SOME EXPERIENCE WITH 57Co-LABELED BLEOMYCIN …jnm.snmjournals.org/content/16/11/1058.full.pdf · SOME EXPERIENCE WITH 57Co-LABELED Bleomycin labeledwith @@Cowasusedasa tumor-localizing

SOME EXPERIENCE WITH 57Co-LABELED

Bleomycin labeled with @@Cowas used as atumor-localizing agent in 132 patients. In patients with pulmonary tumors the primary tocausation concentrated radioactivity in 52 ofthe 54 appropriate cases; out of the 22 dm1-catty known metastases, 19 were visible on thescan; 40 unknown metastases especially in hilus

and mediastinum were found by this methodand subsequently confirmed. In 22 patients withmalignant lymphomas, 18 out of 22 knownpathologic lymph glands above the diaphragmwere visible on the scan; below the diaphragmthe results of scanning in lymph glands andspleen were disappointing, probably because ofthe disturbing concentration of radioactivity inthe kidneys, the bladder, the liver, and sometimes the gut. In 25 patients with various othertumors, 16 out of 22 known localizations above

the diaphragm were visible; 2 were uneertainand 4 negative. Below the diaphragm the resultswere usually negative. In 24 patients with benign lesions, uptake of 57Co-bleomycin was visible on the scintigram in 4 patients with cavitating pulmonary tuberculosis, in 2 withpulmonary infections, in 1 with Caplan lesions

of rheumatoid arthritis in the lung, and in 1with sinusitis ethmoidalis. The significance ofthese results is discussed.

Since the introduction of radioactive agents intomedicine, investigators have been looking for materials that selectively concentrate in malignanttumors. In 197 1 Nouel, et al (1 ,2) published the firstpromising results with 57Co-labeled bleomycin as atumor-seeking agent. Others were able to verify theseresults in two small series of patients with variouskinds of tumors (3,4) : in liver metastases using asubtraction technique (5) , in liver tumors (6), andin brain tumors (7) , all with good results. In patients with malignant melanomas and other epidermal tumors the results were variable or disappoint

ing (8,9). The purpose of our investigation was tore-evaluate these findings because of their importantclinical implications.

Bleomycin, a group of antibiotics with antineoplastic properties that is derived from Streptomycesverticullus, was first isolated in 1962 (10). Thematerial consists of basic sulfur-containing glycopeptides and can be separated by paper chromatography into two fractions, A and B. Further separationby column chromatography gives 19 subfractionswith a common structure called bleomycinic acid(Fig. 1, where R = OH). They differ in their terminal amine moiety, R (1 1 ) . More than 100 artificial bleomycins have been produced. Bleomycinpreparations chelate copper and are obtained fromculture ifitrates as copper-containing complexes. Before clinical use, most of the copper is removed fromthe crude material by treatment with 8-hydroxyquinoline.

Within an hour bleomycin concentrates in normalskin, lung, several kinds of tumors, and probably inthe liver and kidneys ( 1,11â€”13) . This selectivity isexplained by different concentrations of inactivatingenzymes in the various tissues. Blood clearance wasinvestigated in five patients : 20 mm after injection1 liter of whole blood contained 8% (s.d. 4) ofthe injected radioactivity, after 5 hr 1.9% (s.d. 0.4),and after 18 hr 0.1% (s.d. 0.1). These findingsagree with Nouel (2) and Grove (14).

Cobalt-57-bleomycin is excreted mainly by thekidneys : 54% of the dose is excreted within 6 hrafter injection, 82% within the first 24 hr, another7% from 24 to 48 hr after injection, and 1â€”2%from 48 to 72 hr (Table 1). Others found aboutthe same excretion pattern of bleomycin as measured by radioactivity (1,14â€”17) or bioassay (18,19).During the first 12 hr about 99% of the urinary

Received April 20, 1975; revision accepted July 8, 1975.For reprints contact: M. G. Woidring, Isotopenlabora

torium der Rijksuniversiteit te Groningen, Groningen, TheNetherlands.

1058 JOURNAL OF NUCLEAR MEDICINE

BLEOMYCIN AS A TUMOR-SEEKING AGENT

J. J. Rasker,M. A. P. C. van de Poll, H. Beekhujs,M. G. Woldrjng, and H. 0. N@eweg

University Hospital, Groningen, The Netherlands

by on July 31, 2019. For personal use only. jnm.snmjournals.org Downloaded from

http://jnm.snmjournals.org/

FIG. 1. Structureofbleomycin.TABLE

1. EXCRETIONIN THEOF

57Co-BLEOMYCINURINEPercent

of injecteddoseTimeNumber

ofpatientsMeans.d.0â€”6

hr0â€”24hr

24â€”48hr48â€”72hr7

249254.4

20.581J 20.66.8 4.81.5 0.5

RADIOCHEMISTRY AND RADIOPHARMACEUTICALS

NH2

0

0

H0@

Structure of Bleomycin(R:termina( amine)OH

0@A2: R NHCH2CH2 CH2SZ@'@

+ CH3

B2: R NHCH2CH2CH2CH2NHC@@@NH2

Bleomycinic acid: ROH

MATERIALS AND METHODS

Cobalt-Si was obtained as 57CoC12,carrier free,3 mCi/mI in 0.5 N HQ from Philips-Duphar, Petten,The Netherlands. Bleomycin was kindly supplied byLundbeck N.y., Amsterdam, who obtained it fromNippon Kayaku Co., Tokyo. Batches 72 L 21 and72 I 05 were used, with a potency of 15.8 and 15.1mg per vial, respectively, containing the followingpercentages for the two batches : copper, 0.005â€”0.003; A1, 3.9â€”1.7; B1, 0.3â€”0.3; A2, 64.5â€”65.8; A'2,0.4â€”0.0; B2, 29.8â€”30.4; B4, 0.0â€”0.5; A5, 1.1â€”1.5.The totals for the B group were 30.1â€”31.2. The materials were supplied as sterile lyophylized powdersin 5-mi ampules.

