radionuclide usedfor labeling. (i.e., a shorter-lived labellike Tc99m may be better suited for usewith an antibody fragment than an intactantibody, depending on the uptakekinetics of the target). The bottom line isto choose a radionuclide for labeling thatparallels the biologic half-life of thefragment or intact antibody.
Antibody Mass 6An additional consideration with some
antibodies is the mass of product thatmust be administered to achieveadequate tumor levels. That is, there isnon-specific uptake in binding sites of
normal organs that must be saturated sothat the tumor uptake can bedistinguished. Each antibody product istested to determine at what level theantibody dose is optima. Too muchantibody increases the likelihood ofHAMA formation, while too little maynot achieve adequate target levels forimaging. In many cases, a fairly largemass of antibody must be administered toovercome this nonspecific binding,particularly in the liver.
Radiolabeling 4-6Figure 2 below presents a schematic
representation of radiolabeling a
5
rnonoclonal antibody and its subsequent
attachment to a target cell. Because the
antibody molecule is a protein, there are
a variety of potential attachment sites for
drugs and radionuclides. However, the
radionuclide must be attached in such away that the reactivity with the antigentarget is not affected. An additional
consideration that must be made whenradiolabeling is the half-life of theradionuc)ide, which must allow adequate
target to background contrast within areasonable time frame. Fuflhermore, italso is desirable in order to minimize theradiation dose to the patient. A shorthalf-life nuclide is preferred unless thetumor uptake or background clearancerequires the use of a longer-lived nuclideto get adequate counting statistics forimaging. The agents presented in thislesson utilize In- 111 or Tc-99m labeling.
Figure 2. Radiolabeling of Monoclinal Antibody
Q +
PROSTASCINT@ (CAPROMAB cancer thought to be localized, and in
PENDETIDE)7-16 post-prostatectomy patients with risingPS~ negative or equivocal standard
Indications and Disease State evaluations, like bone scan, and who
Information have a high suspicion of occult disease.
ProstaScint@, manufactured and It is not to be used without confirmation
distributed by Cytogen, is indicated for of disease because of the high false
newly diagnosed patients with prostate positive and false negative rate in clinical
6 II
trials. See Figure 3 for ProstaScintButilization in patient work-up.
Cytogen has restricted access to thisproduct to institutions who are enrolledas “PIE” (Partners in Excellence) sites,Enrolling in this Cytogen-sponsoredprogram gives the physicians andtechnologists in the institution access totraining materials and a speaker’s bureau.The program is designed to increasedemand for the product and avoid havingtechnical image difficulties in imageacquisition and interpretation.
There are 244,000 newly diagnosedprostate cancer patients each year, with40,000 cancer-related deaths. Serumblood levels of prostate specific antigen(PSA) are often used to monitor therapyand disease progression in these patients.However, the PSA is normal inapproximately 21 ‘/0 of patients withrecurrent disease. Also problematic isthe fact that CT and MRI only detect300/0 of prostate metastasis. Treatmentoptions for recurrent prostate cancerinclude hormonal therapy if the diseaserecurs outside the prostate fossa, orradiation therapy if localized to theprostate fossa.
Pharmacology, Biodistribution andDosimet~
ProstaScint@ has a small volume ofdistribution and a slow clearance; 8 +3% is excreted in the urine during the 72
hour period post administration. Its
serum half-life is 68 ~ 28 hours. Fecal
excretion ultimately accounts for 25°4 ofthe injected activity. Thus, a bowel prepthe night before the scan and an enema 2-4 hours prior to the scan arerecommended. Catheterization duringthe procedure is also recommended. Theliver has the highest organ residence timefor the drug and is the critical organ,receiving 18.5 rads/5 mCi.
Areas of normal uptake include bloodpool, liver, spleen, kidney, bone marrow,bowel and genitalia. The liver spleenactivity is probably secondary to
catabolism.
Reported causes of false positive
uptake include ostomy sites, abdominal
aneurysms, post-operative bowel
adhesions and degenerative joint disease.
Reported causes of false negative lesions
include small lymph nodes, especially
those less than 5mm in size.
Compounding and Quality AssuranceCompounding is fairly straightforward.
The initial step is to buffer the iridiumchloride with acetate, prior to adding 6-7mCi to the reaction vial containing thecapromab. A 30-minute incubation atroom temperature completes the labelingprocess. The pH is adjusted with theremaining acetate and the product isfiltered. The kit must be used within 8hours of compounding and requiresrefrigeration prior to compounding.Radiochemical purity must be greaterthan 900A. The quality control procedureis similar to that used with OncoScint@,
and involves mixing the final productwith an equimolar amount of DTPAprior to spotting the sample on theITCL-SG strip. The strip is developed in0.9V0 saline; the labeled antibody productremains at the origin.
Dosage and AdministrationThe normal adult dose is 0.5 mg of
Prostascint labeled with 5 mCi indium-111 administered IV over 5 minutesAdverse reactions reported in the
package insert include: 1% of patientsexperienced an increase in bilirubin, hypoor hypertension, 8% of patientsdeveloped HAMA following a singleinjection. As many as 19% of patientswere found to have HAMA titer upon
7
repeat injection in clinical trials. Theantibody may also interfere with PSA anddigoxin assays.
