The necessity of nuclear reactors for targeted radionuclide therapies

Opinion

The necessity of nuclear reactors for targeted radionuclide therapies Gerard C. Krijger1, Bernard Ponsard2, Mark Harfensteller3, Hubert T. Wolterbeek4, and Johannes W.F. Nijsen1 1

Department of Radiology and Nuclear Medicine, University Medical Center Utrecht, Utrecht, The Netherlands Belgian Nuclear Research Centre (SCKCEN), BR2 Reactor, Mol, Belgium 3 ITG Isotope Technologies Garching GmbH, Garching, Germany 4 Department of Radiation, Radionuclides and Reactors, Faculty of Applied Sciences, Technical University Delft, Delft, The Netherlands 2

Nuclear medicine has been contributing towards personalized therapies. Nuclear reactors are required for the working horses of both diagnosis and treatment, i.e., Tc-99m and I-131. In fact, reactors will remain necessary to fulfill the demand for a variety of radionuclides and are essential in the expanding field of targeted radionuclide therapies for cancer. However, the main reactors involved in the global supply are ageing and expected to shut down before 2025. Therefore, the fields of (nuclear) medicine, nuclear industry and politics share a global responsibility, faced with the task to secure future access to suitable nuclear reactors. At the same time, alternative production routes should be industrialized. For this, a coordinating entity should be put into place. Shift towards personalized health care and the role of nuclear medicine Nuclear medicine is the medical specialty that involves the application of radioactive isotopes (radionuclides) in the diagnosis and treatment of diseases and abnormalities. For diagnosis, single photon emission computed tomography (SPECT) and positron emission tomography (PET) are often combined with computed tomography (CT) and magnetic resonance imaging (MRI) to obtain both metabolic and anatomic information noninvasively [1]. For SPECT and PET, radionuclides are required that are produced in nuclear reactors and particle accelerators. In nuclear reactors the neutrons produced from fission reactions are used to make radionuclides, while in accelerators and cyclotrons charged particles, especially protons, are used for this purpose [2]. For therapy with radioactivity, a broad variety of options are available. External beam radiotherapy is the most common approach to use ionizing radiation, and also implanting a radioactive source near or in a tumor (internal radiotherapy or brachytherapy) remains a proven and often-used option [3]. However, it can be expected that radionuclide therapy (endoradiotherapy) will become Corresponding author: Krijger, G.C. ([email protected]). Keywords: nuclear medicine; nuclear reactor; cyclotron; radionuclide production; personalized therapy; targeted radionuclide therapy. 0167-7799/$ – see front matter ß 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/ j.tibtech.2013.04.007

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increasingly used in combination with or as an alternative to chemotherapeutics [4,5]. Treatment has been primarily based on the average patient response, rather than individualizing healthcare to specific patient and disease characteristics [6]. However, today, health care is developing towards personalized therapies. By matching patient and treatment plan, an improvement of efficacy, extension of average life span and improvement of quality of life can be achieved, and a cost reduction per patient per extra year of survival is possible as well [7,8]. The role of nuclear medicine in such individualized patient management is highly significant for diagnostics, treatment evaluation, and therapy. Recent developments in targeted radionuclide therapies A radiotherapeutic agent usually consists of two components: the a-, b-, or Auger-electron-emitting radionuclide and the molecular targeting vector that ensures accumulation at or in tumor cells. Iodine-131 has been in use for decades for the treatment of thyroid cancer [9]. Commercially available and high potential therapeutic radiopharmaceuticals currently include peptides, monoclonal antibodies, microspheres, and phosphonates. In particular, the fields of peptide receptor radionuclide therapy and radioembolization are expanding rapidly now that certain therapies have been approved in several large health care market countries such as the USA, Germany, Spain, and Italy. Box 1 provides detailed information about developments in the four most important types of targeted radionuclide therapies. Also, implementation of the concept of theranostics (also known as theragnostics), which refers to an integrated approach to diagnostics and therapy using suitable combinations of molecular targeting vectors and radionuclides, has started [10]. This is achieved by using therapeutic radionuclides that co-emit imageable g radiation, such as In-111, I-131, Lu-177, and Ho-166 [11,12]. Theranostics can also be performed by using molecular targeting vectors that can be labeled with both diagnostic or therapeutic radionuclides, such as Y-86 and Y-90 [11,12]. The therapeutic radionuclides that are most commonly used – or are expected to be widely used in the near future – are mainly nuclear reactor produced radionuclides, that is, Sc-47, Y-90, I-131, Ho-166, Lu-177, Re-188, and Bi-213.