Labeling procedure [see van de Poll, et al (30)].To 1 ml of 5TCoCl2in 0.5 N HQ, 7.5 mg bleomycin in1 ml 0.9% sterile NaCl, 2.5 ml 0.1 M acetate buffer(pH 5.6), and, under vigorous stirring, 0.5 ml 1 NNaOH are added. The pH of the end product is between 5 and 6. For each patient about 1 mCi 57Cobleomycin containing about 2.5 mg bleomycin wasslowly injected intravenously within a few hours afterpreparation of the compound.

Radiochemical purity. This is determined by paperelectrophoresis (Cellulose acetate, 0.05 M acetatebuffer, pH 5.6, 32 V/cm, 10 mm) and thin-layerchromatography (Kieselgel 60, Alufolie N 20 X20 cm, Merck) ; as eluent, ammonia acetate 10%solution in water and methanol 1: I . In this systemthe R@of 5TCoC12is 0.

NH2

radioactivity is 57Co-bleomycin; after this time thepercentage of free 57Co2+ ions in the urine graduallyrises until it is about 20% in the urine excreted between 24 and 48 hr (20).

As an antineoplastic agent, bleomycin has beenused with significant response rates in the treatmentof many kinds of tumors (21â€”24), including lymphomas (25), epithelial carcinomas of the skin (26),the oropharynx, the head and neck, and the lungs.

The tumor-localizing mechanism by 57Co-bleomycm is still unclear. In tumor and liver tissue 57Cobleomycin is preferentially accumulated in the lysosomes (27) and not in the nuclear fraction. Taylor(28) found a lysosomal and intranuclear accumulation in tumor cells. From the literature (29) it isknown that bleomycin attaches itself to DNA, andit is tempting to suppose that this is important in thetumor-seeking mechanism of 57Co-bleomycin.

Volume 16, Number 11 1059



CorrelationwithfreeTissuesFrequency Time Intensity

RASKER, VAN DE POLL, BEEKHUIS, WOLDRING, AND NIEWEG

TABLE 2. CONCENTRATION IN NORMAL ORGANS AND TISSUES

KidneysBladderLiverThyroidIntestinal tractSpleenBoneSalivary glandsHypopharynxJointsHealing wounds

AlwaysAlwaysAlways35.'.SometimesZeroZeroSometimesAlwaysSometimesSometimes

First 72 hrFirst 24 hrPermanentFirst 24 hrFirst 48 hr

HighHighVariableSlightVariable

+++

First 24 hrFirst 48 hrFirst 48 hrPermanent

SlightSlightSlightVariable

+

+

S@ indicates more than 0.5Â°!..

analyzer for calculating the tumor-to-nontumor(T:NT) ratio. The total number of counts was calculated in a region of interest within the tumor andin one or more regions of equal size around the tumor(usually the regions above and below) or in a corresponding region on the contralateral side of thethorax. From these figures the T:NT ratio was calculated as the ratio of the tumor counts to the meanof the neighboring or contralateral activity.

Interpretation. All scintigrams were interpretedby two of the investigators (JJR and HB). Whenopinions differed the result was called uncertain; thisis noted in the tables where applicable.

All patients were inpatients of the University Hospital, Groningen, mostly in the Department of Intemal Medicine (Prof. E. Mandema, M.D.).

THE NORMALSCINTIGRAM

Concenfration in normal organs and tissues (Table 2). In all patients a high concentration of 57Cobleomycm was found in the kidneys, especiallywithin the first 72 hr, and in the bladder, mainlywithin 24 hr. In all patients the liver showed concentrations of varying intensity, especially high whenthere was more than 0.5% free 5?Co2+ in the injected solution (Fig. 2) . This seemed to be a quantitative relationship. In the thyroid a slight concentration was found in about 35% of the patients,especially within the first 24 hr and if there was morethan 0.5% of free 5TCo2@ in the radiopharmaceutical. In the intestinal tract slight concentration wasfound, especially in the colon, in about 25 % of theinvestigated patients : this also correlated with thepercentage of free 57Co2+. In the absence of constipation, the intestines were free of radioactivityafter 48â€”72hr. We have never seen uptake in normalspleen or bones. In the salivary glands we occasionally saw a slight concentration together with scantyuptake in the region of the hypopharynx. In thecostosternal cartilages and the humeroscapular joints

METASTASIS

LIVER

K I DN EYS

FIG.2. Patientwithmetastasisin firstlumbarvertebrafromanaplastic carcinoma of unknown origin. Anterior scintigrams ofthoracic and abdominal regions show radioactivity in normal liverand kidneys and, unexpectedly, in left retroclaviculararea. Lumbarmetastasiscannot be distinguishedon this anterior scintigram; pa.tient was too ill to permit posteriorscintigram.