Imaging ConsiderationsInitial SPECT images are performed 30
minutes post injection to obtain a blood
pool image, Whole body planar images
are obtained at 3-5 days. Delayed
images may be acquired out to 6-7 daysto distinguish bowel activity fromrecurrence of cancer. It is important todo SPECT of the pelvis to look atactivity adjacent to, but separate from thebladder and blood pool. Blood poolimages may also be co-registered inorder to do a background subtraction.
Figure 3. &ostaScint@ Patient Management 8
Rising PSAI
Prior to Surgery Post-Radical Prostatectomy
I IProstaScint Bone Scan
I IRadical Prostatectom y Non-Surgical ProstaScint
IBiopsy
II I
Radical Prostatectom y Radiation
VERLUMA@ (NOFETUMOMAB)17-21
Indications and Disease StateInformation
Verluma@, manufactured by Thomaeand distributed by DuPont, is indicatedfor detection of extensive disease inpatients with biopsy-proven small celllung cancer (SCLC). It is not indicatedfor screening, nor is it recommended toconfirm limited disease. Extensivedisease indicates there is evidence ofdistant metastasis. Limited diseaseindicates that the disease is confined toone hemithorax without distantnew cases per year. Eighty-seven
percent of those who die are smokers.
Therapy
metastasis. The prognosis for thepatient with lung cancer is quite poor.Those with limited disease have a 10-25% 2-year survival rate; those withextensive disease have a 0-2°/0 2-yearsurvival rate. Two-thirds of patientspresent with extensive disease that, bydefinition, has metastasized at the time offirst diagnosis.
Lung cancer is the leading cause of
cancer death in both sexes, with 177,000
Of the 177,000 cases, approximately20V0 have SCLC, 20V0 have mixed small
8
cell and non-small cell cancer. Themajority of patients, therefore, have
NSCLC, for which Verluma@ is notindicated.
In order that the patient receive propertreatment, it is necessary to correctlystage the progression of the cancer.Patients with limited disease may respondto surgery, radiation therapy, orchemotherapy. Those with extensivedisease ofien have chemotherapy as thesole option due to the extent of spread oftheir disease. Staging is an involvedprocess, which includes CT of theabdomen and head, bone scan and bone
marrow biopsylaspiration, physical exam,
chest X-ray and biopsy. Verluma@ hasthe highest accuracy (82VO) for clinicalstaging of any single diagnostic test andthe highest sensitivity. See Table 1, fromthe Verluma@ package insert. The intent
of adding Verluma@ to the standarddiagnostic modalities is to avoid theexpense of further testing in patientsconfirmed to have extensive disease asdetermined by the monoclinal scan. It isrecommended that patients with limiteddisease still undergo further standardtests to assure that Verluma@ did notunderestimate the extent of their disease.
Table 1. Comparative Accuracy of Verluma@ with Other Diagnostic Evaluations for Staging
Bone Marrow (asp/bx) I 16/57 I 32/32 48/89 (5470)I I 1
CT Head I 12/57 I 32/32 44/89 (4970)I 1 1
Physical Exam 18/57 31/32 39/89 (44Yo)1 1
CT Chest ] 5/57 I 32/32 I 37/89 (42Yo)I I I
Chest X-Ray I 2/57 32/32 34/89 (38%)
Pharmacology, Biodistribution andDosimetry
Verluma@ is a Fab’ fragment of themonoclinal antibody NR-LU- 10 thatreacts with a 40 kD glycoprotein antigenexpressed by a variety of cancersincluding SCLC, NSCLC, andadenocarcinomas of the colon, ovary andbreast. It is expressed on virtually all
9
SCLC, unlike the other types of cancer,This Fab’ fragment is rapidly distributedand clears from the body fairly quickly.Elimination is via the urine with about64% of the injected amount cleared inthe first 24 hours. A secondary route ofexcretion is the hepatobiliary system.
Nonspecific uptake occurs in areas ofhigh vascularity including the midline
nasal area and testes. The antibody alsoexhibits very distinct cross-reactivity withthe thyroid, salivary and pituitary glands.The thyroid will be seen very clearly onthe images. The critical organ is the gallbladder wall (5.6 rads/30 mCi), followedby the kidney (3 ,9rads/30 mCi), andupper and lower large intestine(2.7rads/30mCi and 2.0 rads/30 mCi,respectively). False positive images mayoccur in areas of high blood flow, suchas recent surge~ or inflammation.Additional uptake of an artifactual natureoccurs at the skin folds of the axilla,breast and lower abdomen, particularly inobese patients. It may be desirable toimage with the arms overhead tominimize this uptake. False negativeimages may occur in areas like the brain
and bone, where Verluma@ is not taken
up to any great extent, Verluma@ maymiss small liver lesions, as well.
Compounding and Quality AssuranceThe procedure for compounding
Verluma@ requires several complexmanipulations and takes about 90minutes to complete the labeling process.Temperature and incubation times arecritical, as are the concentration of thereactants used, It is also important to
realize that there are several requiredancilla~ supplies that are not listed in thepackage insert. Detailed coverage of thisprocedure is beyond the scope of thislesson. It may be found in the packageinsert. See Figure 4 for a graphic
explanation of the labeling process.