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Box 1. Important targeted radionuclide therapies Radiommunotherapy Radioimmunotherapy is especially suitable for the control of small and dispersed cancers, such as metastases [31,32]. Currently, several therapeutic antibody (fragment) based radiopharmaceuticals, such as Y-90-ibritumomab tiuxetan (Zevalin) and I-131-tositumomab (Bexxar), are used for the treatment of lymphoma. Pretargeted radioimmunotherapy is also being studied, especially in more recent hematological studies. In pretargeted radioimmunotherapy, the often disadvantageous pharmacokinetic properties of radioimmunotherapy are circumvented by administering the therapeutic radionuclide after targeted antibody accumulation. Several clinical trials are still running or have recently been completed in the fields of radioimmunotherapy and pretargeted radioimmunotherapy [33,34]. Peptide receptor radionuclide therapy I-131-metaiodobenzylguanidine (MIBG) therapy for neuroendocrine tumors (NETs) has been used worldwide for several years [35]. The most prominent example of successful peptide receptor radionuclide therapy implementation is also linked to NETs, that is, Lu-177-DOTAoctreotate (Luthathera). The peptide binds to the somatostatin receptor that is almost exclusively present on NETs. Niche applications have been demonstrated by using specific chelator, somatostatin receptor analogs and/or radionuclide combinations, especially Ga68 and In-111 (diagnostic), and Y-90 (therapeutic) and Lu-177 (both diagnostic and therapeutic) [36,37]. Radioembolization Intra-arterial radioembolization with Y-90 microspheres is an effective treatment for patients with unresectable liver malignancies, and more encouraging clinical results have been reported [38]. Two Y-90microsphere products are commercially available (SIR-Spheres and TheraSphere) and are now reimbursed in the USA and most countries in Europe.

Production and clinical use of radionuclides Taking half-life, decay chain, production route, and chemistry into consideration, only a few dozen radionuclides remain as realistic candidates for clinical applications [12,13]. Before starting the production of a new radionuclide or putting into use a new production unit, several aspects must be investigated. (i) Which production route is convenient, and more importantly, which production route yields a product that delivers sufficient yield as well as the quality required? (ii) Are the distribution logistics feasible? (iii) Is there a suitable chemical separation process available? (iv) How can this radionuclide be produced in Good Manufacturing Practice (GMP) quality? (v) How can a reliable supply be established? From a logistic point of view a radionuclide generator is an ideal source of radionuclides for hospitals. It is a radiochemical system containing a long-lived parent radionuclide selectively bound on a column. The parent nuclide decays into a short-lived daughter radionuclide that is used for clinical applications. There are several parent– daughter radionuclide pairs that are used substantially in nuclear medicine (Mo-99/Tc-99m, Ge-68/Ga-68) or are expected to be in the future (Sr-90/Y-90, W-188/Re-188, Ac-225/Bi-213) [12–16]. Production Considering modes of producing radionuclides for medical use, the key characteristics are yield, specific activity, target integrity, radionuclide purity, and (radio)chemical

An important issue is the possibility of quantitative imaging for dosimetry to ensure optimum deposition of radioactive microspheres in the tumorous tissue. Y-90 microspheres can be detected by Bremsstrahlung SPECT and PET [39]. The yttrium PET imaging is superior to Bremsstrahlung-SPECT-based dose estimates, which give large underestimations in high-dose regions [40]. Nevertheless, the resolution is low and small amounts of activity are difficult to detect accurately. Therefore, microspheres containing radioactive holmium in a matrix of poly(L-lactic acid) have been developed [41]. Ho-166 emits therapeutic (b) and imageable (g) radiation, whereas the high percentage present stable Ho-165 is paramagnetic. This makes small amounts of activity by Ho-166 microspheres quantitatively visible on SPECT and results in high-resolution imaging with MRI, enabling the use of dosimetry and personalized patient treatment [42]. Another form of radioembolization is hepatic arterial administration of radionuclide tagged ethiodized oil (Lipiodol). I-131, Re-188-HDD (HDD = 4hexadecyl-2,2,9,9-tetramethyl-4,7-diaza-1,10-decanethiol) and Y-90EDTB-Lipiodol (EDTB = N,N,N0 ,N0 -tetrakis(2-benzymidazolylmethyl)1,2-ethanediamine) have been prepared and investigated [43,44]. Palliation therapy A high percentage of patients with solid tumors develop painful bone metastases in the course of their illness. Analgesic drugs, antibodies, bisphosphonates, and bone-seeking radiopharmaceuticals appear to relieve the pain and therefore improve quality of life [45,46]. Radiopharmaceuticals bind to the bone matrix in areas of increased bone turnover, and have a therapeutic effect. Various radiopharmaceuticals have been developed for this purpose, including Sm-153-ethylene diamine tetramethylene phosphonate (Quadramet); all with their own specific characteristics [47,48]. They have been shown to be effective in pain palliation, with only relatively small differences in efficacy or toxicity [49], although the relatively new Ra-223 chloride (Alpharadin) could occupy a unique niche in the treatment of metastatic castrationresistant prostate cancer in the near future [50].

