Nieweg, Omgo Edo

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   University of Groningen57 Co-Bleomycin scintigraphy and 57Co-Bleomycin positron emission tomography.Experimental observations and clinical results in lung cancerNieweg, Omgo EdoIMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:1983Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Nieweg, O. E. (1983). 57 Co-Bleomycin scintigraphy and 57Co-Bleomycin positron emission tomography.Experimental observations and clinical results in lung cancer. Drukkerij van Denderen.CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 07-06-2022SUMMARYIt is often difficult to detect a malignant tumor and assess the presence ofmetastases. Therefore it is important to have a non-invasive test than canvisualize these lesionsruCo-bleomycin (lz6o-Ot-, is a radiopharmaceutical that is used for thesepurposes especially in patients with lung cancer. The aims of the presentstudy were to determine the value of ,7Co-blm scintigraphy as it is used inclinical practice and to improve the radiopharmaceutical and detectionprocedure. This work is a sequel to the work of Rasker (251).The properties of the ideal tumor imaging radiopharmaceutical are out-lined in cbapter í. This hypothetical agent should accumulate in malignanttumors but not in other lesions and not in normal tissues. It should have fewside effects, a short half-life, emit radiation with a suitable energy for in vivodetection and be generally available for a reasonable price.The specific and non-specific mechanisms by which tumor imaging radio-pharmaceuticals are accumulated in tumor tissue are discussed.Tumor imaging radiopharmaceuticals canbe arcanged roughly into threemajor groups: metabolite related agents, immunological substances andnon-specific compounds. Many radiopharmaceuticals that have been used arone time or another are briefly discussed. In the section on metabolite relatedagents, special attention is paid to bleomycin (blm) and tTCo-blm. The groupof immunological substances consists of radiolabeled antibodies againstantigens that are presenr in tumors. 67Ga-citrate is the best known tumorimaging agent among the non-specific compounds. It is widely used innucleas-medicine. Its history, indications and disadvanrages are discussed.In cbapter 2, a brief. review is presented on lung cancer epidemiology,pathology, etiology, prevention, clinical symproms and signs, therapy andprognosis. New developments in this field are reviewed. Various techniquesto establish the diagnosis of lung cancer and to detect metastases are dis-cussed more extensively. The importance of assessing the correct stage ofthe disease is stressed.The labeling procedure of blm with tTCo and the value of tTCo-blm in thedetection of primary lung cancer are described in chapter 3. Over a5 yearperiod, tTCo-blm scintigraphy for tumor detection was performed in ourr13Iinstitute with a large field of view gamma camera. The scintigrams of 287well documented patients with lung cancer' other types of neoplasm, non-malignant lesions or no abnormality in the lung were reviewed. A sensitivityof g6% was found for the detection of lung cancer. False negative and equi-vocal scintigrams were seen in Patients with small lesions'Nineteen parients proved to have anorher type of malignant tumor in thelung, mostly merasrases from rumors elsewhere in the body. of these lesions'l3 6S%) were visual ized. 57co-blm scint igraphy cannot dif ferentiatebetween lung cancer and other malignancies'It is important to determine the value of tTco-blm scintigraphy in patientsin whom a preoperative parhological diagnosis cannot be obtained by reaso-nable means. In such a subgroup of 194 cases, sensit ivi ty was957o and speci-Ircltv ó / u/o.correlation between tumor size and tumor-to-non-tumor ratio (TNT-rario) was established for squamous cell carcinoma, adenocarcinoma andsmall cell carcinoma. Adenocarcinomas were smaller and showed lowerTNT-ratios than other histological types. A correlation between histologicaldifferentiation and TNT-ratio could nor be established for squamous cellcarcinoma.Forty of 46 scintigraphic studies in patients with a non-malignant lesionor no abnormality