The basic steps in compounding are:I. Formation of IigandII. Formation of the Iigand ester111. Reaction of the ligand ester with
the antibody
IV, Purification and filtration of thelabeled antibody via ion exchangecolumn.
The Verluma@ labeling reaction is
accomplished by forming a Tc99m
gluconate ligand that acts as an
intermediate chelate to stabilize the
Tc99m until it is transferred to the
phenthioate ligand. This transchelation
requires the proper temperature, pH and
reaction time. The Tc-ligand complex isadded to the antibody vial, the pH isadjusted and the antibody is conjugatedto the phenthioate ligand to form thefinal product. Careful attention must bepaid to the age of the generator eluateand the contamination of the reactants bytrace metals. Trace metals, such as thosethat leach from rubber stoppers, interferewith the transchelation process. There isvery little tin in the initial reaction ofgluconate with Tc99m, necessitating theuse of “fresh” Tc99m with little Tc99 tointerfere with tagging.
Careful handling of the antibodyproduct is necessary to avoid the loss ofproduct to “plating out” on the frothproduced by vigorous agitation of thevial. Careful filtration is necessary toassure that the integrity of the filter ismaintained. The final product should be>85°A radiochemically pure and be used
within 6 hours of preparation. Thequality control procedure requires a 12%trichloroacetic acid solution and a silicagel glass fiber sheet cut into 2x1 O cmstrips, Following strip development in
the solvent, the strip is cut into threepieces. The labeled product remains atthe origin, while the non-protein boundTc99m labeled impurities and unboundpertechnetate migrate with the solventfront,
10
Dosage and AdministrationThe adult dose of Verluma@ is 5-10
mg nofetumomab labeled with 15-30 mCi
of Tc99m, infused in a total volume of15-20 rnL over 3-5 minutes. Someinstitutions prefer to administer the dosein a smaller total volume. IV bags
should not be used for administration,
but three-way stopcock assemblies are
acceptable.
Adverse reactions were rare and
consisted of self-limited elevations in
temperature, mild urticaria or allergic
reaction, transient changes in serum
lipase or amylase; 6% of patients had a
HAMA response that subsequently
normalized within 3-4 months,
Imaging ConsiderationsImaging is performed 14-17 hours post
injection. Whole body planar views ofthe anterior and posterior are obtained
Figure 4. Radiolabeling of Verluma@
routinely. SPECT in areas of interest
and lateral skull views may be useful, as
well.
Verluma@ performs well in patients
with extensive disease, howeverunderstaged those thought to havelimited disease 10VOof time. In another15Y0, however, antibody imaginguncovered metastatic sites missed by
other modalities. Verluma’s@ positivepredictive value (PPV) in extensivedisease was 95-1 00Y0, comparable tothat of the 96-100% obtained with allother diagnostic modalities combined.Therefore, in a patient thought to havelimited disease afier Verluma@ scan, thestandard battery of tests is still necessaryto contirrn the staging. Those found tohave extensive disease with Verluma@may be spared the cost of furtherdiagnostic tests, as the PPV is so high.
Work Routine1. Formulation of Ligand I
+[
Io%n+ho”imqIsopropyl
Reaction VialLigand
AlcoholGlacial Acetic
Acid#
Incubation 15 min. 75v c
Ill.$
99mTc Antibody Labeling I Incubation 2 min. 0° C
n~
1
0.5 m+
Sodium Bicarbonatem
II II Incubation 20 min. RT I
Il. Formation of 99rn Tc-Ligand Ester
H0.1ml
n
/1 ml
~m
/ Stannous
<“iGiuconate
\p odium pertechnetate (75-100mCi)
IV. Purification and Filtration of99m Tc-Labeled Antibody
0+9%saline
\\ 5 ml
mGColumn Filter
Assembly
1.~
11
CEA-SCAN@ (ARCITUMOMAB)2232
Indications and Disease StateInformation
CEA-Scan@, manufactured anddistributed by Immunomedics, isindicated for use with standarddiagnostic modalities to detect thepresence, location and extent of recurrentor metastatic colorectal cancer involvingthe liver, abdomen and pelvis in patientswith a histologically confirmed diagnosisof colorectal carcinoma. It is notindicated as a screening or follow-up tooland is recommended only in patients withconfirmed disease.
Colorectal cancer has an annualincidence of 133,500 cases with 54,000related deaths each year. The onlychance for cure is surgery. In thosepatients who have localized disease, the5-year survival rate following surgery is90%. Survival decreases as the diseasespreads. Unfortunately, many patientsalready have metastatic disease at thetime of diagnosis. Up to 50% havemicrometastasis and will eventually die ofthe disease,
Accurate staging is important to avoidthe unnecessary morbidity and cost ofsurgery or chemotherapy in a patientwho will not ultimately benefit. Stagingof colorectal cancer requires an extensivework-up prior to surgery, including CT,barium enema, chest X-ray, MRI,colonoscopy, endoscopy with biopsy,ultrasound and sometimes liver/spleenscanning. ~er surgery, patients aregenerally followed with a physical exam,CEA levels, liver function tests, chest X-ray and yearly colonoscopy. CT andMRI may be performed at follow-up, aswell. Unfortunately, standard stagingmodalities, such as CT, may missmicrometastatic lesions in normal-sizednodes. The intent of monoclinalantibody imaging then is to improve thediagnostic accuracy and staging. Themanufacturer has developed a patientmanagement paradigm, as shown in oFigure 5, for physician use in using theresults of CT and CEA-Scan in order tomake decisions about resection.
