19 December 2008

Radioisotopes in Medicine
Foresight of the use of reactor isotopes until 2025

SPECT nuclear imaging of the heart, Patrick J. Lynch,

www.technopolis-group.com

Table of contents
1. Introduction 1.1 Commission VROM 1.2 Background HFR 1.3 Request 1.4 Delineation 1.5 Structure of the report 2. Method of investigation 2.1 Foresight studies 2.2 Expert Committee 2.3 Exploratory interviews 2.4 Survey of a broad-based group of high-level experts 3. Current system 3.1 Description of the technologies 3.2 Production of radiopharmaceuticals 3.3 Use of radiopharmaceuticals by the respondents 4. Explorations into the future use of radiopharmaceuticals in medical practice 4.1 Modalities 4.2 Future use of technetium 4.3 Therapy 5. Conclusion 1 1 1 2 3 3 4 4 4 4 5 7 7 11 13 21 21 28 33 34

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1. Introduction
1.1 Commission VROM1
In April 2008, Technopolis received a request from the Ministry of VROM to conduct a foresight study of the use of reactor isotopes, as part of the decision-making process regarding the construction of a new research reactor. Expectations are that the High Flux Reactor (HFR) in Petten, the Netherlands, will reach its end of life around 2016. In the HFR in Petten, one of the materials that is irradiated with neutrons is uranium. In this process, molybdenum is generated, which decays into technetium. Technetium is used for imaging techniques in nuclear medicine on a large scale. In 2003, a report of the official steering group of the Ministry of VROM indicated that at present, there is no alternative for the medical uses of technetium2. Furthermore, the use of the products generated by the HFR in medicine for imaging techniques contributes substantially to the operating results of the HFR. Vital medical uses and an economic right of existence are important factors in the justification of the construction of a new research reactor. The Dutch government, including the Ministry of VROM, will have to decide on permission for a new research reactor and its justification. That is why for the Ministry of VROM it is not only relevant to know the need for the products of the HFR (and in particular Technetium), but also what alternative technologies have to offer in the longer term, i.e. after 2015. The request from VROM therefore concerns a foresight study into the possibilities of future, alternative technologies to gain an understanding of the relevance of a new research reactor. This involves both a study into alternative production methods and a study into alternative (imaging) technologies. This report only addresses the latter. The Reactor Institute Delft performs a study into alternative production methods also commissioned by VROM.

1.2 Background HFR

Since 1962, the HFR is owned by the Institute for Energy (IE) of the Joint Research Center (JRC) of the European Committee (EC). The Nuclear Research and Consultancy Group (NRG) is the licensee of the reactor. The reactor is operated and maintained by NRG-staff. The HFR is Europe's largest manufacturer of radiopharmaceuticals. The vast majority of the radiopharmaceuticals are used for the imaging of biological processes in the body. The most widely used isotope for medical imaging is technetium. For imaging procedures with technetium, proteins are labelled with this isotope. Subsequently, these proteins are administered to patients. In the body, these proteins adhere to targeted areas, thereby enabling visualisation by means of external scans with an imaging device. This application is used for different diagnostic purposes, in particular in oncology, neurology, cardiology, for bone scans, and for imaging the function of organs such as kidneys, liver, brain and lungs. Technetium is of great importance to the medical world: Around 80-85% of all nuclear-medicine procedures performed use technetium; there are about 40 million procedures performed each year, 50% of which

VROM: Dutch Ministry of Housing, Spatial Planning and the Environment Medical isotopes and the high flux reactor. Letter to the Dutch Lower House, no. 25422-27 with annex, March 2003.
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in North America3 and 30-40% in Europe4. In the Netherlands, in 2007 approximately 393,000 nuclear medical procedures were performed5. Apart from technetium, other products of the HFR are used for medical purposes (see Table 1). Next to technetium, the most important isotopes in terms of market volume are iodine-131 and iridum-192. These are highly important to certain groups of patients. In addition, there are other isotopes that are increasingly used, such as lutetium-177 and ytrrium-90. This is connected with new developments in therapeutic uses of radioisotopes.

Table 1 Overview of the medical uses of HFR products

HFR Product Molybdenum900/Technetium-99m Use Diagnostic imaging for oncology, bone scans, cardiology, and the imaging of the function of organs such as kidneys, liver, brain and lungs. Therapy for thyroid disorders, cancer therapy Diagnostic imaging of lung function Therapy for metastatic bone pain Cancer therapy, e.g. lung cancer, head and neck cancer, tongue and mouth cancer, cancer of the throat and treatment of stenosis Therapy for metastatic bone pain and bone cancer Therapy for metastatic bone pain Therapy for prostate and eye cancer Therapy for arthritis Therapy for arthritis of smaller joints Therapy for tumours Development of therapy for liver cancer and blood cancer.