purity. A simplified production equation for both nuclear reactors and cyclotrons in relation to yield is given in Box 2. The specific activity (SA) is the radioactivity at a specific time (At) per unit of mass (m) of the corresponding chemical element: SA = At/m. A high SA can be important, especially in targeted therapies involving peptides and (fragments of) antibodies when saturation of targeted receptors occurs at relatively low concentrations. A further consideration concerning the selection of production routes is to minimize side reactions that give rise to the production of undesired other radionuclides. These side-reactions may occur due to the presence of other isotopes (and/or elements) in the target or due to competing nuclear reactions on the same target isotope. An examples is the production of Lu-177 from Lu-176 in which the longlived Lu-177m (160 days half-life, m = metastable) is coproduced [17]. In most cases, irradiation targets consist of inorganic element compounds (such as metal oxides). Sometimes, organic targets are chosen, for example the Ho-166 microspheres as described in Box 1. In such cases, irradiation conditions should be optimized to avoid substantial target damage [18]. Clinical use Radionuclides in radiopharmaceuticals are commonly defined as active pharmaceutical ingredients (APIs) or medical devices (brachytherapy seeds and microspheres). They require a manufacturing authorization that depends on the fulfillment of GMP regulations [19]. 391

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Box 2. Radionuclide production calculations The amount of produced radioactivity (yield) is given by a simplified production equation for both nuclear reactors and cyclotrons:   NAV m ui At ¼ lN t ¼ FðEÞ s ði;EÞ ð1  e lt ir Þ M in which At is the produced radioactivity (in Bq), l is the decay constant (l ¼ TLn2 in s–1, with T1/2 in s as the radionuclide half-life), Nt 1=2

is the number of produced radioactive nuclei, FE is the particle flux used to irradiate the target. E is the particle energy (usually in eV or MeV), s(i,E) is the probability of isotope i capturing particles of energy E (s = cross section given in barns with 1 barn = 10–24 cm2), NAV is the Avogadro constant, m is the mass of the target of a specific element of molecular mass M, ui is the fractional abundance of isotope i within the target element, and tirr is the length of the irradiation period (in s). It should be noted that, for charged particles, s(i,E) represents thin targets only: target thickness may affect effective overall capture probability. As can be inferred from this production equation, the yield of a certain radionuclide may be increased by increasing the target mass, target material enrichment in the isotope of interest, particle flux, and irradiation time. Increasing the target mass is generally easier in a nuclear reactor than in a cyclotron, because neutrons have a much higher penetration depth than charged particles. The particle flux is generally set by the particle source characteristics. As a rule of thumb, the irradiation time can be extended to about three times the half-life of the radionuclide until one saturation. A key characteristic for radionuclide production is the cross-section, describing the probability that a beam particle will lead to a specific physical process with the target atomic nucleus. This cross-section depends on the energy of the particle. A high SA is generally obtained for cyclotron-produced radionuclides, because the target material contains a different chemical element than the produced radionuclide. For nuclear-reactorproduced radionuclides, a careful selection of the production route is essential. When a low SA is sufficient, no problems arise when the product cannot be separated from the target, that is, in the case of neutron capture reactions (n, g reaction). If a high SA is required, a common method is to substitute a proton in the atomic nucleus for a beam neutron (n, p reaction), which implies that target and product can be chemically separated after production.