Scintigraphy. A scintillation camera (Searle Radiographics HP) with a parallel-hole collimator(15,000 holes), or with a Divcon diverging collimator,was used. Photographs were taken 24 and/or 48 hrafter injection, sometimes even after 72 or 96 hr.A triple-lens Polaroid camera was employed, with10 mm of preset time. When the counts appearedto be less than 10,000, an exposure of 15 or 20 minwas used until at least 10,000â€”15,000 counts wereregistered. All images were obtained by the sametechnique, regardless of the area scanned. Datawere also stored in a 4,096-channel dual-parameter




SurgicallyUntreatedtreatedMetastasesLocalization(A)(B)(C)Primary

localization5OÂ°t2$2Â°

NewlyfoundKnownLocalizationmetastasesmetastases


FIG.3. Patientwithbronchialcarcinomainleftupperlobeand catingclavicles;and(C)leftlateralviewof skullshowingradiometastasisin brain. (A) Anterior scintigramof thorax showsradio- cobalt activity in brain metastasis (line indicates border ofactivity in tumor; (B) anterior scintigram of thorax with lines mdi. skull).

MetastasesHilusMediastinumLungSupraclavicularBrainLiverOrbitSpineElsewhere

13Â°10Â°4*2Â°4*2Â°

3.2Â°3*2Â°

3.2Â°3.25 15

1Â°2Â°1Â° 2Â°

. Definite abnormal focus of activity at site.t Inoneof thesepatientstheprimarysiteofanoat-cell

carcinoma has never been found.$ Uncertainwhetheruptakeis significant.S Noabnormalfocusof activity.IILocalrecurrence.

slight concentration was seen in about 30% of thepatients (Fig. 3) . This was the case especially whenthere was more than 0.5% of free 5TCo in the injected solution; some other joints were visible inpatients with rheumatoid arthritis. A healing woundsometimes concentrated 57Co-bleomycin; this difficulty was avoided by performing our tests beforeoperations such as a mediastinoscopy.

It is very easy to recognize the concentration inkidneys, bladder, and liver; if the concentration inthe colon makes interpretation difficult, one mayrepeat the scanning procedure after 1 or 2 days, ifnecessary, after purging. The other localizationsrarely presented problems in interpretation : the concentration of radioactivity was slight and never exceeded 1.5 times that in the surrounding tissue; thisratio is usually less than 1.2S.

HilusMediastinumLungSupraclavicularBrainLiverSpineGroin lymph glandFemurOrbitAxilla

1413324

2

5

72

3*

Totals 40 19 3Â°

* No abnormal focus of activity; all others had definite

abnormal focus of activity at site.


TABLE 3. GROUP I(PULMONARYTUMORS,63 PATIENTS)

A Untreated bronchialcancerPlanocellular carcinoma 30Oot.cell carcinomaÂ° 6Not further dassified 15Carcinoma solidum 1Adenocarcinoma 1

Total 53

B Surgicallytreated bronchialcancerPlanocellular carcinoma 5Not furtherclassified 1

Total

C LungmetastosesAdenocarcinoma of colon 1Adenocarcinoma solidum 1Mammary carcinoma 1Planocellular rhinopharyngeal

carcinoma 1

Total 4

S In one of these patients the primary tumor in the lung

hasneverbeenfound.

TABLE4. GROUP I(PULMONARYTUMORS,63 PATIENTS)

TABLE 5. GROUP I(PULMONARYTUMORS,63 PATIENTS)



HodgkinsdiseaseReticulosarcomaLocalization

(11 patients)(8 patients)

RASKER, VAN DE POLL, BEEXHUIS, WOLDR.ING, AND NIEWEG

&

FIG.4. Patientwithplanocellularcancerofleftlung.(A)Chestx-ray; (B) anterior scintigram of thorax showing radioactivity intumor and mediastinum (at operation malignant tissue was found

in the mediastinum); and (C) same scintigram with lines markingright axilla, clavicles, and outline of neck. Chest x-ray was inconclusive.

FIG.5. Patientwitholdtuberculousscarinleftupperlobeoflung. (A) Chest x.ray; (B) anterior scintigramof thorax showsradioactivity in lesion (first indication of malignancy in addition to

CLINICAL RESULTS

scar; at operation planocellular cancer was found); and (C) samescintigram with lines marking axillae and neck. Pertechnetate studyhad been inconclusive.

TABLE 6. GROUP IIA (LYMPHOMAS)Based on a preliminary investigation, we divided

the 132 patients into four groups for the sake ofconvenience: Group I, pulmonary tumors (63 patients) ; Group II, lymphomas (22 patients) ; GroupIII, various tumors (25 patients) ; and Group IV,benign disorders (24 patients).

Group I. This group was divided into three subgroups (Table 3) : (A) Untreated patients withbronchial cancer (the primary site for one of theoat-cell carcinomas was unknown, the diagnosisbeing made on metastases) ; (B) patients who hadbeen treated surgically for their primary lung cancerand presented one or more metastases or a localrecurrence; and (C) patients with metastases in thelung from a primary tumor located elsewhere. (Thepatient with mammary carcinoma had been operatedon and given radiotherapy; the adenocarcinoma of

Above diaphragmNeckTonsilSupraclavicularAxillaMediastinum

2Â° 3f 4Â°

1. it 3Â°5* 1*

8Â°* 4t 10Â°4:BeneathdiaphragmPara-aorticInguinal

2f 15 2t1Â° 15

2t 1Â° 25 2t4f 1Â° 2t (1correct)Spleen

.Definiteabnormalfocusofactivityatsite.t No abnormalfocusof activity.$ Of these 18 positivefindings4 were not anticipated.




AbdominalPatientslocations Elsewhere


the colon had been removed surgically 3 years before; lymph nodes of the rhinopharynx cancer hadbeen removed previously and thereafter the neck wastreated with radiation.)

