SKELETAL SURVEY FOR METASTATIC TUMORS OFBONE USING 18F AND 85Sr WITH SCINTILLATION

CAMERA AND WHOLE-BODY SCANNER

Peter Ronai, H. S. Winchell and H. O. Anger

Donner Laboratory of Medical Physics, University of California, Berkeleyand Donner-Highland Radioisotope Unit, Highland Alameda Hospital, Oakland, California

Radioisotope scanning is able to detect metastaticlesions of bone before radiological changes or evenclinical symptoms are present (1-3). In most centers, clinical symptoms and radiological changes areused as the basis of selection of sites for scanning.Clearly, this approach will fail to detect asymptomatic or radiologically negative lesions. The effective detection of bone métastasesdemands that thedistribution of radioisotope in the entire skeleton bescrutinized. This is impractical with conventionalrectilinear scanners because of the time involved.The counting rate with 85Sr is low because of dose

limitations, and the scanning of even small areas canbe a long and, for the patient, a painful process. Theshort-lived radioisotopes 87mSrand 18F can be given

in relatively large doses, but even with the highercounting rates provided by these isotopes, rectilinearscanning of the whole skeleton is not practical.

The concept of the radioisotopic skeletal surveywas introduced by DeNardo, Horner, Leach andBowes (4) who used the profile scanner (5) todetect regions of abnormal activity after the administration of 85Sr and a conventional rectilinear scan

ner to examine the abnormal areas in detail. Insteadof a profile scanner, a rapid imaging whole-bodyscanner has been used in this laboratory to determine directly the skeletal distribution of 18F and85Sr. This device allows direct visualization of areas

of abnormal isotope uptake in the entire body in an11-min scan. Abnormal or suspicious areas on thewhole-body scan were then examined at high resolution with the positron/gamma scintillation camera.

The purpose of this paper is to show that withthese two instruments, a radioisotopic survey of theentire skeleton can be a simple, rapid and accurateprocedure.

MATERIALS AND METHODS

Radiochemicals. Each patient was studied with18F and S5Sr so that the efficacy of these twoisotopes when used with the whole-body scanner

and scintillation camera could be compared. 18F

was prepared according to the method of Thomas,Sondel and Kerns (6). It was administered carrier-free as sodium fluoride in physiological saline. 8BSr

was obtained from Squibb as strontium chloride inphysiological saline with a specific activity of 9.15mc/mg.

Instrumentation. Initial pictures of the distribution of each isotope were taken with the Mark IIWhole-Body Scanner. This instrument has been described in detail elsewhere (7). Collimation wasachieved with 64 Vi-in.-aperture straight-bore col

limatore. For more detailed pictures of abnormalareas the scintillation camera was used, operatingin the positron coincidence mode for 18F and in thegamma mode for 83Sr.This instrument has also beendescribed elsewhere (8). For 85Sr a multichannel

collimator with maximum design energy of 445 kevwas used. This was the highest-energy collimatoravailable and was not really adequate for the 514-kev gamma rays of 85Sr.

Patients were referred for the study because ofknown metastatic tumors of bone. The study wasaimed at delineating known lesions and detectingpreviously unsuspected ones. Patients were given500 /¿e18F intravenously, and the study commenced

1 hr later. In the interval patients were given threeglasses of water and asked to void twice since urinaryexcretion accounts for approximately 50% of theinjected activity and the bladder receives the highestradiation dose (9). When the I8F study was completed, patients were given 100 /¿c8r'Sr intravenously

and asked to return in 3 days. During the intervalthe patients took two doses of a mild laxative and

Received March 7, 1968; original accepted June 14, 1968.

For reprints contact: P. Ronai, Div. of Nuclear Medicine,Institute of Medical and Veterinary Science, Frome Rd.,Adelaide, South Australia 5000.

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RONAI, WINCHELL AND ANGER

were given an enema on the morning of the strontium study.

The scanning procedure was the same for bothradioisotopes. Eleven-minute whole-body scans weretaken. Only posterior views were taken in the earlystages of the study until it was realized that anteriorlesions were being missed. Thereafter both anteriorand posterior 11-min scans were performed. Thepatient was then moved to the scintillation cameraand photos of pelvis, hips, vertebrae and skull takenon each patient. Further photos were taken of anysuspicious areas noted on the whole-body scans.In the case of 18F, photos of the pelvis were taken

soon after the patient voided. Exposure times were2-3 min for 18F and 5-10 min for 85Sr.

RESULTS

A summary of results in five patients is presentedin Table 1.