Iodine-131 Xenon-133 Strontium-89 Iridium-192 Samarium-153 Rhenium-186 Iodine-125 Yttrium-90 Erbium-169 Lutetium-177 Holmium-166 NRG, 2008: www.nrg-nl.com

1.3 Request
The request from the Ministry of VROM concerns a foresight study into the possibilities of future, alternative technologies for medical imaging and the future need in medicine for radioisotopes in general and technetium in particular. At present, HFR is of great importance for nuclear imaging in the medical world at national, European and worldwide level. How this will be in the period from 2015-2025 has to be answered with the following research questions: 1. What is the expected volume of imaging technologies for medical purposes in the future, i.e. from now till 2025 and what will be the relative share of technetium-based imaging in these technologies?"

Triumf, 2008. Making Medical Isotopes. http://www.nrg-nl.com/product/fuel/isotopes/index.html, visited in Augustus 2008. 5 RIVM, http://www.rivm.nl/ims/object_document/o5n1150.html, visited in November 2008.
4 NRG:

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2. "What new or upcoming imaging technologies for medical purposes may affect or displace the technetium-based imaging in the period till 2025, both in terms of quality and quantity?"

1.4 Delineation
An estimated 90% of the radiopharmaceuticals are used for medical imaging procedures. That is why we will essentially concentrate on imaging techniques in medicine in this report. Within the imaging technologies, not only isotopes such as technetium are used, but also isotopes that are generated in a cyclotron (particle accelerator)6. In this report, the context of the different imaging technologies is indicated, as well as developments within each technology. Pharmaceuticals are also used for therapeutic treatments. This use has also been included in this study because of its importance in medicine in terms of quality, but less emphasis is placed on it because of its limited importance compared to medical imaging in terms of quantity. In this foresight study, a time span till 2025 has been chosen. Although a newly constructed reactor will have a useful life substantially beyond the year 2025, this report does not go beyond 2025 because of the increasing uncertainties when looking further into the future. The research questions not only deal with technological aspects or feasibility, but also non-technological aspects. As for technology development, the time that it takes to develop a certain technology for medical use is relatively long because of stringent regulation in health care. And even if a new technology becomes available, it will not automatically mean that it will be used as widely as technetium at present. As for nontechnological aspects, costs (of treatment, but also investments in equipment), patient safety, limitation of radiation exposure, logistics, infrastructure (e.g. suitability for cyclotron), and technical expertise of personnel may all be important in the selection of a certain imaging technology or modality. Furthermore, this study focuses on the Netherlands in particular. In the Netherlands, medical imaging is well developed, partly due to the presence of a large Dutch manufacturer. In other countries, the proportions between the various imaging technologies may differ, which means that the results of this study cannot be simply applied to any other country. As a result of the current problems with the supply of reactor isotopes, however, the same questions are raised internationally.

1.5 Structure of the report

This report aims at providing a broadly based answer to questions of position and volume regarding the future use of radioisotopes for medical procedures. To that end, chapter 2 explains what methodology has been used and why. Subsequently, chapter 3 addresses the current medical imaging modalities and the present use of these modalities. It also deals in more detail with the manufacturing of radiopharmaceuticals and related market developments. Chapter 4 discusses the expectations for the future regarding the use of different imaging modalities and technetium in particular, as well as the expectations regarding the use of reactor isotopes for therapy. Chapter 5 summarises the conclusions.

In this report, we use the term reactor istopes for the isotopes produced in nuclear reactors, HFR in particular.

Radioisotopes in Medicine

2. Method of investigation
The research questions have been answered through a combination of methods to identify future developments. A large number of experts were involved in the entire process, enabling a sound picture of future developments in imaging technologies in general and the use of technetium in particular. Technopolis itself did not make any technological choices: an expert committee guarantees the independence and scientific accuracy.

2.1 Foresight studies

The importance of foresight is that it retrieves knowledge that can be used to anticipate and respond timely to developments that have yet to take place. This is particularly important for problems that may have far-reaching consequences and a large time span before solutions may be realised. Shortage of radiopharmaceuticals could cause great difficulties that would take years to remedy. That is why today we need to know the problems of tomorrow. There are different ways to study the future, in which experts often play an important part. More and more, the influence of the user is also seen as a determining factor in this process. Any future study is plagued by uncertainty; the further ahead you look, the higher the level of uncertainty and the greater the variation in the results. In this study, we use a combination of methods to arrive at a maximally reliable result: Expert committee; Structured and exploratory interviews with the industry, physicians and specialists; A survey of a broad-based group of experts.