in the lung were rrue negative. This leads to a specificityor 877o. tTCo-blm scintigraphy results in 112 Patients with various non-malignant lesions in rhe lung were collected from the literature, includingthe present results. overall specificity wasSl(y'o. Most false positive studieswere seen in patients with active tuberculosis and unspecified pneumonia. Itis concluded that tTCo-blm scintigraphy is helpful in patients suspected ofhaving lung cancer in whom a pfeoperarive pathological diagnosis cannot beobtained.In chapter 4, the vailue of 57Co-blm scintigraphy for staging lung cancerwas investigated.inlT4 patients. In the detection of lymph node metastasesin the hilus and mediastinum' the sensitivity was J47o and the specificity98Vo. tlCo-blm scintigraphy proved to be more reliable than chest radio-graphy and roentgen tomograPhY.Distant merasrases were sought in 44 patients. False positive or falsenegarive results were nor found in this group. The tTco-blm brain scinti-grams were of particularly good quality.The value of mediastinoscopy and roenrgen cT-scanning in the detection| 4of metastasereported inIt is conchlymph nodescintigram irblm scintigrStaging oÍscintigraphytinoscopy isextensive m,graphy indicincluding rergraphy doesotherwise n(latter group,always l imit61Ga-citrastaging of lr63 patientsshowed the(p(0.0)).  Tsignificant iProven rrwith 67Ga-ci(89%) (p<(suitable forgraphy.Blm, as i tBlm-mixturrlabeled withIn chapteinvestigatednoma, YoshtTCo-blm-m:showed a h:three compcIrtigrams of 287neoplasm, non-ed. A sensitivitygative and equi-nnt tumor in the3f these lesions,ot differentiateaphyinpadentsrtained by reaso-9)Vo anàspeci-or ratio (TNT-)carcinoma andI showed lowereen histologicalr squamous cellnalignant lesions to a specificityth various non-ature, includingpositive studiesd pneumonia. Itrts suspected of;nosis cannot being lung cancerrode metastasesI the specificityLan chest radio-ositive or false.m brain scinti-in the detectionof metastases in the hilus and mediastinum is discussed on the basis of datareported in the literature.It is concluded that ,7Co-blm scintigraphy has a limited potential to detectlymph node metastases in the hilus and mediastinum. llowever, a positivescintigram is highly suggestive of the presence of metastatic disease. tTCo-blm scintigraphy is a reliable technique to visualize brain metastases.Staging of lung cancer patients in our hospital routinely includes tTCo-blmscintigraphy in addition to conventional roentgen tomography. Medias-tinoscopy is rarely done nowadays. Síhen tTCo-blm scintigraphy showsextensive mediastinal involvement, surgery is not performed. Iíhen scinti-graphy indicates limited hilar or mediastinal involvement, extensive surgeryincluding removal of the affected lymph nodes is considered. \íhen scinti-graphy does not show met4stases, radical resection is carried out whenotherwise no contra-indications are present. In a number of patients in thislatter group, lymph node metastases will be found during surgery, but this isalways limited and rarely modifies the intended radical resection.67Ga-citrate is a widely used radiopharmaceurical for the derection andstaging of lung cancer. A comparative study of 67Ga-citrare and tTCo-blm in63 patients with proved lung cancer is described in cbapter 5.67Ga-citrateshowed the primary tumor in 34 patients (54%) and tTCo-blm in 58 (92%)(p(0.05). The mean difference in TNT-ratios in individual patients wassignificant in favor of tTCo-blm scintigraphy.Proven metastases in the lung hilus and mediastinum were visualizedwith 67Ga-citrate in only 8 out of 18 patients (45%) and with tTCo-blm in 16(89%) (p(0.05). These results indicate that tTCo-blm scintigraphy is moresuitable for detecting and staging lung cancer than is 67Ga-citrate scinti-graphy.Blm, as it is commercially available, is a mixrure of various blm fractions.Blm-mixture and the isolated fractions blm-A2. blm-Á5 and blm-B2 werelabeled with 57Co.In chapter 6 the tumor seeking properries of these compàtrnds wereinvestigated. Biodistribution was determined in rars bearing \Talker carci-noma, Yoshida sarcoma or rhabdomyosarcoma. Tissue concenrrarions oftTCo-blm-mixture and tTCo-blm-A2 were