Figure 5. Suggested Patient Management Paradigm
CT+ CEA-Scan
12
Concordant Findings Discordant Findings
Respectable Non-resectable Negative Biopsy or additional tests
I IOperate Don’t Operate Re-evaluate in
2-3 months
Pharmacology, Biodistribution andDosimet~
CEA-scan@ is a Fab’ fragment of anIW-4 IgG antibody directed at the200,000 Da membrane-bound form ofcarcinoembryonic antigen(CEA). Thiscarcinoembryonic antigen is expressed bynormal tissues, as well as a variety ofcancers and circulates in thebloodstream. The circulating antigen isprimarily a 180,000 Da form and isnormally present at levels less than 2ng/rnL of serum. These levels increase10-20 fold as a cancer grows. CEA-
Scan@ has little cross-reactivity with thiscirculating 180,000 Da form and bindsinstead to the 200,000 Da form presentorI the surface of the cell membrane.
Following injection, CEA-Scan@ isvery rapidly cleared by the glomerulus,with about 28°/0 excreted in the urine
oover the first 24 hours. About 23°A ofthe original amount remains in the bloodat 5 hours, and 7°/0 at 24 hours. Theserum half-life of Fab’ is about 4 hours.There is some catabolism of the Fab’ bythe kidneys and the resultant Tc99m-labeled peptide products may clear moreslowly than intact Fab’. There is alsosome dimerization of Fab’ to form Fabz’during labeling, so there will be a smallpercentage (<5VO) of hepatobiliaryexcretion, as well. The critical organ isthe kidney(-0.5rads/mCi), followed bythe bladder (-O.08rads/mCi), spleen(-0,08rads/mCi) and liver(-O.05rads/mCi).
Potential causes of false positive uptakelisted in the package insert and literatureinclude: adenoma with atypia, gallbladder and gut in late images, uterineactivity in patients with hypermenorrhea,TM injection site, nonspecific uptake atsurgical scar/incision, blood pool on early
images and adhesions. False negative
lesions may result from small lymph node
and peritoneal mets, ovarian mets, and
any recurrence less than 1cm in size.
Compounding and Quality AssuranceCompounding is fairly straightforward.
The Fab’ fragment was formulated tohave an intrinsic receptor with a highafftnity for binding Tc99m. In preclinicalstudies, this receptor was demonstratedto quantitatively bind up to 50mCi ofTc99m within 5 minutes. Compoundinginvolves the addition of 25-30 mCi ofpertechnetate to the lyophilized vial thathas been allowed to equilibrate to roomtemperature following its storage in therefrigerator. An incubation period of 5minutes is sufficient to obtain very highbinding efficiency. The kit may bediluted to final volume with saline andstored at room temperature for up to 4hours post compounding. The productmust be 900/0 radiochemically pure. Thepackage insert recommends a qualitycontrol procedure using ITLC-SG andacetone to determine the radiochernicalpurity.
Dosage and AdministrationThe recommended adult dose is 1mg
arcitumomab labeled with 20-30 mCi ofpertechnetate. It maybe administered IVin 2 mL of volume or infused over a 5-20minutes period in a 30 mL volume.Adverse reactions are generally minor,with fever, minor GI upset, transienteosinophilia, headache, itching and rashlisted in the package insert, There wasone case report of an unwitnessedseizure in a severely hypertensive patientthat could not be directly attributed tothe drug’s administration.
13
I
Imaging ConsiderationsInitial planar and SPECT images are
obtained of the chest, abdomen and
pelvis at 2-5 hours post administration.
Delayed planar and SPECT images are
acquired of the head, chest, abdomen and
pelvis at 18-24 hours. It is recommendedthat images be read from a computer, asup to 1/3 of liver metastasis were missedorI plain film. The tine mode may helpdistinguish bowel from tumor and theintensity may be adjusted to improve theimage contrast, as the kidneys will bevery hot. Liver metastasis may be seenon the scan as hot, iso-intense with a hotrim, or cold with a hot rim. Late imagesare useful because the “rims” of theseliver lesions get hotter with time.
CEA-Scan@ is indicated in conjunctionwith other diagnostic modalities. CT +
CEA-Scan@ together more accuratelypredict surgical outcome following tumordetection than either test alone. In 122patients with surgical/ histological
confirmation of disease, CEA-Scan@showed a sensitivity of 78°/0, specificityof 86°/0, accuracy of 79°/0, PPV of 990/0and negative predictive value WV) of19Y0. When used in conjunction withstandard diagnostic modalities, thesensitivity was 97°/0, specificity 29°/0,accuracy 93°/0, PPV 96°/0 and NPV 33°/0.Both sensitivity and specificity decreasedin recurrent disease, CT is moresensitive for detecting liver lesions due tothe normal uptake ofIn111 in the liver aswas discussed earlier.