TABLE 1. SUMMARY OF RESULTSFOR FIVE CASES

Case No. x-ray

Case 1R. hipL. shoulderR. ankle

Case 2L. tibiaL. ulnaR. ulna

Cas»3spinepelvisL. femurR. femurribsL. humérusR. humérus

Case 4D 8D 12L hipL. 7th ribR. 5th ribL. scapulaR. scapula

Case 5D 11D 12L 3L 5

L. femoral headL. femoral shaftR. acetabulumR. femoral shaft

* Whole body scon only.

FIG. 1. A-D are whole-body scans of Case 1 with metastatibreast carcinoma made with 1SF(A) and " Sr (C). Transmission scanwith ""Am taken simultaneously (B,D) show body outline. View iposterior in all cases. Patient's left is to left of page. 1SFscan show

lesion in left shoulder and right hip. Central bright spot in pelvis ibladder. Right ankle shows greater uptake than left. Uptake invicinity of large joints is greater than normal but symmetrical. Patient had suffered from arthritis for many years. "Sr scan shows

hip and shoulder lesions but not the increased uptake in the rightankle. Uptake at ends of long bones is normal for ""Sr. E is positron camera scintiphoto study of same patient (Case 1) with 18F.View is anterior. Patient's left is to the right of page. Left shoulder

lesion is in acromion process. Right hip lesion is in acetabulum.Uptake in right ankle is diffusely distributed over lower tibia andbones of foot. Uptake in knees is greater than normal but is symmetrical. F is gamma camera scintiphoto study of Case 1 after" Sr. View is anterior. Left shoulder lesion is poorly seen. Lesion

in right hip is unequivocal.

Case 1. A 53-year-old white female was admittedto Highland Hospital with a fracture of the righthip. A radical mastectomy had been performed 16years previously for adenocarcinoma of the rightbreast. For 6 months before the present admission

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**

FIG. 2. A-D are whole-body scans of Case 2 with pulmonarycarcinoma made with WF (A) and ^Sr (C). Transmission scans taken

simultaneously in each case (B,D) show body outline. View is posterior in all cases so that patient's left is to left of page. In T

scan increased uptake occurs in left elbow and left knee. In Srscan increased uptake occurs in right elbow and left knee. E contains ' F camera scintiphotos which show increased uptake in bothulnae and in left tibial tuberosity. F contains ""Sr camera scmti

photos and shows suggestion of increased uptake in left tibialtuberosity.

the patient experienced pain in the right hip andprogressive weight loss. Roentgenogram of the righthip showed a pathological fracture of the rightacetabulum and biopsy of this area confirmed thepresence of adenocarcinoma. A skeletal x-ray survey detected no other metastatic lesions, and shewas given radiation therapy to the right hip.

After the administration of 18F, whole-body scan

and positron scintiphotos demonstrated the right hiplesion and in addition areas of increased isotopeuptake were seen in the region of the acromionprocess of the left scapula and in the right ankle(Fig. 1A.E).

After the administration of S5Sr,whole-body scan

and gamma scintiphotos detected the hip and shoulder lesions only (Fig. 1C,F).

Subsequent radiological studies of the left shoulder and right ankle demonstrated replacement of theacromion process of the left scapula by tumor and"degenerative changes" in the right ankle. Biopsy

of the left shoulder lesion confirmed the presenceof adenocarcinoma.

Case 2. A 54-year-old white male presented in Oct.1967 with chest pain and hemoptysis. Chest x-rayshowed carcinoma of the right lung. Skeletal x-raysurvey was negative but pain in the back prompteda 85Srrectilinear scan of the dorsal spine which gave

equivocal results. At the time of the studies in thislaboratory back pain was no longer present.

The 18Fstudy (Fig. 2A,E) failed to show a lesion

in the spine. However, increased isotope uptakewas seen in the proximal ends of both ulnae and inthe left tibial tuberosity. Only the tibial lesion couldbe identified in the 85Sr study (Fig. 2C,F). Biopsy

of the left tibial tuberosity showed osteoporosis withno evidence of neoplasm. This patient subsequentlyhad resection of the carcinoma.

Case 3. A 60-year-old Negro male was admittedto hospital complaining of urinary frequency, noc-turia, dysuria and multiple aches and pains. Onphysical examination a small nodule was felt in theprostate and a hard enlarged lymph node in theneck. Biopsy of the lymph node showed adenocarcinoma and a skeletal x-ray survey demonstratedwidespread metastatic involvement of the spine,pelvis, femora and ribs.

18F studies (Fig. 3A,B,E) confirmed the exten

sive involvement of the spine, pelvis, femora andribs and in addition detected lesions in the upperends of both humeri.