The results of Group I are summarized in Table 4.In the scintigrams the primary tumor was clearlydistinguishable in 52 of the 54 appropriate cases(96.3 % ). In two cases only slight concentration wasvisible; these concerned one small planocellular cancer and one spindle-shaped adenocarcinoma, 1.5 X0.5 cm.

Of the metastases known at the time of the studywith 57Co-bleomycin, 19 showed high concentrationof radioactivity whereas 3 did not. These concernedtwo metastases from a planocellular cancer withdiameters of 0.5 and 1 cm, respectively, and onemetastasis from an adenocarcinoma of the colonwith a diameter of 1.5 cm.

We diagnosed 40 metastases that had not beendetected previously by radiologic procedures (tomography, bronchography, etc.). These metastases werelocated mainly in hilus and mediastinum (Table 5).They were later confirmed by clinical followupstudies, mediastinoscopy, thoracotomy, etc. (Figs.3 and4).

The T:NT ratio of the primary tumor was estimated in 32 patients, and the average was 2.9 (s.d.1.2) . The primary tumor-to-liver ratio was investigated in 11 patients, and the average was 1.4 (s.d.0.7).

Several times the 57Co-bleomycin scan providedthe first hint that the case involved a malignanttumor of the lung (Fig. 5). In two cases a brainmetastasis could be visualized clearly whereas ascintigram with Â°Â°â€˜Â°Tc-pertechnetatehad been inconclusive.

Group II. This group was subdivided into (A)patients with Hodgkin's disease ( 11 patients) orreticulosarcoma (8 patients) and (B) patients withchronic leukemia (2 patients) or lymphosarcoma (1patient).

The results of Group hA are summarized in Table 6. They appear to differ above and below thediaphragm. As a rule the involved glands above thediaphragm were clearly distinguishable from thebackground: 18 showed up plainly (4 of these hadbeen unknown until then) and 4 did not. Of the fournegative glands, three had almost disappeared clinically after radiotherapy (lymph glands in the neck)and cytostatic treatment (glands in neck and axilla).The T:NT ratio estimated in five patients was 1.8(s.d. 0.3).

Below the diaphragm the involved glands as arule were hard to see. Of the locations clinicallyknown, four were indistinguishable from the back

TABLE 7. GROUP Ill(VARIOUS TUMORS, 25 PATIENTS)

AUntreoted (11) 6tB Treated (7) ifC Unknownprimary tumor (7) if

is 7f

7. 2f

5* 2t 2f4.

16Â° 4t 2$Total 25 patients

* Definite abnormal focus of activity at site.

t No abnormalfocusof activity.:$:Uncertainwhether uptake was significant.

ground, two were dubious, and only one was clearlyvisible. In the spleen scans, the results were alsodisappointing. We examined the spleen preoperatively in eight patients : four with Hodgkin's diseaseand four with reticulosarcoma. The spleen of onepatient with reticulosarcoma showed high concentration of radioactivity, and necropsy confirmed ourinterpretation that the large spleen consisted almostwholly of sarcoma tissue. None of the spleens ofthe other patients produced visible uptake, butsplenectomy showed six of the seven spleens to beneoplastic. In Group II no false-positive results wereobtained.

We gave 57Co-bleomycin to five patients withHodgkin's disease to see if there was local recurrencein the mediastinum after radiotherapy and cytostatictreatment. It is often difficult for the clinician to differentiate between radiation-induced fibrosis and alocal recurrence, especially when the site is hilar ormediastinal. In four cases there appeared to be localconcentration of 57Co-bleomycin, and local recurrence was later confirmed clinically. In one case therewas no concentration of radioactivity, and there isstill no evidence of recurrence after more than 6months.

In Group IIB the involved gland of the patientwith lymphosarcoma was surgically removed in toto,the 5TCo-bleomycin scan was negative, and in spiteof extensive clinical search no other tumor sitescould be found. In the two patients with chroniclymphatic leukemia a lymph gland in the neck andone in the mediastinum showed high concentrationof radioactivity, but large glands in the axilla and thesupraclavicular area were not visible in the scan. Theabdominal lymph glands and an inguinal gland alsocould not be visualized.

Group ifi. This group was divided into three subgroups: (A) patients ( 11) with untreated tumors;(B) patients (7) after surgical removal of a primarytumor, with metastases elsewhere (three of thesepatients had also been irradiated or had receivedcytostatics for the metastases before the 57Co




â€˜I,..@@-

\

p..

ResultsofscanNoAbnormalabnormalfocus

offocusofLocalizationactivityactivity

ResultsofscanNoAbnor

abnormalmalfocusfocusofofUncer.Localization

activityactivitythin


ences between the abdominal region and elsewhere;these were attributed to obscuring uptake in normalorgans.

In Subgroup lIlA it appeared impossible to visualize any of the six primary tumors below the diaphragm (Table 8). As a rule neoplasms elsewherewere greatly visible (Fig. 6). Only a malignant melanoma of the eye, smaller than 1 cm in diameter, andone of the metastases from a planocellular cancerof the fossa of Rosenmiiller in lymph glands in theneck could not be seen.

In Group IIIB (Table 9) a metastasis from ahypernephroma, in the first lumbar vertebra and thusagain below the diaphragm, was not visible on thescan. Tumors elsewhere usually gave good contrast.A metastasis from a breast carcinoma in a lymphgland in the neck, less than 1 cm in diameter, showedonly slight concentration (T:NT ratio, 1.5). Oneof the metastases in the lung from a neuroblastomawas less than 1 cm in diameter and did not showconcentration; this patient had been treated withcytostatics before our investigation. The nonconcentrating metastasis in C4 from the basocellular cancerof the orbit had been treated with radiation. Onepatient had been operated on for a malignant melanoma of the eye and had no sign of recurrence whenwe performed the investigation with 5TCo-bleomycin;the scan did not show any abnormal uptake.