Before new radionuclides can be authorized for clinical use, all relevant documents must be provided and the necessary clinical trials conducted. However, the legal situation in Europe, for instance, is heterogeneous. In countries like Germany the use of new, unregistered nuclides/therapies is the responsibility of the physician. In other countries, such as France, the product must be registered before it can be used. Naturally, this has a massive impact on the research possibilities. An alternative to marketing authorization is establishing a monograph in the Pharmacopoeia and consequently implementing all tests demanded by the Pharmacopoeia. This possibility is likewise based on a process that can take several years. There are national/regional differences in the process of marketing authorization as well as in the different Pharmacopoeias (e.g., British, European, and American), thus, it is essential to comply with all of the various regulations in the relevant markets. Regulatory issues aside, it is necessary to establish the GMP production environment. The complexity of these processing facilities strongly depends on the production route: if a product is derived from fission, considerably more attention must be focused on security than if operating a generator. A radiochemistry laboratory is focused on protecting personnel and the environment from the 392

radioactive product. To obtain GMP quality in these processing units, the radioactive product must also be protected against influences from environment and personnel. This means that a quality assurance and quality control system must be established and that the process must be transferred to clean environments as in clean rooms and hot cells (shielded isolators). In the production of radiopharmaceuticals several compromises must be reached to integrate the requirements of the pharmaceutical world and issues of radiation protection. Hence, the third annex of the internationally accepted but not yet harmonized GMP guidelines for manufacturing radiopharmaceuticals has been established; this annex defines exceptions for such issues releasing diagnostic products for use before all test results are available, because the product would have been decayed before release [20]. Securing future needs for medical radionuclides If one could start from scratch in meeting the demands of a static global market for radionuclides, it would be relatively easy to create a reasonably priced and secure global radionuclide supply network. However, the demand for medical radionuclides is not static but dynamic and many historical, political, economic, and scientific reasons have created the complex situation that we face today. Current nuclear reactors are aging, expensive to replace and, due to safety issues, a continuing source of public and political debate. Nevertheless, the demand of medical radionuclides still requires nuclear reactors. Other production routes of radionuclides such as particle accelerators, especially the compact cyclotrons, have become smaller, cheaper, and commercially available from various companies. There are more than 700 cyclotrons in operation worldwide today and this number is rapidly increasing [21]. However, they are often specifically dedicated to one or a few radionuclides, mainly F-18 for the production of 2-F-18-fluoro-2deoxy-D-glucose (F-18 FDG). Nuclear reactors for radionuclide production The supply of reactor-produced medical radionuclides relies on a limited number of research reactors and processing facilities. Worldwide, only four processing facilities supplied by eight reactors are able to produce Mo-99 for Tc99m generators on an industrial scale (Figure 1). The radionuclide supply chain consists of target manufacturers, nuclear research reactors for target irradiation, processing facilities to dissolve the irradiated targets and extract the radionuclides of interest, generator manufacturers if applicable, transport companies, and radiopharmacies. The manufacturing process along the supply chain must be carried out in a ‘last-minute’ manner as a result of the short half-lives of the radionuclides involved. Nuclear reactors are situated in Canada (NRU), The Netherlands (HFR), Belgium (BR2), France (OSIRIS), Poland (MARIA), the Czech Republic (LVR-15), South Africa (SAFARI), and Australia (OPAL). The same reactors are also involved in the production of the majority of the medical radionuclides mentioned earlier, and there are a few additional reactors for specific radionuclides, including MURR and HFIR (USA), SM-3 (Russia), FRM-II

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2 11

2

1 1

1 1 Key:

= Reactor = Processing facility Mo-99 = Manufacturer generators TRENDS in Biotechnology

Figure 1. Global map of the geographical distribution of the main actors involved in the global supply of Mo-99/Tc-99m and represented within the Association of Imaging Producers & Equipment Suppliers (AIPES) Reactors & Isotopes Working Group.