NON-MONOCLONALANTIBODIES: M~LUMATM 33-~]
Indications and Disease StateInformation
MiralumaTM,which is manufactured anddistributed by DuPont, is indicated for
use in planar breast imaging
(scintimarnmography). Miralumam is asecond-line diagnostic drug to be usedafter mammography to assist in theevaluation of breast lesions in patientswith an abnormal mammogram or apalpable breast mass. It is not indicatedfor breast cancer screening or to confirmthe presence or absence of malignancy.It is not indicated as an alternative tobiopsy.
Breast cancer is the second leadingcause of cancer related deaths in womenof all ages and the leading cause of deathin women ages 40-55. One in every 8women will develop breast cancersometime during their lifetime. Eachyear, one of every 33 breast cancerpatients will die of the disease. Five orsix women will have a negative biopsy(benign) for every one patient diagnosedwith cancer.
Nearly 20 million women will seephysicians for potential breast cancereach year. Fifiy-six percent of all womenover 50 years of age will have amammogram study performed routinely.This test continues to be the bestscreening tool available for diagnosingbreast cancer. One study reportedmammography sensitivity of 80°/orn
specificity of 20-50°/0, a false negative
rate of 10- 15°/0 and a positive predictive
value of 15-30°/0. Each patient with a
palpable mass and/or questionable
mammogram requires additional
evaluation to determine if treatment is
necessary. Mammography’s low
specificity infers that the 50-80°/0 false
positives go to biopsy unnecessarily.
Mammography in patients with dense
breasts has an even lower specificity of
200A. In patients with difficult tointerpret mammograms, such as those
with dense breasts, scarring from
14
previous biopsy, breast implants, or With additional adjunct screening,fibrocystic disease, many breast cancers many unnecessruy biopsies could beare missed (35. 7°/0) due to a false prevented. Scintimammography withnegative mammogram. sestamibi has demonstrated significant
The need for accurate diagnosis and improvement in sensitivity, specificity,staging has resulted in a variety of negative predictive value and positiveadditional breast cancer screening tools. predictive value, as indicated below in
Table 2.
Table 2: Sestamibi Statistics from Multi-Center Trials of 673 women ’37)
The literature concludes that high-quality mammography, scintimammography canimaging with sestarnibi has a high help diagnose breast cancer at an earlierdiagnostic accuracy for the detection of stage in women with dense breasts. Anprima~ breast cancer in patients who example of the role of sestamibihave palpable lesions. When used as a mammography in patient management is
complementary method to conventional shown in Figure 6.
15
Figure 6. Patient Work-up Example
I
Mammography
1[ 1 I
Clearly benign Indeterminate Suspicious
I
I
Negative
I Control in 3-6 months I
Pharmacology, Biodistribution andDosimetry
Tc99m-sestamibi, the active ingredient
of Miralumam is well established asCardiolite@, a cardiac imaging agent.An isonitrile derivative, it also localizesin many malignant tumors, includingmost malignant breast cancer tumors.
After injection, MiralumaTM is distributedthroughout the body in proportion toblood flOW. It is cleared from thebloodstream rapidly and is fixedintracellularly in proportion to thevascularity. Since malignant cells have ahigher metabolic activity than normalcells, lesions appear on the images as“hot spots”. Elimination is primarily viathe hepatobiliary system. Twenty-sevenpercent of the injected dose is excreted inthe urine and about thirty-three percent iscleared through the feces in 48 hours.The critical organ for this procedure isthe upper large intestine wall, receiving a
1
Positive
Excisional biopsy
radiation dose of 5.4 rads/30 mCi. Thebreasts receive a radiation dose of 0,2rads/30 mCi.
Compounding and Quality AssuranceReaders are most likely very familiar
with the compounding procedure from
experience with Cardiolite@. Mer
reconstitution with Tc-99m, the vial is
heated for ten minutes. Radiolabeling
occurs through a series of Iigand
exchange reactions. Quality control is
TLC using ethanol and aluminum oxideplates.
Dosage and AdministrationThe dosage of Miraluma is 20-30 mCi
injected in the arm contralateral to the
suspected lesion. If bilateral lesions aresuspected, the patient should be injectedthrough the dorsal veins. The choice ofan inappropriate injection site couldresult in activity localizing in the axillary
16
lymph nodes, No drug interactions havebeen reported. Adverse reactions includetransient parosmia and taste perversion.Other mild reactions, such as headache,flushing and hypersensitivity have beenreported,
Imaging Considerationsln order to achieve the best separation
of breast tissue from the chest wall, thepatient’s breast should be freelysuspended with no compression. Thismay be accomplished with a specialoverlay for the imaging table. Beginningfive minutes post-injection, a ten-minutelateral image of both the abnormal andnormal breast is acquired. This isfollowed by a ten-minute anterior imageof both breasts.
As the only radiopharmaceutical withan approved indication for breastimaging, Mlraluma, as an adjuvant tomammography, may offer an answer forthose patients with dificult orquestionable mammograms or thosereluctant to have a biopsy. Theimprovement in patient management mayalso decrease health care costs byavoiding unnecessary biopsies.