BeneathdiaphragmCarcinomaof body of the

stomachPlasmocytomaof 5th lumbar

vertebraExtraosseousplasmocytoma

of perirenal tissueUndifferentiatedtumor in

duodenumChordomain 2nd and 3rd

lumbar vertebraeNeuroblastomaof right adrenal

glandElsewhere

Malignant melanoma of eyeBasocellular carcinoma of orbitRhabdomyosarcomaof ethmoidbone(Fig.6)

Planocellularcarcinomaof lymphgland metastases

Nasopharynx carcinoma withskin metastases

Neuroblastomawith cerebralmetastases

1

3

. -s.: :@. :@@@ â€¢

5@.@.... .:

#@: .@ ,P

@ â€˜@t: â€¢@ @.

Beneath diaphragmMetastatichypernephroma

in 1st lumbar vertebraElsewhere

Carcinomaof solidummammaeLung metastasesLymph gland metastases

Metastatic mammarycarcinoma in lymphgland ofthe neck

Basocellular carcinoma oforbit

Brain metastasesMetastatic In 4th cervical

vertebraWilms' tumorwith lungmetastases

Hypernephroma with brainmetastases

Malignant melanomaof eye(no known metastasis)

1

1 1

FIG.6. Anteriorscintigramof skullof7-month-oldchildwithsevereright exophthalmosshowsradioactivityin regionof righteye.At surgeryrhabdomyosarcomawasfound.Skullis outlined.

bleomycin investigation) ; and (C) patients (7) withan unknown primary tumor, the known metastaseshaving been treated by surgery, cytostatics, or radiotherapy.

The results of Group III are summarized in Table7. In this group also the scans showed great differ

1 (correct)


TABLE 8. GROUP lIlA(UNTREATED TUMORS)

TABLE 9. GROUP IIIB(PRIMARY TUMOR SURGICALLY REMOVED)



OrganUptakeTimeÂ°Radiationdose

(rads)Liver5Â°!.T112

= 5days0.4Kidneys100%T11,

5hr2.0Bladder50%

30%15Â°f.

501*T3hr

T9hrT12hrT2.Sdays1.4

Concentrationon thescanNoAbnor

abnor.malmalfocusfocusofofUncer

activityactivitytam

Total body 0.09

ResultsofscanNoAbnor

abnormalmalfocusfocusofofUncer

activityactivitytam


In seven cases (Group IIIC) we were not successful in locating the primary tumors (Table 10).Even after a followup period of 1â€”2years, however,the primary tumor has not been located in any ofthese patients. In four cases there were no clinicalsigns of tumor growth at the time of our investigation (presumably as a result of therapy) nor did wefind any uptake of 5TCo-bleomycin. The remainingthree patients had clinically demonstrable metastases.One patient's first@ lumbar vertebra concentrated57Co-bleomycin only slightly more than the surrounding tissues and in two cases the remainingmetastases showed high concentration even afterirradiation (Fig. 2).

Group IV. The patients of Group N (Table 11)were referred to us to determine whether a clinicallydiscovered abnormality (as a rule in the thorax)was malignant or not. Further clinical study revealedbenign disorders. In 16 cases the abnormality didnot take up 5TCo-bleomycin. In one patient the concentration was slight, and in eight it was definite. Infour patients a very active tuberculous cavity wasfound at thoracotomy; the primary lesions wereclearly visible by scintigram, and in three of the fourthe hilar glands as well. The T:NT ratio in two of thecases was 2.2. One patient with rheumatoid arthritis,silicosis, pulmonary fibrosis, and Caplan lesions inthe lungs showed good concentration in the Caplan

TABLE 11. GROUP IV(BENIGN DISORDERS,24 PATIENTS)

Pulmonaryembolism 2Sarcoidosis 1Postpneumonicabnormalities 1Lobusvenae azygos 1Bronchiectasias 3Bronchiectasiasand atelectasisOld tuberculousscars 2Liver abscess 1Subphrenic abscess 1Abnormal liver scanwith

mmTc.colloid 1Exophthalmos of the eye of

unknownoriginÂ° 3Sinusitis ethmoidalis 1Cavitating lung tuberculosis 4Caplan lesions 1Untreated infection in atelectatic

pulmonary segment 2

* One of these patients had the sinusitis ethmoidalis men

tioned here.

TABLE 12. RADIATION DOSE OF1 mCi 57Co-BLEOMYCIN

TABLE10. GROUPIIIC(PRIMARY TUMOR UNKNOWN)

Clinically no sign of tumorgrowth

Carcinomasolidum(treatedwith cytostatics)

Lymphgland metastasesfromplanocellular carcinomaÂ°

Adenocarcinoma lymph glandmetastasesÂ°

Clinically apparent metastasesOne undifferentiated

carcinomaMetastasisinfirstlumbar

vertebraRetroclavicular metastasis

One anaplasticcarcinomasolidum with metastasisin humerus

One sarcomaMetastasisin femurMetastasis in lung

* Metastasis surgically removed.

80% T112= 5 hr20% T11,= 5 days

2

S Given exponential decay the radiation time T equals

1.44 times the biologic half-life, T112.

lesions (T:NT ratio, 2.8 ) . In two patients untreatedinfection in an atelectatic pulmonary segment accumulated 57Co-bleomycin.