(Germany) and HANARO (Korea). In addition, a number of reactors are used for regional production, including RA-3 (Argentina) and GA SIWABESS Y MPR (Indonesia). The vast majority of the main research reactors involved in the global supply of reactor produced radionuclides are about 50 years old (Table 1). They are subject to increasing shutdown periods due to the inspections and maintenance operations necessary for safe and reliable operation. Lessons have been learned from previous severe shortages experienced by the supply chain, especially since 2009–2011, in which three main reactors involved in the production of Mo-99 were shut down for several months for major maintenance operations [22,23]. Due to this crisis, many thousands of patients were denied diagnostic procedures using Tc-99m. The minority was diagnosed using inferior and/or more expensive radiopharmaceuticals. The main actors in the supply chain (research reactors, processing facilities, and Mo-99/Tc-99m generator manufacturers) are represented in the Reactor & Isotopes Working Group of the Association of Imaging Producers & Equipment

Suppliers (AIPES), with the primary goal of achieving optimal coordination of their operating periods. At least three of the reactors shown in Figure 1 are routinely operating simultaneously, depending on their geographic location. Around 80% of all diagnostic procedures in nuclear medicine (about 30 million per year) depend on Tc-99m obtained from reactor-produced Mo-99, and coordinating the activities of supply reactors can provide an adequate global supply of radionuclides for nuclear medicine all year round in the immediate future. Parallel to initiatives such as the AIPES Reactor & Isotopes Working Group, individual companies such as ITG Isotope Technologies Garching GmbH (Germany) are agreeing to business deals within a global nuclear reactor and technology network. Their exploitation of the FRM-2 reactor in Germany and collaboration with NTP Radioisotopes SOC Ltd. (South-Africa) and ANSTO (Australia) will, for example, ensure a reliable worldwide supply of Lu-177 (non-carrier added) by building more of these radionuclide processing facilities compliant to GMP conditions.

Table 1. Main research reactors involved in the production of medical radionuclides Reactor

Country

Start of operation

Expected shut-down

Power [MW]

NRU LVR-15 HFR BR2 SM-3 SAFARI HFIR OSIRIS MURR MARIA HANARO FRM-II OPAL

Canada Czech Rep Netherlands Belgium Russia South Africa United States France United States Poland Rep Korea Germany Australia

1957 1957 1961 1961 1961 1965 1965 1966 1966 1974 1995 2004 2006

2016 ? 2018 2020 ? 2020 ? 2015 2026 ? ? ? ?

135 10 45 120 100 20 100 70 10 30 30 20 20

Max thermal neutron flux [e+14 n/cm2.s] 4 2 3 10 30 3 20 2 4 4 4 2 3

Operating days per year 300 200 280 140 ? 300 170 180 300 240 220 240 300 393

Opinion Improving current reactor facilities and non-reactor options Initially, most of the reactors mentioned above were built for research purposes. Local medical radionuclide production was initially just one of their tasks, but in recent decades, it has become more important and more internationalized. In theory, there are about 244 research reactors in over 50 countries, of which at least a few dozen could be upgraded for regional production of medical radionuclides (http://nucleus.iaea.org/RRDB/). However, this is often logistically challenging and not cost-effective as transportation of highly radioactive target material to the current limited number of processing facilities is a time-consuming, costly, and delicate matter, whereas building new processing facilities is expensive. Due to the historical context, the current design of neutron irradiation facilities for the production of medical radionuclides in existing reactors is not optimal to meet requirements of new production routes. In the meantime, a challenge concerning the production of standard fission products (Mo-99, I-131, and Xe-133) is the conversion of targets from highly enriched uranium into low enriched uranium in 2015, for security and non-proliferation reasons. So far, no operational problems have been encountered, but the reactor capacity demands for target irradiations and the produced nuclear waste from targets processing will increase. Much attention has been given to alternatives for Mo-99 production, such as aqueous homogenous reactors (AHRs), direct production from Mo-98 by neutron activation, production in power reactors or by target fuel isotope reactor (TFIR) approaches, in which the fuel elements themselves may serve as targets for Mo-99 [24,25]. Additionally, nonreactor options are being investigated, in assemblies such as ADS (Accelerator Driven Subcritical Assembly) and SHINE (Subcritical Hybrid Intense Neutron Emitter) [24]. Some of the current reactor facilities could be improved in terms of fluxes or selected neutron energy characteristics. Other options are moderation of thermal neutrons to cold neutrons or exploitation of the resonance neutron energy peaks for higher yields. The Reactor Institute Delft in The Netherlands plans to build a cooled neutron facility (http://www.tnw.tudelft.nl/en/cooperation/facilities/reactor-instituut-delft/oyster/) that enables recoil and bondrupture separation studies in more detail [26]. To date, neutron generator systems (other than reactors) have not yielded the neutron densities required for most industrial scale medical radionuclide production processes. The French company Advanced Accelerator Applications (AAA) has demonstrated the possibility of utilizing ion-beam-generated neutrons using the adiabatic resonance crossing technique for radionuclide production for specific purposes and a local market, such as Ho-166 and Re-188 for brachytherapy [27]. Accelerator-based neutron flux in the neutron beams as anticipated in for instance the European Spallation Source in Sweden have pulsed beams that, when time-integrated, yield insufficiently high densities for significant medical radionuclide production possesses as yet. Social–political aspects and perceptions of nuclear reactors stimulate efforts to explore the potential of cyclotrons 394