NON-MONOCLINAL ANTI-BODIES: QUADRAMET@(SAMARIUM SM 153LEXIDRONAM) 42-4R
Indications and Disease StateInformation
Quadramet@ is manufactured by Dow
and distributed by DuPont under licensefrom Cytogen. It is indicated for relief ofpain in patients with confirmedosteoblastic metastatic bone lesions. The
exact mechanism by which Quadramet@relieves bone pain is unknown. A routineradionuclidic bone scan is used to
confirm lesions before administering
Quadramet@ to patients.Bone metastasis are the most common
cause of cancer pain and predisposepatients to immobility, pathologicalfractures, bone marrow failure,neurological symptoms andhypercalcemia. The reported incidenceof bone metastasis varies according totumor type. Post-mortem studiesindicate that up ,to 85°/0 of patients with
breast or prostatic carcinoma develop
bone metastasis. The management of
skeletal metastasis is directed toward
pain palliation and demands a multi
disciplinary approach. Traditional
treatments include chemotherapy,
hormonal therapy, radiotherapy,
surge~, and high dose analgesics. Each
of the traditional treatments has inherent
adverse reactions that significantly
impact the patient’s quality of life.
The use of radionuclides for palliative
therapy of bone malignancies, was
reported in the earliest days of the
nuclear era. Both Sr-89 and P-32 were
investigated in the early 1940’s. The
underlying principle of any form of
unsealed source therapy is that the
absorbed dose to the lesion should be
high enough to produce a significantclinical effect. The dose to the criticalorgan, usually bone marrow, should below enough to avoid significant adverseevents. The duration of response shouldbe prolonged and the onset should occursoon afier administration. In theory, theagent is incorporated into areas ofgrowing bone. Bone growth rate isslowed with the beta emission cellularablation. Slowing the metastatic boneinvasion will reduce the pain. Theappropriate administered dosage is
determined afier consideration of betaenergy, physical and effective half-lives.
17
The FDA approved Strontium-89 decay and avidly seek areas of growingchloride for bone pain palliation in 1993 bone. A comparison of the approvedand Sm- 153 Iexidronam in 1997. Both radiopharrnaceuticals used for bone pain
of these agents emit beta-particles during palliation is provided in Table 3.
103 keV gammaOnset of action 7-20 days 7 daysExcretion 66% renal, 33% fecal 1OOOArenalDosirnetry: bone surface 63 rad/mCi 26 rad/mCiDosimetry: bone marrow 40,7 rad/mCi 5,7 rad/mCi
Pharmacology, Biodistribution andDosimetry
Quadramet@ is a therapeutic agent ofradioactive samarium and atetraphosphonate chelator. The reactorproduced radionuclide emits three betas
and a 103 keV gamma ray. Quadramet@has an affinity for bone and concentratesin areas of bone turnover in associationwith hydroxyapatite with a lesion-to-normal bone ratio of approximately 5 to1. The bone surface is the critical organ
for Quadramet@, receiving 25 rads/mCi.The radiation dose to the red marrow,which receives a radiation dose of 5.7rads/mCi, limits the dosage ofQuadramet administered to a patient,The skeletal uptake varies with thenumber of metastatic lesions. A patientwith 5 lesions had a skeletal uptake of56% of the injected dose, while a patientwith 52 lesions had uptake of 76°/0 of theinjected dose. There is no metabolism of
Quadramet@. “Free” radiopharma-ceutical, which is not taken up by bone,is promptly excreted renally with lessthan 1% of the dose remaining in thebloodstream after 5 hours.
Handling ConsiderationsThere is no compounding of
Quadramet@, as it arrives ready foradministration from the manufacturer.Prior to dispensing, the product must bethawed at room temperature, havingbeen shipped and stored frozen. Theproduct expires 8 hours afier thawing or48 hours tier calibration, whichever isearlier. Those who handle Quadramet@should use radiation safety proceduresappropriate to beta emitting isotopes.Dose calibrators may need to be adjustedto accurately assay patient doses.Contaminated waste products should bestored separately from other isotopes
since Quadramet@ contains microcurieamounts of Europium- 154 with a half-lifeof 8.8 years.
Dosage and AdministrationA patient dose of 1 rnCi/kg
administered by slow IV injection isrecommended. The patient should bewell hydrated and urged to voidfrequently, There is a delayed onset ofpain relie~ usually 7 days post injection,Many patients have reported a transientincrease in pain followed by relief. This
“flare response” can be treated withanalgesics. Well-hydrated patients canbe imaged as soon as 6 hours post
injection.
No drug interactions have been studied,
but those drugs that interfere with
routine bone scans would most likely
alter the biodistribution of Quadramet@.
Adverse reactions include the “flare
response”, and reversible
myelosuppression. White blood cell and
platelet counts will decrease to a nadir of
40-50% of baseline within 3-5 weeks.
Blood counts should be monitored
weekly for at least 8 weeks, or until
recovery of adequate bone marrow
function.
As an adjuvant to traditional therapy,
Quadramet@ is effective in bone painmanagement in cancer patients. Sincemuch of the morbidity and mortalityassociated with cancer can be attributedto skeletal metastasis, any improvementin effective treatment for metastatic bonepain must therefore represent a majoradvance in cancer management.