GENERAL REMARKS

Tumor size. The smallest tumor detected was ametastasis from a breast cancer: a lymph node in theaxilla 0.5 cm in diameter. In the thoracic region our57Co-bleomycin technique visualized all clinicallyknown and many unrecognized tumors with diameters of more than 1.5 cm.




..,@ ..B_@@@@CI


Adverse reactions. It is known that in 10â€”50%ofthe patients, especially in those with lymphomas, afebnle reaction with shock or even death may followthe first injection of bleomycin in therapeutic doses.In one patient with a reticulosarcoma we saw a shaking chill, fever, and shock several hours after theinjection of 57Co-bleomycin, and blood cultures werepositive for bacteria. Apart from this our patientsshowed no fever, nausea, vomiting, or anorexia. Onepatient with a planocellular cancer in the lung cornplained of pain in the tumor region the night afterthe 5TCo-bleomycin injection. Such reactions afterbleomycin are also described in the literature (24),and this was actually one of the reasons why peoplestarted to evaluate bleomycin as an agent for tumorlocalization (31).

Radiation dose. The maximum whole-body dosefor 1 mCi 5TCo-bleomycin was calculated to be 0.09rads (Table 12) . Nouel (1 ) calculated 0.5 rads andGrove (14) 0.03 rads. The critical organ is the bladder wall, which receives a maximum dose of 1.4 rads[Grove (14) calculated 0.45 rads]. The maximumradiation dose to the liver was 0.4 rads and to thekidneys 2.0 rads.

Our estimates were based on the MIRD Tables(32,33) and our experimental findings concerningthe distribution and excretion of the radiopharmaceutical.

DISCUSSION

In the thoracic region, especially in the lung hiliand mediastinum, 57Co-bleomycin seems to be auseful tumor-localizing agent, probably superior toall others known. Almost all primary lung tumorsconcentrated 57Co-bleomycin clearly and many tumors and metastases in the mediastinum and hiliwere also well demonstrated. Many of these were notdetectable with conventional radiologic methods. Thesmallest tumor found in the thorax by this methodwas about 1 cm in diameter; here 57Co-bleomycinscintigraphy should be highly reliable if the tumor ismore than 1.5 cm in diameter. In five patients, activetuberculosis and the hilar glands concentrated radioactivity, as did the Caplan lesions of rheumatoidarthritis and untreated pulmonary infection in twopatients. No other benign lesions in the lung concentrated 5TCo-bleomycin. These findings are in accordance with Nouel (2) and Grove (14) , who mentionedthat active inflammation may concentrate the material.

Cobalt-57-bleomycin shows good concentration inlymphomas located above the diaphragm. The scanmay be of some help in patients who have receivedradiotherapy to the mediastinum and in whom localrecurrence is difficult to establish. Below the diaphragm the method is handicapped by the variable

FIG.7. Patientwithplanocellularcancerin rightupperlobeof lung. (A) Chest x-ray; (B) anterior scintigram of thorax takenwith Â°TCo.bleomycinshows concentration in tumor; (C) similar scantaken with mln.bleomycin 72 hr after injection shows no concentration in tumor. (D and E) Same scintigramswith lines markingaxillae, clavicles, and xiphoid process.

uptake in liver, kidneys, bladder, and less often inthe colon. Because of this, it is often impossibleto locate lymphomas or other tumors in the abdominal region. After radiotherapy or cytostatic treatment, the tumors frequently do not concentrate57Co-bleomycin. Searching for unknown tumors notdetectable by extensive clinical investigation was unsuccessful in our series possibly due to small tumordiameter.

In primary and metastatic tumors of the brain the5TCo-bleomycin scan sometimes supplements pertechnetate brain scans (7) . In our series all sevenclinically proven cerebral metastases were clearly visible on the scintigrams. We did not use subtractiontechniques for the liver as other authors did (5)





and we did not investigate epidÃ³rmal tumors sincethe scan data would add nothing useful.

Outside the abdominal region, the concentrationin normal tissues seldom impedes interpretation ofthe scans. The accumulation of 5TCo-bleomycin wefound in normal tissues agrees well with Nouel (2),who found the same correlation with free 57Co2+ions and uptake in liver, colon, and various othertissues (personal communication, 1973). Haubold(3,5) and Laconi (9) also found uptake of 5TCobleomycin in normal liver. It is not clear why Grove(14) found no concentration in normal liver or colonin patients since he too mentions accumulation inthe livers of animals (15). This was also found intumor-bearing animals by Nouel (personal communication, 1973 ) and Rasker (20).

A disturbing artifact may be produced in the scmtigram by urinary contamination. In one patient withimpaired renal function, a considerable amount of57Co-bleomycin was present in the circulation evenafter 72 hr, and an extremely high concentration wasfound in the colon. This has led us to consider renalimpairment an absolute contraindication for 5TCobleomycm study.

Cobalt-57 has a long physical half-life (270 days);contamination and waste disposal may thereforepresent a problem. In order to minimize environmental pollution we collected urine during the first24 hr after injection, thus catching about 80% ofthe injected dose. Only 7% and 1.5% of the dosewas excreted on the second and third day, respectively; further collection of urine, therefore, seemsunrewarding.

As have other investigators, our group has beenlooking for more appropriate radioactive labels forbleomycin, but the results have been disappointing.

Indium-i 11-bleomycin circulates for a considerable time, thus causing prolonged concentration inthe cardiac poo1, it gives a high concentration inbones (14,34â€”42), and it probably is unstable inmammals (28,33,34,43). In agreement with others,we found 57Co-bleomycin superior to 1111n-bleomycin as a tumor-seeking agent in animals (13,28,38)and in man (14,44) (Fig. 7).