generally similar. tTCo-blm-B2showed a higher uptake in most tissues. Tumor-to-tissue rarios of thesethree compounds were similar. tTCo-blm-A5 showed clearly inferior tumor1 1 5seeking properties. It is concluded that, in the experimental models that weused, the investigated labeled blm fractions are not superior to tTCo-blm-mixture for tumor detection.;7Co-blm, as it is administered to patients, contains a considerable amountof unlabeled blm. To limit side effects to the patients and to reduce costs, thequantity of blm should be as low as possible. Reduction of the amount of blmhowever should not result in an increase in the percentage of free 57Co2+ions, since these are largely retained in the body and considerably add to theradiation dose. Variations in the ratio of tTCo and blm in the labeling proce-dure were investigated in chapter 7. A fixed amount of 7.4MBq (0.2 mCi)tTCo was added to successively 21.0,9.0,0.9,0.09 and0.009 mg (weight) blmin the preparation of tTCo-blm.Iíhen the smallest amount of blm was used, the labeling yielded a percen-tage of t7co2+ that was far too large. The percentage of free t7co2+ in theorher four compounds was acceptable, being less than 3% of the totalactivity.Biodistribution of radioactivity of all five compounds was investigated inrats bearing Yoshida sarcoma. Of the compound with excess stco2+, radio-activity uptake in the rumor was similar to uptake of the other compounds,but uptake in normal tissues was clearly higher. This resulted in inferiortumor-to-tissue ratios. Tissue concentrations and tumor-to-tissue ratios ofthe other four compounds were similar.It is concluded that, compared to the quantity traditionally used, theamount of blm in the labeling procedure can be reduced without increase inthe percentage of free t7co2+ and without reduction in the tumor seekingproperties in rats with Yoshida sarcoma. On the basis of these results, thequantity of blm administered to patients for tTCo-blm scintigraphy (1.5 mgweight) will be reduced.The long half-life of tTCo (272 d:ays) ius discoo.rged the widespreadacceptance of tTCo-blm. Because a major fraction of the radioactivity isquickly excreted by the kidneys, the contaminated urine should be collectedand stored to prevent environmental contamination. Since the labeling ofblm with other radionuclides did not lead to a useful tumor imagingagett,we investigated ttCo (hàlf-life 17.5 hours) as potential label. The results aredescribed io chapter 8.::Co is produced by the tóFe(p, 2n);sgo reaction in the cyclotron of theI16University,procedure acancer wef(administertscintigraphcamera wasdescribed. iquality. Senpositron imof ttCo-blnscintigraphfiltering wHowever, tttCo-blmnode metasstudy was frwith a braitomogramsAdvantagdiscussed. Irblm scintig:recently belfuture.In chaptedose to thecalculated uradioactivit'assumed ththroughoutResidencradioactivitderived frodose was c,somaticallydose is 70 :pGy/MBqthe t6Co irt models that weior to tTCo-blm-iderable amountreduce costs, there amount of blmge of free rzCgz*erably add to thee labeling proce-í MBq (0.2 mCi)mg (weight) blmyielded a percen-:ree t7co2+ in the3% of the totalrs investigated ina* rz69z*, radio_ther compounds,;ulted in inferioro-t issue rat ios ofionally used, thethout increase inL€ turTrof seekingrhese results, thetigraphy (1.5 mgL the widespread: radioactivity isrould be collected:e the labeling of>r imagi.ngagent,:1. The results are: cyclotron of theUniversity of Groningen. After purification, tsCo is attached to blm with theprocedure as described for tTCo in chapter 3. Fifty patients with proven lungcancer were investigated with t tCo-blm. A dose of 37 MBq (1.0 mCi) wasadministered intravenously. The results were compared with tTCo-blmscintigraphy. Since ttCo is a positron emitting radionuclide, a positroncamera was used for imaging. The characteristics of rhis device are brieflydescribed. Tomographic images were obtained and proved ro be of goodquali ty. Sensit ivi ty in the detection of primary tumors was967o for rtCo-blmpositron imaging, whereas for tTCo-blm imaging this was 98%. TNT-ratiosof ttCo-blm scintigraphy were significantly lower than those of tTCo-blmscintigraphy. TNT-ratios obtained