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to further complement or even replace reactors where the production of reactor produced medical radionuclides is concerned [16,28]. Cyclotrons are available worldwide and are specifically used to produce short-lived positron emitting radionuclides such as C-11 (half-life = 20.3 min) and F-18 (half-life = 109.8 min) suitable for diagnostic purposes in nuclear medicine. In addition, small table-top devices are available for the local production of mainly C-11 and F-18, because of their limited current and particle energy [29]. Several groups in the USA and Canada are investigating new production routes of reactor-produced radionuclides using cyclotrons. For example, the Government of Canada has decided that the NRU reactor will stop its global production of Mo-99 in 2016 and that Tc-99m should be directly produced by accelerators to cover domestic needs. This will provide a major challenge, both from the production capacity and exploitation costs points of view, although serious options are available [22–29]. Worldwide logistics optimization Currently, radionuclides are produced by heavily subsidized operation hours of the research reactors. The ‘molybdenum crisis’ has driven awareness of the importance of radionuclides for nuclear medicine and the complexity of the processes and facilities needed to produce them. A reasonable cost structure must be established to include the real cost of radionuclide productions. As a midterm target, existing reactors should be enabled to produce radionuclides by way of incentives, for example, reasonable service fees. Nuclear reactor production of medical radionuclides will still be required to meet the demands of health care in the decades to come, and certainly not only Mo-99. From a global market point of view the distribution of the radionuclides for nuclear medicine is far from optimal, especially because a rapidly increasing demand from upcoming markets in Asia and South America is expected. Russia is developing irradiation and processing capabilities in Dimitrovgrad (Isotop-NIIAR), China in Chengdu (HFETR), and Egypt in Inshas (ETRR-2). Despite this, 2015–2025 could prove vulnerable to significant shortages of medical radionuclides due to reactor shutdowns and political decisions. The OSIRIS reactor is scheduled to shut down in 2015, but will be replaced by the JHR reactor that is currently under construction in Cadarache (France) and scheduled to start in 2017. Other replacement projects are presently being investigated, mainly PALLAS (The Netherlands) and MYRRHA (Belgium) to replace HFR in 2022 and BR2 in 2023, respectively. Scheduled replacement of a small number of reactor facilities should go in parallel with ongoing research to produce securely medical radionuclides for a dynamic global market with low waste and at low cost. In the long term, alternative production routes for radionuclides should be explored on a more industrial scale; preferably in a global coherent way. Such global initiatives to test alternative radionuclide production routes should preferably be coordinated by an international entity, for example the International Atomic Energy Agency (IAEA). This would result in a better alignment of the activities and thus reduction of overall costs.