Results with 9Â°â€•Tc-bleomycinseemed promising(16,45,46), but we found prolonged concentrationin the blood and inadequate tumor-localizing capability in patients and tumor-bearing animals (44).

With Â°7Cu-bleomycmour results in tumor-bearinganimals were disappointing and inferior to thosewith 5TCo-bleomycin. The results in the literature arevariable (2,17,47â€”49).

Mercury-197-bleomycin also remains in the circulation for a long time and the complex is probablyunstable in vivo (44).

@..-. w@

For these reasons tumors in the hili or mediastinumcannot be visualized well with 111In-, 9omTc@,and197Hg-bleomycin. Since these are the only thoracicregions actually giving diagnostic problems to theclinician, investigation with these materials seemsunpromising for the staging of lung tumors (Fig. 8).

In animals 57Co-bleomycin gave a better T:NTratio than Â°7Ga-citrate(15) . A comparative study of57Co-bleomycin and 6TGa-citrate as tumor-seekingradiopharmaceuticals in man has recently been done(14) : in iS patients 57Co-bleomycin gave 73%

FIG.8. Patientwithanaplasticcarcinomaof left lung.(A)Chestx-ray;(B)anteriorscintigramof thoraxwithâ€˜Â°mTc-bleomycin24 hr after injection (diverging collimator) showsno concentrationin tumor; (C) similar scan taken with â€œCo-bleomycinclearly showstumor; and (0) repeat scan with â€œ1ln-bleomycin72 hr after injection (parallel-hole collimator) shows no concentration in tumor.(E, F, and G) Duplicate photographs with anatomic markings asbefore.





limites dans le diagnostic des Ã©pithÃ©liomascutanÃ©sdesmÃ©lanomesmaims Ct de leurs mÃ©tastases.Nouv Presse Med3: 193â€”195,1974

10. UMEZAWAH, MAEDAK, T@xnUcmT, et at: Newantibiotics, Bleomycin A and B. I Antibiot Ser A 19: 200â€”209, 1966

11. UMEZAWA H: Natural and artificial bleomycin: chemistry and antitumour activities.Pure App! Chem 28: 665â€”680,1970

12. ICHIKAWA T, UMEZAWA H, Oa@sHI 0, et a!: Animal

experiments con@firmingthe specific effect of bleomycinagainst squamous cell carcinoma. In Progress in Antimicrobial and Anticancer Chemotherapy, Proceedings of the 6thinternational Congress of Chemotherapy, vol 2, Tokyo,University of Tokyo Press, 1970, pp 315â€”316

13. GROVE RB, [email protected] WC, REBA RC: Distribution

of labeled bleomycin in normal and tumor-bearing mice.I Nuci Med 14:917â€”919,1973

14. GROVE RB, REBA RC, ECICELMANWC, et al: Clinicalevaluation of radiolabeled bleomycin (bleo) for tumor detection.I Nuc! Med 15:386â€”390,1974

15. KoNo A, KOJIMA M: The tumor specific localizingagents for radioisotope image. The preparation of labeledbleomycin and their distributions in the tumor-bearing mice.Radioisotopes21: 118â€”120,1972

16. Lmr SM, GOODWINDA: Method of preparation andpharmodynamics of a mmTc-bleomycin. I Nuci Med 14:422, 1973

17. LILIEN DL, JONES SE, O'M@u@RE, Ct at: A clinicalevaluation of indium-bleomycin as a tumor-imaging agent.I Nucl Med 15:512,1974

18. FUJITA H, Kmsmt& K: Blood level, tissue distributionexcretion and inactivation of bleomycin. In Progress inAntimicrobial and Anticancer Chemotherapy, Proceedingsof the 6th international Congress of Chemotherapy, vol 2,Tokyo, University of Tokyo Press, 1969, pp 309â€”314

19. ONNUMA T, HOLLAND JF, MASUDA H, et al: Microbiologicalassay of bleomycin: inactivation, tissue distribution and clearance. Cancer 33 : 1230â€”1238, 1974

20. RASKERJJ: Opsporing van tumoren met radioactiefgemerkt bleomycine. Thesis, Drukkerij van DenderenGroningen,January 1975

21. BLUM RH, CARTER 5K, AGRE K: A clinical reviewof bleomycin,a new antineoplasticagent. Cancer 31: 903â€”913,1973

22. YAGODAA, MUKHERJI B, Youwo C, et al: Bleomycin, an antitumor antibiotic. Ann intern Med 77 : 861â€”870,1972

23. EORTC (European Organization for Research on theTreatment of Cancer): Study of the clinical efficiencyofbleomycin in human cancer. Br Med I 2: 643â€”645,1970

24. BONADONNAG, DE LENA M, Mo1'@ti'@uwrNI5, et at:Clinical trials with bleomycin in lymphomas and in solidtumors. Eur I Cancer 8: 205â€”215,1972

25. RUDDERSRA: Treatment of advanced malignant lymphomas with bleomycin. Blood 40: 317â€”331, 1972

26. IcHw@wA T: The clinical effect of bleomycin againstsquamous cell carcinoma and further developments. InProgress in Antimicrobial and Cancer Chemotherapy, Proceedings of the 6th international Congress of Chemotherapy,vol 2, Tokyo, University of Tokyo Press, 1969, pp 1â€”3

27. KONINGS AWl', RASEER JJ: Posthuma trumpie: Thesubcellular distribution of â€œCo-bleoand Â°@COChin tumor andliver of tumor-bearing animals: to be published

28. TAYLOR DM : Comparison of Â°TCo,mZn and mmbleomycin complexes for tumor localization. In Radiophar

positive findings whereas Â°TGa-citratescans werepositive in only 47 % ; of 3 squamous-bronchial carcinomas, all were negative with 67Ga-citrate whereaswith 57Co-bleomycin 2 were positive and 1 negative.From this study we may not draw final conclusions,but Â°7Gaconcentrates in bones and other tissuesbesides tumors and shows prolonged concentrationin the blood. For these reasons we may suppose thatexplotation with 57Co-bleomycin is superior to thatwith Â°7Ga-citratein localizing tumors in mediastinumor lung hili.

