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Chapter 2THE EMERGENCE AND DEVELOPMENT OF NUCLEAR MEDICINEThe vast majority of the public thinks thatresearch reactors, such as the High FluxReactor (HFR) in Petten, the Netherlands, areessential for the supply of medicalradioisotopes. And indeed these nuclearreactors are currently producing the vastmajority of the isotopes. The nuclearindustries like to maintain this widespreadmisunderstanding to justify their right toexist. A brief look in the history of nuclearmedicine learns that all medical radioisotopeswere originally manufactured by another typeof production. The first medical applicationsof radioisotopes paralleled the development ofthe nuclear physics instruments which allthese isotopes produced: the (charged) particleaccelerators. Currently, these instruments aremistakenly purely seen as tools infundamental scientific research.2.1 Original production of radioisotopesTracer principalRadiopharmaceuticals are used as radioactive tracersfor the diagnosis and treatment of patients. TheHungarian chemist George Charles de Hevesy, bornas Hevesy György, published the first paper on theradioactive tracer concept in 1913. He coined theterm radioindicator or radiotracer and introduced thetracer principle in biomedical sciences. Animportant characteristic of a tracer is that it canfacilitate the study of components of a homeostaticsystem without disturbing their function. In 1924, thetracer concept paved the way for the use ofradioisotopes as diagnostic tools. In 1927, the USphysicians Hermann Blumgart and Soma Weissinjected solutions of bismuth-214 (214Bi) into theveins of men to study the velocity of blood.32 (32P). Soon 32P was employed for the first time totreat a patient with leukemia. Ernest Lawrencerecognized the medical potential of radioisotopes. Hisbrother, John, a hematologist, helped researched thefield’s potential and established and administered thetherapeutic procedures. In 1936 he treated a 28-yearold leukemia patient using 32P produced in one of hisbrother’s cyclotrons. It was for the first time that aradioisotope had been used in the treatment of adisease, marking the birth of nuclear medicine.Particle acceleratorAfter the discoveries of the cyclotron by ErnestLawrence in 1931 and artificial radioactivity by IrèneCurie and Jean-Frédéric Joliot in 1934, it waspossible to make practically every imaginableradioisotope for use in diagnostics or in therapy.Isotopes such as iodine-131 (131I), phosphorus-32(32P) and cobalt-60 (60Co) are already used indiagnostics and therapy since the mid-1930s.4 Bybombarding an aluminum sheet with particles emittedby polonium Curie and Joliot created for the firsttime a radioactive element, which they baptizedradio-phosphorus. Coupled with the Geiger counter’sdetection capabilities, their discovery markedlyexpanded the range of possible radioisotopes forclinical tracer studies. Enrico Fermi produced awhole range of radioisotopes, including phosphorus-In 1938, Emilio Segre discovered technetium-99m(99mTc), and thyroid physiology was studied by usingradioactive iodine. It was discovered that thyroidaccumulated radioiodine (131I). Consequently it wassoon realized that 131I could be used to studyabnormal thyroid metabolism in patients with goiterand hyperthyroidism. More specifically, in patientswith thyroid cancer, distant metastases wereidentified by scanning the whole body with theGeiger counter. The names radioisotope scanningand atomic medicine were introduced to describe themedical field’s use of radioisotopes for the purposeof diagnosis and therapy. Strontium-89 (89Sr), anothercompound that localizes in the bones is currentlyused to treat pain in patients whose cancer has spreadto their bones, was first evaluated in 1939.5 All ofthese radioisotopes are now considered as ‘typicalreactor-produced isotopes’(The first successful cyclotron)4From Radioisotopes to Medical Imaging, History ofNuclear Medicine Written at Berkeley, 9 September uclear-medhistory.htmlLawrence And His Laboratory - A Historian's View of theLawrence Years: Ch2 The Headmaster and His School.Lawrence Berkeley National Laboratory, eview/Magazine/1981/81fchp2.html35Chemistry Explained - Nuclear uclearMedicine.html