Patient ConsiderationsPatient instructions following the
administration of Quadramet@ include
personal hygiene instructions similar tothose given following therapeutic dosesof I-131. Patients are instructed aboutthe importance of follow-up bloodcounts and cautioned to report signs orsymptoms that might indicate a fall inWBC or platelet count. (i.e., sore throat,bleeding or bruising, infection) It maybeadvisable to warn patients of the “flarephenomenon,” and its management withtraditional pain medications. Manyclinicians encourage patients to keep arecord of pain medication use, and theduration, intensity and frequency of their
pain. As Quadramet@ begins to providepain relief the patient’s use of othermedications should begin to decrease.
CONCLUSIONThe information presented in this article
is intended to provide a cursory overviewof the radiopharmaceutical productsreleased by the FDA in 1996-1997. Priorto dispensing or makingrecommendations about the clinical useof these products, the reader isencouraged to consult the manufacturer’spackage insert and nuclear medicineliterature for firther detail.
I
19
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Bogard WC, Dean RT, Vashwant D,Fuchs ~ Mattis JA, McLean AA,Berger HJ. “Practical Considerationsin the Production, Purification, andFormulation of MonoclinalAntibodies for Immunoscintigraphyand Immunotherapy. Semin Nut!Med ]989;] 9(3): 202-220,
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in Patients with Elevated Prostate-Specific Antigen: Positron EmissionTomography and Biopsy
Correlation.” Clin Nucl Med 1996;
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Sodee BD, Chalfant M, Miron S,Klein E, Bahvison ~ Spirnak P, etal. “Preliminary Imaging ResultsUsing In-1 11 Labeled CYT-356(Prostascint) in the Detection of
Babaian R, Lamki LM.“Radioimmunoscintigraphy ofProstate Cancer.” Semin Nucl Med
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Immunoscintigraphy Said to SurpassCT, MRI for Imaging ProstateCancer Patients,” Oncolo~ News[ntl, Vol 3, #5, May 1994
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Mardirossian G, Brill AB, DuyerKM, Kahn D, Nelp W. “RadiationAbsorbed Dose from Indium-lll -CYT-356.” J N~{cl Me~ 1996:37:1583-1588,
Verluma Package insert, DuPont,Billerica, MA revised Aug 1996.
Kasina S, Tripuraneni ~,Srinivas?n ~ Sanderson J~ FitznerJN, Reno JM, et al. “Developmentand Biologic Evaluation of a Kit forPreformed Chelate Technetium-99mRadiolabeling of an Antibody FabFragment Using a DiamideDimercaptide Chelating Agent.” JNz/clMed 1991:32:1445-1451.
19. 13alaban EP, Walker BS, Cox JV,Bordlee RP, Salk D, Abrams PC, etal. “Detection and Staging of Small
@Cell Lung Carcinoma with aTechnetium-labeled MonoclinalAntibody: A Comparison withStandard Staging Methods.” ClinN~{clMed1992;17 (6): 439-444.
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I)M, Stewati JR, Sonin AH,McCook BM, et al. “Staging LungCarcinoma with a Tc99m LabeledMonoclinal Antibody.” Clin NuclMed 1992;17 (6): 431-438.
Grebenau R, Blazejewski N, Kunz A,et al. “Preclinical Evaluation of an“Instant” ‘Tc-labeling Kit forAntibody Imaging.” CancerResearch 1990; (Suppl) 50: 794s-798s,
Doerr RJ, Abdel-Nabi H, Krag D,Mhchell E, et al. “RadiolabeledAntibody Imaging in theManagement of Colorectal Cancer.”Annals of Surgery 1991 ;214 (2):118-124.
Podoloff DA, Patt YZ, Curley S4Kim EE, Bhadkamkar VA, SmithRA. “Imaging of ColorectalCarcinoma with Technetium-99mRadiolabeled Fab’ Fragments.”Semin in Nucl Med 1993;23(2): 89-98.
Behr T, Becker W, Hannappel E,Goldenberg DM, Wolf F. “Targetingof Liver Metastasis of ColorectalCancer with IgG, F(ab’)z and Fab’Anti-Carcinoembryonic AntigenAntibodies Labeled with ‘Tc: TheRole of Metabolism and Kinetics.”Cancer Research 1995; (Suppl)
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Swayne LC, Goldenberg DM, Diehl
WL, Macaulay RD, Derby L4
Trivino JZ. “SPECT Anti-CEA
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occult Colorectal Carcinoma
Metastases.” Clin Nucl Mea’1991; 16:849-852.
Moffat F, Jr., Pinsky CM,
Hammershaimb 1, Petrelli NJ, PattYZ, Whaley FJ, et al. “Clinical
Utility of External
21
Immunoscintigraphy with H-4Technetium-99m Fab’ AntibodyFragment in Patients UndergoingSurgery for Carcinoma of the Colonand Rectum: Results of a Pivotal,Phase III Trial.” J Clin Oncolo~1996; 14 (8): 2295-2305.
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Miraluma Package insert, DuPont,Billerica, MA, Revised Jan 1997
Clifford EJ, Lugo-Zamudio C.“Scintimammography in theDiagnosis of Breast Cancer”. .4mer
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Iraniha S, Khalkhali I, Cutrone J~Diggles LE, Klein SR. “BreastCancer Imaging: Can Tc-99mSestamibi scintimammography fit in?fi)om a compilation of sol~rces onthe world wide web:Www.medscape, comfwomens. health~1997/v02.04.