In the 85Sr whole-body scans (Fig. 3E,D) count

ing rate was low and abnormal areas could not beidentified with certainty. In the 8IÃŽSrcamera study

(Fig. 3F) lesions were seen in both shoulders andhips. Unfortunately the study had to be discontinuedbecause of withdrawal of patient cooperation.

Case 4. A 55-year-old white female had a leftradical mastectomy in 1955 for adenocarcinoma. In1960 a local recurrence was treated by radiotherapy.In 1961 she developed pain in the right hip andleft chest and lost 20 Ib. Skeletal x-ray survey detected a pathological fracture of the left 7th rib andmétastasesin the 8th and 12th dorsal vertebrae. Shewas given 18,600 rads of alpha-particle irradiationto the pituitary. An x-ray survey in 1967 showedhealing of the rib fracture and little change in thevertebral lesions.

18F studies (Fig. 4A,B,E,F,) showed areas of in

creased uptake in the 8th and 12th dorsal vertebrae,the left hip the left 7th rib, the right 5th rib andboth scapulae. In the S5Sr studies (Fig. 4C,D,G,H)

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the left hip and rib lesions were seen but not the vertebral or scapular lesions.

Case 5. A 46-year-old white female had a radicalmastectomy for carcinoma of the left breast in 1963at which time axillary nodes were found to be involved. In 1965 back pain prompted a skeletal x-raysurvey which showed lesions in Dll, D12 and L3vertebrae and in the left femoral head. She wasgiven 17,000 rads of alpha-particle irradiation to thepituitary but back pain persisted, and she lost weight.However, at the time of the isotope studies in Feb.1968 the radiological lesions were unchanged.

In the 1SFstudy (Fig. 5A,B,E) areas of increased

isotope uptake were seen in Dll, D12, L3 and L5

FIG. 3. A-D are whole-body scans of Case 3 with melastaticprostatic carcinoma. A is ISF anterior scan and B is '"F posteriorscan; C is 'Sr anterior scan and D is 'Sr posterior scan. l"F scans

show lesions in femora, pelvis, spine, ribs and humeri. Sr scansshow no lesions that can be identified with certainty. E contains1SFcamera scintiphotos which confirm widespread metastatic disease

of skeleton. Lesions are present in femora, pelvis, dorsal spine andboth humeri. F contains ""Sr camera scintiphotos. Study is incom

plete but lesions are seen in both shoulders and both hips.

FIG. 4. A-D are whole-body scans of Case 4 with metastaticbreast carcinoma. A is '"F anterior scan and B is !"F posteriorscan; C is ""Sr anterior scan and D is ""Sr posterior scan. 18F scansshow lesions in left hip, left chest, and right shoulder. ""Sr scans

show lesion in left hip only. E and F are F camera scintiphotoswhich show lesions in left hip, dorsal spine (D8, D12), ribs on bothsides of chest and both shoulders. G and H are 'Sr camera scin

tiphotos which show lesions in left hip, ribs on both sides andright shoulder.

vertebrae, in the right acetabulum and upper shaftof the right femur and in the head and upper shaftof the left femur. The 85Sr study (Fig. 5C,D,F)

showed a lesion only in the dorsal spine.

DISCUSSION85Srdecays by electron capture with 100% 0.51-

Mev gamma emission and associated x-ray emissioncharacteristic of 85Rb. Radiation dose to bone has

been variously estimated at 1.5 rads/100 /¿e(10),2.3 rads/100 /¿c(11) and 4.6 rads/100 /*c (12,13). 18Fdecays by 0.65-Mev positron emission withassociated 0.51-Mev annihilation gamma rays. Radiation dose to bone has been estimated at 0.23 rads/me (14) and to bladder at 0.5-1.0 rads/200 ^ (9).

Strontium is a cation and exchanges with calcium ions in the hydroxyapatite crystal, whereasfluoride is an anión and exchanges with hydroxide(75). It has been suggested that strontium uptakereflects osteoblastic activity (7) and fluoride uptakereflects bone blood flow (9). The quantity of anisotope in bone at any time is the net result of

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deposition rate and résorptionrate. The depositionrate depends on vascular perfusion and on the fraction of the isotope cleared by the bone on a givenpassage of blood though the bone (extraction ratio).The deposition rate is therefore a measure of boneblood flow only when the extraction ratio is thesame throughout the skeleton. This latter conditionhas not been proven for either 18F or 85Sr.