The first commercial medical cyclotron was installedin 1941 at Washington University, St. Louis, whereradioactive isotopes of phosphorus, iron, arsenic andsulfur were produced. Soon there hadn’t been enoughcyclotron capacity to fulfill the rising demand ofisotopes. Civilian use of a military nuclear reactorprovided relief to the producers of pharmaceuticals.The Manhattan Project – the US-led project todevelop the first atomic bomb - resulted in anunprecedented expansion of radiation research andexpertise, as well as its diagnostic and therapeuticapplication in nuclear medicine, including humanexperimentation. As a byproduct of nuclear reactordevelopment, radioisotopes came to abound. As aresult of this most radioisotopes of medical interestbegan to be produced in a nuclear reactor duringWorld War II. Especially in the Oak Ridge reactor,which was constructed under the secrecy of theManhattan Project. To protect this secrecy, the 32Pproduced by the reactor had to appear as if it hadbeen produced by a cyclotron. Thus, 32P was sentfrom Oak Ridge to the cyclotron group at theUniversity of California at Berkeley, from which itwas distributed to the medical centers. The shortageof radioisotopes ended in 1945, when isotopesbecame widely available for research and medicaluse, including reactor-produced 131I from Oak Ridge.Globally, particle accelerators produced the vastmajority of radioisotopes with medical applicationsuntil the 1950s when other countries followed the USby using reactor-based isotopes.2.2 The rise of reactor-produced radioisotopesAfter the war, the US continued its atomic research ina series of national laboratories, among them LosAlamos and Oak Ridge. These labs were supervisedby the then Atomic Energy Commission (AEC), agovernmental agency to coordinate the military,economic, political, and scientific work in atomicenergy. The main mission of the AEC was promotingthe military use of nuclear material, but “givingatomic energy a peaceful, civilian image” was alsopart of it. Including the promotion of research, amongwhich radiobiology and nuclear medicine.Immediately after the war, radioisotopes flooded thelaboratories and hospitals. In 1946, as part of theIsotope Distribution Program of the AEC, the OakRidge Reactor (see archive picture below) begandelivering radioisotopes to hospitals and universitiesnationwide. In 1948 isotopes for biomedical research,cancer diagnostics and therapy even became free ofcharge, which can be considered as an earlyforerunner of the Atoms for Peace Campaign in theearly 1950s aimed to promote the ‘the peaceful use ofnuclear energy’. The rest of the western worldfollowed this change in isotopes production. Entirelyprospectless the particle accelerators tasted defeat inthe competition with the subsidized nuclear reactors.6The cyclotron-based radioisotopes production formedical applications revived a little in the 1950s,after the discovery that thallium-201 (201Tl) could beused as an ideal tracer for detecting myocardialperfusion. Thallous chloride labeled with 201Tlremains the gold standard for measuring cardiacblood flow despite the availability of technetium-99mmyocardial perfusion agents.(Oak Ridge National Laboratory – early 1950s)6Rheinberger, Hans-Jörg; Putting Isotopes To Work:Liquid Scintillation Counters, 1950-1970. Max-PlanckInstitut für Wissenschaftsgeschichte, Berlin 1999. pp.4-5http://edoc.mpg.de/get.epl?fid 3199&did 46724&ver 04

2.3 Nuclear imaging modalitiesGamma cameraThe era of nuclear medicine, as a diagnostic specialtybegan following the discovery of the gamma camerabased on the principle of scintillation counting, firstintroduced by Hal Anger in 1958. Since then, nuclearmedicine has dramatically changed our view oflooking at disease by providing images of regionalradiotracer distributions and biochemical functions.Over the last five decades, a number ofradiopharmaceuticals have also been designed anddeveloped to image the structure and function ofmany organs and tissues.Molybdenum-99/Technetium-99m (99Mo/99mTc)generatorsIn 1959 the U.S. Brookhaven National Laboratory(BNL) started to develop a generator to producetechnetium-99m from the reactor fissionable productmolybdenum-99, which has a much longer half-life.The first 99mTc