The long physical half-life of 57Co makes the investigation with 57Co-bleomycin unsuitable for usein a routine program. In selected cases it may givethe clinician important new information he will notbe able to get with other nonsurgical methods. Untilanother radioactive label with the same qualities as57Co has been found, the investigation with @@Cobleomycin may be indispensable for clinical use.

ACKNOWLEDGMENTS

This study was made possible by a grant from the Koningin Wilhelmina Fonds, Nederlandse Organisatie voor deKankerbestrijding.

The authors are grateful to J. J. Pratt, C. F. v.d. Merwe,and A. Versluis for their helpful suggestions.

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Accepted Articles to Appear in Upcoming Issues (Continued from page 1032)

In Vivo Behavior of sSmTc..pjbnnogenand Its Potential as a ThrombusImaging Agent. Accepted 8/6/75.

Sylvia S. L. Harwig, John F. Harwig, R. Edward Coleman, andMichael J. welch

Gallbladder Visualization in Adrenal Scanning (Case Report). Accepted 8/6/75.

John C. Harbert, John J. Canary. and Kenneth L. SandockTechnetium-99m-Human Serum Albumin : Evaluation of a CommerciMly Produced Kit. Accepted 8/7/75.

Ronald J. Callahan, Kenneth A. McKusick. Frank P. Castronovo,Myles Lamson, III. and Majic 5. Potsaid

Evaluation of Labeling Procedures and In Vivo Stability of mmTc@RedBlood Cells. Accepted 8/11/75.

U. Yun Ryo, All A. Mohammadzadeh, Aslam Siddiqui, Lelio G.Colombetti, and Steven M. Pinsky

Evaluation of the Posterior Flow Study in Brain Scintlgraphy. Accepted 8/12/75.

Thomas R. Martin, James 5. Moore, and Rex B. ShaferTransient Brain Scan Abnormalities In Renal Dialysis Patients. Accepted 8/13/75.

Ralph S. Wolfstein. Doina E. Tanasescu, Alan D. Waxman, andJan K. Siemsen

Measurement of Acute Myocardial Infarcts in Dogs with Â°Â°mTc-Stannous Pyrophosphate Scintigrams. Accepted 8/13/75.

Ernest M. Stokely. L. Maximilian Buja, Samuel E. Lewis, Robertw. Parkey,FrederickJ. Bonte,RobertA. Harris,Jr.. andJamesT. Wilierson

Unreliability of Combined Pneumoencephalography and Scinticisternography (Concise Communication). Accepted 8/15/75.

Thomas H. Milhorat, Techen Chien, Massoud Majd, and David L.Breckbill

Optimized Collimators for Scintillation Cameras. Accepted 8/I 5/75.S. 5wann, D. Palmer, L. Kaufman C. B. Lim, and P. B. Hoffer

Alteration of the Cerebral Bloodflow @tudyDue to Reflux in InternalJugular Veins (Concise Communication). Accepted 8/18/75.

Jehuda J. Steinbach, Add G. Mattar, and Dorsey T. MahinInfusion Cisternography (Concise Communication) . Accepted 8/18/75.

BlÃ¸rnMagnaes, Kjell Rootwelt, and Ottar SiaastadAnalytical Study of a High-Resolution Positron Ring Detector 5ystemfor Transaxial Reconstruction Tomography. Accepted 8/18/75.

Stephen E. Derenzo, Haim Zaklad. and Thomas F. BudingerTechnetium-99m-Labeled Stannous Imidodiphosphate, a New Radiodiagnostic Agent for Bone Scanning: Comparison with Other mmTcComplexes. Accepted 8/18/75.

G. Subramanian, J. G. McAfee, R. J. Blair, M. Rosenstreich, M.Coco. and C. E. Duxbury

Initial Assessment of a Simple Functional Image of Ventilation. Accepted 8/18/75.

Nathaniel M. Alpert, Kenneth A. McKusick. John A. Correia.William Shea, Gordon L. Brownell, and Majic S. Potsaid

Marked Suppression of Thyroid Function in Rats with Gram-NegativeSepticemia. Accepted 8/20/75.

Michael K. Kan Joseph F. Garcia. James McRae. Lee-TzuuChang. John A. [email protected]. and Victor Perez-Mendez

Simplified Method of Determining Cardiac Flow/Volume Values Usinga Scintillation Camera. Accepted 8/24/75.

Gerald S. Freedman, Andrew Dwyer. and John WolbergMIRD/Dose Estimate Report No. 7 : Summary of Current RadiationDose Estimates to Humans from â€œ@I,124I @I,1@@I.and â€˜@â€˜Ias SodiumRose BengalMIRD/Dose Estimate Report No. 8 : Summary of Current RadiationDose Estimates to Normal Humans from mmTc as Sodium Pertechnetate




1975;16:1058-1069.J Nucl Med. J. J. Rasker, M. A. P. C. van de Poll, H. Beekhuis, M. G. Woldring and H. O. Nieweg

Co-Labeled Bleomycin as a Tumor-Seeking Agent57Some Experience with

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