Opinion Concluding remarks Nuclear medicine will play an increasingly important role in medicine due to its increasingly personalized approach. Important radionuclides used for diagnostics (Tc-99m) and targeted therapies (Y-90, I-131, Sm-153, Ho-166, Lu-177, and Re-188), as well as for brachytherapy (Co-60, Ru-106, I-125, and Ir-192) are currently produced by nuclear reactors. Although cyclotrons can produce complementary radionuclides, and further research can result in alternative routes for several reactor-produced radionuclides, it will not be sufficient to make nuclear reactors redundant in the next few decades. However, the aging of the main reactors involved in global supply of medical radionuclides makes secure radionuclide supply difficult. To prevent new and more frequent medical radionuclide shortages, a shared global responsibility is needed by (nuclear) medicine, nuclear industry, and politics, which should lead to replacement of a small number of aging reactor facilities by modernized ones. It should be taken into account that dedicated production reactors are not economically viable, if the full cost recovery principle defined by the OECD-NEA (Organisation for Economic Co-operation and Development – Nuclear Energy Agency) applies [30]. The replacement projects should go hand in hand with up-scaling projects of most promising alternative radionuclide production routes, preferably under the auspices of an international entity, for example, the IAEA, to make nuclear medicine less vulnerable to shortages. References 1 Histed, S.N. et al. (2012) Review of functional/anatomical imaging in oncology. Nucl. Med. Commun. 33, 349–361 2 IAEA (2008) Cyclotron Produced Radionuclides: Principles and Practice, International Atomic Energy Agency 3 Mundt, A.J. et al. (2006) Principles of radiation oncology. In Cancer Medicine (7th edn) (Kufe, D.W. et al., eds), pp. 517-536, BC Decker 4 Chamarthy, M.R. et al. (2011) Radioimmunotherapy of non-Hodgkin’s lymphoma: from the ‘magic bullets’ to ‘radioactive magic bullets’. Yale J. Biol. Med. 84, 391–407 5 Forstpointner, R. and Dreyling, M. (2011) Rituximab maintenance versus radioimmunotherapy consolidation in follicular lymphoma: which, when, and for whom? Curr. Hematol. Malig. Rep. 6, 207–215 6 Bartlett, G. et al. (2012) Theranostics in primary care: pharmacogenomics tests and beyond. Expert Rev. Mol. Diagn. 12, 841–855 7 Velikyan, I. (2012) Molecular imaging and radiotherapy: theranostics for personalized patient management. Theranostics 2, 424–426 8 Unger, F. (2012) Health is wealth: considerations to European healthcare. Prilozi 33, 9–14 9 Gabriel, M. (2012) Radionuclide therapy beyond radioiodine. Wien. Med. Wochenschr. 162, 430–439 10 Alberti, C. (2012) From molecular imaging in preclinical/clinical oncology to theranostic applications in targeted tumor therapy. Eur. Rev. Med. Pharmacol. Sci. 16, 1925–1933 11 Srivastava, S.C. (2012) Paving the way to personalized medicine: production of some promising theragnostic radionuclides at Brookhaven National Laboratory. Semin. Nucl. Med. 42, 151–163 12 Nijsen, J.W.F. et al. (2007) The bright future of radionuclides for cancer therapy. Anticancer Agents Med. Chem. 7, 271–290 13 Neves, M. et al. (2005) Radionuclides used for therapy and suggestion for new candidates. J. Radioanal. Nucl. Chem. 266, 377–384 14 Montan˜a, R.L. et al. (2012) Yttrium-90 -current status, expected availability and applications of a high beta energy emitter. Curr. Radiopharm. 5, 253–263 15 Pillai, M.R. et al. (2012) Rhenium-188: availability from the (188)W/ (188)Re generator and status of current applications. Curr. Radiopharm. 5, 228–243

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Opinion 44 Jeong, J.M. and Knapp, F.F., Jr (2008) Use of the Oak Ridge National Laboratory tungsten-188/rhenium-188 generator for preparation of the rhenium-188 HDD/lipiodol complex for trans-arterial liver cancer therapy. Semin. Nucl. Med. 38, S19–S29 45 Cleeland, C.S. et al. (2013) Pain outcomes in patients with advanced breast cancer and bone metastases: results from a randomized, doubleblind study of denosumab and zoledronic acid. Cancer 119, 832–838 46 Lam et al. (2007) Bone seeking radiopharmaceuticals for palliation of pain in cancer patients with osseous metastases. Anticancer Agents Med. Chem. 7, 381–397

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47 Jansen, D.R. et al. (2010) Targeted radiotherapy of bone malignancies. Curr. Drug Discov. Technol. 7, 233–246 48 Paravati, A.J. et al. (2011) Adverse events in the long-term follow-up of patients treated with samarium Sm 153 lexidronam for osseous metastases. Int. J. Radiat. Oncol. Biol. Phys. 81, 506–510 49 Ogawa, K. and Washiyama, K. (2012) Bone target radiotracers for palliative therapy of bone metastases. Curr. Med. Chem. 19, 3290–3300 50 Harrison, M.R. et al. (2013) Radium-223 chloride: a potential new treatment for castration-resistant prostate cancer patients with metastatic bone disease. Cancer Manag. Res. 5, 1–14