radiotracers were developed at theUniversity of Chicago in 1964. Between 1963 and1966, the interest in technetium grew as its numerousapplications as a radiotracer and diagnostic toolbegan to be described in publications. By 1966, BNLwas unable to cope with the demand for 99Mo/99mTcgenerators. BNL withdrew from production anddistribution in favor of commercial generators. Thefirst commercial generator was produced by NuclearConsultants, Inc. of St. Louis, later taken over byMallinckrodt (Covidien), and Union Carbide NuclearCorporation, New York.7Computed Tomography (CT)CT is a medical imaging method employingtomography created by computer processing. TheCT-scan was originally known as the EMI-scan as itwas developed at a research branch of EMI, acompany best known today for its music andrecording business. It was later known as computedaxial tomography (CAT or CT scan) and bodysection röntgenography. Although the term computedtomography could be used to describe positronemission tomography and single photon emissioncomputed tomography, in practice it usually refers tothe computation of tomography from X-ray images.The initial use of CT for applications in radiologicaldiagnostics during the 1970s sparked a revolution inthe field of medical engineering. In 1972, the firstEMI-Scanner was used to scan a patient’s brain. CTprovided diagnostic radiology with better insight intothe pathogenesis of the body, thereby increasing thechances of recovery.87The Technetium-99m .asp8Bartlett, Christopher A.; EMI and the CT Scanner [A]and 5Positron Emission Tomography (PET)Another major breakthrough in the history of nuclearmedicine arrived with the preparation offluorodeoxyglucose (FDG) labeled with fluorine-18(18F) in the mid-1970s. Use of 18F-FDG for studyingthe glucose metabolism lead to the development ofthe imaging modality positron emission tomography(PET). The use of 18F-FDG in combination with aPET-camera produced images of an excellent qualityof the brains and the heart for studying aberrations,and the detection of metastases of tumors.Subsequently a large number of other 18F-labeledradiopharmaceuticals were developed and the use ofnew isotopes grows fast. PET scans are performed todetect cancer; determine whether a cancer has spreadin the body; assess the effectiveness of a treatmentplan, such as cancer therapy; determine if a cancerhas returned after treatment; determine blood flow tothe heart muscle; determine the effects of a heartattack, or myocardial infarction, on areas of the heart;identify areas of the heart muscle that would benefitfrom a procedure such as angioplasty or coronaryartery bypass surgery (in combination with amyocardial perfusion scan); evaluate brainabnormalities, such as tumors, memory disorders andseizures and other central nervous system disorders;and to map normal human brain and heart function.9Single Photon Emission Computed Tomography(SPECT)At the end of the 1970s single photon emissiontomography (SPECT) was introduced. Itsdevelopment parallels the development of PET.SPECT images are produced from multiple 2Dprojections by rotating one or more gamma camerasaround the body. Reconstruction using methodssimilar to those used in X-ray CT provides 3D datasets allowing the tracer biodistribution to bedisplayed in orthogonal planes. SPECT uses gammaemitting radioisotopes, such as 99mTc and thecyclotron-produced indium-111 (111In) and iodine123 (123I). The advantages of SPECT over planarscintigraphy can be seen in the improvement ofcontrast between regions of different function, betterspatial localisation, improved detection of abnormalfunction and, importantly, greatly improvedquantification.10Hybrids of CT, PET, SPECT and MRIThe last decade has seen the development of hybridimaging technologies. PET or SPECT are combined9Positron Emission Tomography – ComputedTomography (PET/CT); Radiology Infohttp://www.radiologyinfo.org/en/info.cfm?PG pet10What is SPECT?: http://www.spect.net/: NuclearTechnology Review 2007, IAEA. p.61