The rapid disappearance of 18F from the bloodand the slower disappearance of 85Sr (76) cannotbe taken as evidence that 18F uptake measures boneblood flow while S5Sr uptake measures osteoblastic

activity. Like chloride, fluoride equilibrates rapidlywith the extravascular fluid compartment, and theinitial rapid clearance of fluoride from the bloodreally represents a mixing phase. The slower disappearance of R5Srfrom the blood is probably related

to binding of strontium to plasma proteins (in muchthe same way as calcium is bound) and to the morerapid urinary excretion of fluoride. Behavior of thetwo isotopes at the bone level is in fact remarkablysimilar. Spencer, Herbert, Rish and Little (17)found no difference in the concentration of strontium and fluoride in fractured and normal ratfibulae up to 3 hr after injection. French and Mc-Cready (16) found identically shaped uptake curveswhen 87mSrand 18Fwere injected simultaneously and

uptake into a femoral bone tumor measured overVI hr.

Possibly the major difference between the distribution of the two isotopes in the skeleton in thepresent study relates to the fact that scans are taken1 hr after 18F administration and 3 days after 85Sr

administration. If there is significant feedback ofstrontium from certain bone lesions back into theblood, the distribution of 85Sr could be considerably

altered over 3 days. This could explain at least inpart why some lesions visualized with 18F are missedwith 85Sr and why scanning at 1 hr with 87mSrismore successful than at 3 days with 85Sr (77).

Admittedly the 8r>Srscintiphotos were technicallypoor because the gamma-ray energy of the isotopeexceeded the design energy of the collimator. Forthis isotope, the whole-body scanner or a specialhigh-energy rectilinear scanner would be the instruments of choice. However, a valid comparison of thetwo isotopes could be made in the whole-body scansbecause the gamma-ray energies were virtually identical and the same collimation method was used forboth isotopes. In the whole-body scans, fewer lesionswere detected with 8r'Sr than with 18F. At least someof the additional lesions detected by 18F were radio-

logically confirmed metastatic lesions (see Cases 3,4 and 5).

This study also coi.firms the findings of others

-

FIG. 5. A-D are whole-body scans of Case 5 with metastaticbreast carcinoma. A is ' F anterior scan and B is F posteriorscan; C is Sr anterior scan and D is Sr posterior scan. ' 'F scans

show lesions in multiple areas of spine, right hip and upper femurand left upper femur. Sr scan shows lesion in right hip only.Uptake in other joints is normal for Sr. E contains F sc'nli-

photos with lesions in DU, Dl2, 13, L5, right acetabulum, rightupper femur, left femoral head, and left upper femur. F contains"Sr scintiphotos which show lesion in D12 only.

(1—3)that radioisotope scanning can detect bonemétastasesbefore x-ray changes are found. In Case 1the left shoulder lesion was detected radiologicallyonly in retrospect. In Case 3 the humen were radio-logically normal but strikingly positive in the 18F

scintiphotos. The same applies to the left hip lesionin Case 4 and the lesions in L5 and both femora inCase 5. Since increased 18F uptake is seen in non-

metastatic lesions as well as metastatic lesions (9),it is possible that some of these radiologically negative lesions were non-metastatic (e.g. the tibial lesionin Case 2). It seems most unlikely, however, thatthey were all non-metastatic. In this particular studyit was difficult to justify the biopsy of lesions in pa-

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RONAI, WINCHELL AND ANGER

tients with known multiple métastases.In any case,18F scanning and scintiphotography serve not to

make a definitive pathological diagnosis, but to indicate areas for careful radiological assessment and,if necessary, biopsy.

SUMMARY

While no attempt has been made in this study toaccumulate a series large enough for statistical analysis, it can be concluded that:

1. A rapid radioisotopic skeletal survey is feasible using 18F, the whole-body scanner and the

positron scintillation camera.2. A larger number of bone lesions can be de

tected with 18F than with either conventionalskeletal x-ray surveys or 85Sr radioisotopic

skeletal surveys.3. 18F is taken up by both malignant and non-

malignant lesions of bone and the 18F skeletal

survey primarily serves to indicate areas forcareful radiological assessment and, if necessary, biopsy.

4. Since 85Sr radioisotopic skeletal surveys have

previously demonstrated the capability of detecting metastatic bone lesions in the absenceof radiologie changes and since the presentstudy strongly suggests the superiority of 18Fover 85Sr in this regard, we propose that 18Fskeletal survey using a whole-body scanner andpositron camera is the most efficient means yetdeveloped for detection of metastatic bonedisease.

ACKNOWLEDGMENTS

This work was supported in part under AEC contract# W-7405-ENG-48. Peter Ronai's work was supported by

a Winston Churchill Memorial Fellowship.The authors wish to acknowledge the invaluable aid

provided by Dr. Fish of the Palo Alto Medical Clinic, PaloAlto, Calif., Dr. Linfoot of the Donner Laboratory, Drs.Parker and Tenny of the Highland-Alameda Hospital, Oakland, California in referring and clinically evaluating thepatients reported in this study.

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