Scintimammography to DetectPrimary Breast Cancer and Axilla~Lymph Node Involvement”. J NuclMed1995;36:1758 -1765.
Villanuevba-Meyer J, Leonard MH,Briscoe E, Cesani F, Alis A, RhodenS, et al. “Mammoscintigraphy withTechnetium-99m-Sestamibi inSuspected Breast Cancer”. J NuclMed 1996;37:926-930.
1. Which of the following factorscontributes to increasedlikelihood of HAMA formationfollowing IV administration?a. slow IV infusionb, use of chimeric antibody
productc. use of an antibody
fragmentd. harsh labeling conditions
2. Monoclonal agent XB has a
serum half-life of 90 minutes and
clears the blood pool veryrapidly. Imaging will beperformed shortly afieradministration. Which of thefollowing radionuclides would bemost desirable for labelingMonoclinal XB?
1-131:: Tc-99mc. Ga-67d. in-111
3, Staging of colorectal cancerinvolves the use of severaldiagnostic tests. Unfortunately,these standard diagnosticmodalities may miss metastasis ina, liverb. lower abdomenc. normal-sized nodesd. lungs
4. CEA-Scan is primarily eliminatedfrom the body via the
hepatobiliary system:: fecesc. urined. spleen
5.
6.
7.
8.
9.
Labeling of CEA-Scan involvesattaching Tc99m to the antibodyvia dan
characteristic of extensive smallcell lung cancer?
limited to one hemithorax:: spread of metastasisc. no distant metastasisd. 25% 2-year survival rate
VerlumaTM is indicated for thedetection ofa. limited small-cell lung
cancerb. non-resectable prostate
cancerc. extensive small cell lung
cancerd. small-cell lung cancer
without metastasis
Which of the following organsare considered to be part of thenormal biodistribution pattern
seen on VerlumaTM images?a. brainb. pancreas
thyroid:. bone
10. The compounding of VerlumaTMis labor-intensive and involvesseveral manipulations to achievelabeling. Which of the followingterms best describes thechemistry of the labelingreaction?a. isotopic exchangeb, transchelation reactionc. Iigand extractiond. substitution reaction
for use of ProstaScint@?Patient A: unconfirmedlocalized prostate cancerPatient B: rising PSAfollowing successfulprostatectomyPatient C: equivocal bonescan with unconfirmeddiseasePatient D: low suspicionof disease with rising PSA
of the following bestdescribes the elimination of
ProstaScint@ from the body?a. approximately 50%
excreted via kidneysduring first 72 hours
b, renal accounts for 25°/0during the first 24 hours
24
c. fecal accounts ultimatelyfor 25% of injectedactivity
d. fecal elimination accountsfor 50% of injectedactivity
14. is arecommended patient preparationfor a ProstaScintw study.
barium enema;: oral catharticc, NPO x 12 hoursd, CEA blood levels
15. What is the purpose for addingacetate to the InC13 vial prior to
labeling Prostascint@?Increase volubility
:: Decrease reaction timec. Minimize competitive
interferenced. pH adjustment
16. Whole body planar images areobtainedpost- administration of
ProstaScint@,
30-45 minutes:: 3-5 hoursc. 8-10 daysd. 3-5 days
17. The proper injection technique
for MiralumaTM includes injection
a. by rapid bolus IVinjection
b. into the arm proximal to
the suspected lesionc, into the arm contralateral
of the suspected lesiond. through a central line
18. The critical organ
is the
liver;: bladder
for Miraluma~
c. large intestine
d. bone marrow
19. The quality control test forMiralumaTM uses
ITLC-SA and acetone:: ITLC-aluminum oxide
plate and ethanolc. ITLC-SG and salined. ITLS-SG and methanol
20. Scintimammography using
MiralumaTM in a patient work-upis best described asa. an effective tool for breast
cancer screeningb. an effective method to
confirm malignancyc. a second line diagnostic
drug for use afier anindeterminatemammogram
d. a second line diagnosticdrug for use after physicalexamination
21. The usual dosage of MiralumaTMisa. 10-20 mCi
b, 20-30 mCid. 1-5 mCie. determined from patient
statistics
22. The purpose of the
tetraphosphonate chelator in
Quadramet@ isa. To sequester any Eu-154
contaminantsb. To bind samarium to
hydroxyapatite
c. To function as an 25
antioxidantd. To function as a reducing
agent
23. The dose-limiting organ for
Quadramet@ isred bone marrow
;: bladderf. large intestine
g thyroid
24. The recommended patient dosageof Quadramet isa. 4 mCi
b. 1.0 mCi/kgc. 0.57 mCi/kg
d. 20 mCi
When compared to Strontium-89,the recommended patient dosage a
of Quadramet@ is much higherbecause of itsa. shorter physical half-life
and higher energy betaemissions
b. shorter effective half-life,lower energy betaemissions and reduceddosimetry
c. shorter effective half-life,reduced dosimetry anddelayed onset of action
d, longer effective half-life,reduced dosimet~ andrapid onset of action