with X-ray computed tomography (CT). Expertsagree that PET/CT and SPECT/CT are superiortechniques over stand-alone PET and SPECT interms of diagnostic accuracy. Insiders expect thatthese hybrid imaging technologies will become thegold standard for conventional scintigraphy. Hybridcameras combining PET and MRI have already beenintroduced. They also prospect the development ofnew hybrid forms for a certain organ or body part.These systems will offer the virtually unlimitedpotential of simultaneously acquiring morphologic,functional, and molecular information about theliving human body.112.4 Drawbacks of using PET, SPECT andespecially (devices combined with) CTDespite the major improvements in nuclear medicineby using modalities such as CT, PET and SPECT,investigations in the US uncovered that 20 to 50% ofthese high-tech scans have been unnecessary, becausethey offer no support by making a diagnosis.12 TheU.S. National Cancer Institute reports alarmingfigures on the high radiation exposure of patients. Itprojects 29,000 excess cancers from the 72 millionCT scans that Americans got in 2007 alone. Nearly15,000 of those cancers could be fatal.13An investigation by the US National Council forRadiation Protection and Measurements shows thatfrequent use of radioisotopes at one patient can resultin a too high radiations exposure. It uncovered thatthe average dose has been increased from 3,6millisievert (mSv) in the early 1980s to 6,2 mSv in2006. The average dose per person is an average overthe population of the United States.14 Apparently theenthusiasm to use these modern modalities has gone11Nuclear Medicine 2020: What Will the Landscape ?option comarticles&view article&id -look-like12Where Can 700 Billion In Waste Be Cut AnnuallyFrom The U.S. Healthcare System? Robert Kelley,Thomson Reuters, October 2009.http://www.ncrponline.org/PDFs/Thomson Reuters WhitePaper on Healthcare Waste.pdf13Radiation From CT Scans May Raise Cancer Risk, 15December toryId 121436092&ft 1&f 100714Medical Radiation Exposure of the U.S. PopulationGreatly Increased Since the Early 1980s, NCRP PressRelease, 3 March 2009.http://www.ncrponline.org/Press Rel/Rept 160 Press Release.pdfPeople Exposed to More Radiation from Medical Exams,Health Physics Society, 9 March 2009.http://hps.org/media/documents/NCRP ReportPeople Exposed to More Radiation from Medical Exams 9Mar.pdftoo far, which reminds to the widespread use of Xray equipment in the 1950s.By the end of February 2010, the U.S. Food andDrug Administration announced a federal program toprevent unnecessary radiation exposure from nuclearimaging devices and new safety requirements formanufacturers of CT scans. Medical doctors areurged to think twice before ordering such scans inorder to weigh the risk and the benefit. According toestimates of David Brenner, director of ColumbiaUniversity's Center for Radiological Research in NewYork, 20 million adults and one million children arebeing irradiated unnecessarily and up to 2% of allcancers in the U.S. at present may be caused byradiation from CT scans.15 The American Society forRadiation Oncology (ASTRO) issued a six-point planthat has to improve safety and quality in using CTand other nuclear imaging modalities and reduce thechances of medical errors.16 So far, there are nofigures known about the situation in Europe.Though CT produces images with far greater clarityand detail than regular X-ray exams, it has beenestimated that the average radiation dose of one CTscan is equal to roughly 500 chest X-rays. Aninternational study, conducted by the IAEA andpublished in April 2010 has shown that somecountries are over-exposing children to radiationwhen performing CT scans. These children arereceiving adult-sized radiation doses, althoughexperts have warned against the practice for over adecade. An additional problem in developingcountries is that the available CT machines are oldermodels without the automatic exposure controlsfound in modern equipment. This function can detectthe thickness of the section of the patient s body thatis being scanned and can therefore optimize the levelof radiation dose, avoiding unnecessary exposure.The IAEA has started a program to reduceunnecessary child radiation doses.17Meanwhile newer CT technology has been developedto reduce a patient’s exposure to excess radiation.Patients who got a type of heart CT scan calledcoronary angiography received 91% less radiation15Radiation Risks Prompt Push to Curb CT Scans. WallStreet Journal, 2 March 8704299804575095502744095926.html16Medical Group Urges New Rules on Radiation. NewYork Times, February 4, diation.html17IAEA Aims to Reduce Unnecessary Child RadiationDoses - New Study Shows Global Variation in DoseLevels for Child CT Scans. IAEA, 23 /childctscans.html6