with t5Co-blm after compurerizedfiltering were significantly higher than those obtained with tTCo-blm.However, the filtered images were not always easy to evaluate.ttCo-blm and tTCo-blm were equally sensitive in the detection of lymphnode metastases in the hilus and mediastinum. One false positive ttCo-blmstudy was found versus no false positive tTCo-blm studies. In all six patienrswith a brain metastasis, this was clearlv demonstrated on the ttCo-blmtomograms.Advantages and disadvantages of ttCo-blm positron scintigraphy arediscussed. It is concluded that the results are good enough to replace rTCo-blm scintigraphy. The more refined positron imaging equipment that hasrecently become available will probably improve the results in the nearfuture.ln chapter 9, organ radiation doses and somatically effective total bodydose to the adult patient from a study with tTCo-blm or , tCo-blm werecalculated using the MIRD (Medical Internal Radiation Dose) scheme. Theradioactivity is mainly concentrated in bladder, kidneys and liver. It isassumed that the rest of the radioactivity is distributed homogeneouslythroughout the remainder of the body.Residence times - cumulated activities per unit of injected amounr ofradioactivity - for these three organs and the remainder of the body werederived from tTCo-blm clearance measurements in patients. The radiat iondose was calculated for the gonads and all organs that contribute to thesomatically effective total body dose. The somatically effective total bodydose is 70 + 8 pGy /MBq Q.26 + 0.03 rad/ mCi) for :7Co-bl m and 170 * 24pGylMBq (0.63 L 0.09 radlmCi) for I tCo-blm (* t  s.d.).  The inf luenceofthe t6Co impurity in tsCo and the ::Fe daughter act ivi ty of t tCo on the;iIiJL 1 7radiation dose are discussed. The calculated somatically effective total bodydose of both radiopharmaceuticals is comparable to rhat of other scinti-graphic studies.New developments in tumor imaging are describedín chapter 10. Tesringnew blm fractions might lead ro a componenr rhat has better tumor seekingproperties. Research in the labeling of a ligaod of non-radioactive cobalt andblm with radionuclides that emit a suitable gamma energy might lead to acompound that carries no risk of environmental contamination and that cangenerally be used for imaging with a gamma camera.In the near future, the introduction of a rotatable double headed gammacamera, adapted for positron imaging, offers the opportunity to quantify theamount of radioactiviry in a certain aÍea in the body. This feature mightenable us to guide tumor therapy more accurarely.Two main directions can be discerned in the search for more specifictumor imaging agents: metabolite related agents (such as amino acidslabeled with the posrtron emitt ing "C, trN, "O) and (monoclonal) anri-bodies against tumor specific anrigens.Nude mice bearing human rumors might make it possible ro test rumorimaging radiopharmaceuricals in animals and obtain resulrs rhat are highlypredictive for human beings.Síhen a truly specific tumor imagin g agent is found, we should considerconverting this compound into a therapeuric agenr by labeling it with aradionuclide with suitable physical characteristics.Nuclear magnetic resonance (NMR) is another new clinical imaging tech-nique. Its potential in tumor imaging is briefly discussed.SAMENllet aantoneis niet altijd eezichtbaar kan rblm) is een radihet bijzonder tHet doel varvan de waarde.in de praktijk rfarmacon en dedat van Rasketln hoofd.stukzoekende radioopgenomen in Jniet in normalekorte halveringgunstig is voorzijn voor een aDe specifiekrfarmaca in gezrTumorzoekerradiofarmaca rmetabolisme vanisme berust opvan het opnamein de loop de:besproken. Bij dhet bijzonder aalogische radiofa.wezigzijn.6TGa.radiofarmaca. Hschiedenis, de irHoofdstak 2anatomie, ,oorz1 1 8t

57 Co-Bleomycin scintigraphy and 57Co-Bleomycin positron emission tomography. Experimental observations and clinical results in lung cancer

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57 Co-Bleomycin scintigraphy and 57Co-Bleomycin positron emission tomography. Experimental observations and clinical results in lung cancer

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