than those who were scanned with a traditional CTscanner. Although in the U.S. heart CTs onlyaccounted for 2.3 million out of 65 to 70 million CTscans performed in 2006, they are worrisome becausethey deliver high radiation doses.182.5 Methods in radiotherapyBrachytherapy is used for primary cancer treatment,for bone pain palliation, and for radiosynovectomy,used for patients that are suffering from joint pain. Incancer treatment the radionuclides are placed veryclose to or inside the tumor. During the therapy,controlled doses of high-energy radiation, usually Xrays, destroy cancer cells in the affected area. Theradiation source is usually sealed in a small holdercalled an implant. Implants may be in the form ofthin wires, plastic tubes called catheters, ribbons,capsules, or seeds. The implant is put directly into thebody. Brachytherapy dates back to the time beforethe discovery of the cyclotron when naturalradioisotopes, such as radium-226 (226Ra), were usedin the treatment. Currently, common radionuclidesare iridium-192 (192Ir), yttrium-90 (90Y), iodine-125(125I) and palladium-103 (103Pd).19(accelerator used in fundamental scientific research)18Newer heart CTs deliver far less radiation. Reuters, 24February 201019Flynn A et al. (2005). “Isotopes and delivery systemsfor brachytherapy”. in Hoskin P, Coyle C. Radiotherapy inpractice: brachytherapy. New York: Oxford UniversityPress.7

Chapter 3MEDICAL RADIOISOTOPES & APPLICATIONSOver 10,000 hospitals worldwide useradioisotopes in medicine. The vast majorityof these isotopes is produced by researchreactors. Currently, there are 232 operationalresearch reactors in 56 IAEA memberstates.20 Most of these reactors are used fornuclear research, including the ones involvedin isotope production. Only 78 out of these232 research reactors in 41 IAEA memberstates are used for isotope production.21Twelve research reactors, distributed over 11member states, are temporary shutdown22, ofwhich three of them are involved in isotopeproduction.23 The IAEA database mentionsthat seven research reactors are underconstruction or planned in 6 member states.24It is not clear how many of these are involvedin isotope production. More than half of theresearch reactors involved in isotopeproduction (43 out of 78) is 40 years old orolder.41There are about 40 neutron-activated radioisotopesand five fission product ones made in reactors. By1970, 90% of the radioisotopes in the US, the largestconsumer of medical radioisotopes, utilized eitheriodine-131 (131I), cobalt-60 (60Co), or technetium99m (99mTc). 60Co was used for over 4 milliontherapeutic irradiations a year, 131I for diagnosis andtreatment more than 2 million times a year, and 99mTcin nearly one million annual diagnostic procedures.Today the statistics are somewhat s/research ry/status operational cs/research ation/isotope esearch ry/status temp shutdown cs/research ation/isotope prod esearch ry/status reactors construction.html25Prof. G.T. Seaborg - Hundred Years of X-rays andRadioactivity iles/news.htmlTechnetium-99m (99mTc) is now the worldwideworkhorse of nuclear medicine. In the next 40 yearsthere will be steady increase in the demand forcyclotron-produced PET isotopes in the worldwideproduction of radiopharmaceuticals.Cyclotron-produced radionuclides are generallyprepared by bombarding stable target material (eithera solid, liquid, or gas) with protons and are thereforeproton-rich, decaying by β -emission. Theseradionuclides have applications for diagnosticimaging with planar scintigraphy, PET and SPECT.Different cyclotron models for the energy range 1012 MeV with moderate beam intensity are used forproduction

Medical imaging is one of the fastest growing disciplines in medicine. The development of . routine use of X-rays, the most common imaging techniques in current clinical practice are: computed tomography (CT or CAT), magnetic resonance imaging (MRI), ultrasound (US), planar . 4 From Radioisotopes to Medical Imaging, History of Nuclear .