Below, the steps taken are explained in more detail.

2.2 Expert Committee

An Expert Committee (EC) is important to safeguard the quality of the study. The committee is composed of high-level experts with a collective insight in the different areas that are relevant to medical imaging and diagnostics and medical, scientific research (see Appendix A.1). The Expert Committee made important contributions at three stages in the entire process: Identification of experts, both for the interviews and for the survey; Providing an outline of the present state of the art; Validation of the survey results and generation of consensus.

2.3 Exploratory interviews

The first step in explorations is to identify the domains in which radioisotopes are used and for what medical indications, the availability of any other imaging techniques and what these are used for, the prospects, and the present and future issues and uncertainties. What changes in the environment affect these domains? To this end, interviews were conducted with 10 experts (researchers and users) in the field of imaging and nuclear medicine as well as with industry representatives (see Appendix A.2). These exploratory interviews provided greater insight into the most

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recent technological developments, as well as in the possible role of non-technological aspects in future developments.

2.4 Survey of a broad-based group of high-level experts

The purpose of a survey is the identification of the views held by a certain target group, and the development of a joint image of the future. Often, the studies involve the generation of a design orientation in relation to research, which is predominantly technological in nature. In this survey, a large group of experts and specialists are consulted and asked to give their opinion. This contributes to an understanding of future developments that are important for the different stakeholders in the target group and their expectations regarding these developments. Preferably therefore, the participants are involved stakeholders and experts. In the present case, it means that experts from various fields share their expert views of future developments of medical uses of radiopharmaceuticals and imaging techniques that might be an alternative to technetium. The survey used an online questionnaire7 to guarantee efficiency and efficacy. The Expert Committee validated the survey questions. Subsequently, these questions have been presented online to a group of 102 mainly Dutch experts. These experts have received two reminders, which resulted in a response rate of 45%. In total, 44 persons completed the survey. Given the fact that for this explorative study involvement of high-level experts was preferred, the majority of the respondents are working in a university or leading hospital. Figure 1 presents an overview of the geographic distribution of the respondents.

Figure 1 Geographic distribution of the respondents in the Netherlands

SurveyMonkey

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The majority of the respondents are nuclear physicians (42%). This group of respondents are the ones with the best understanding of the use of reactor isotopes in clinical practice. The other respondents are radiologists, internists, oncologists, (clinical) physicists, (radio)chemists and pharmacists. Approximately 70% of the respondents are physicians; the others mainly have a technical background (see Figure 2).

Figure 2 Expertise of the respondents

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Radioisotopes in Medicine

3. Current system
3.1 Description of the technologies
Since the discovery of X-rays in 1895, many kinds of imaging techniques have been developed in the course of the 2oth century to afford, as it were, a look inside the human body. It is impossible to imagine present-day medicine without medical imaging, a process in which the computer is indispensable. In 2006, as many as 8.5 million X-rays were taken. More advanced technologies such as CT and nuclear imaging was also used frequently and the number of procedures is increasing rapidly. For example, in 1991, 360,000 CT scans were made; in 2006 this number increased to 890,000. The number of nuclear medicine procedures increased from 200,000 in 1991 to 380,000 per year in 2006.8 Medical imaging is a domain that is still rapidly changing: several aspects, such as the refinement of imaging techniques, increase of the resolution and specificity, improvement of the efficiency, moderation of radiation, etc., still demand a great deal of research involving physicians, engineers, physicists, chemists, information scientists, biologists, and mathematicians. Finally, ICT systems also continue to evolve, enabling image processing of ever-increasing quality.

3.1.1 Current imaging techniques

The following technologies are important in medical imaging. CT scan

CT is short for 'computed tomography'. It is a method to examine the human body using X-rays. The principle is as follows: On one side of the patient the X-ray source is located, on the other side an X-ray detector. The source emits a small radiation beam that passes through the patient in a straight line and is weakened by all tissues through which it passes. The detector measures the strength of the remaining radiation. CT produces a large amount of data that can be manipulated through a process called 'windowing', visualising various structures based on their ability to block the X-ray beam. With the aid of digital geometric processing, a threedimensional image is generated from a large series of two-dimensional X-rays taken around an axis of rotation. Although in the beginning mainly axial or transversal images were made, nowadays there are a number of modern CT scanners on the market (dynamic volume, electron beam (EBCT), helix, multi-slice, peripheral Quantitative (pQCT)), enabling 3D images and structures at different angles. The advantage is the excellent visualisation of all sorts of defects and abnormalities with a resolution of 0.3 millimetres, not only of bones but also of all kinds of tissues. The main disadvantage is the higher exposure to radiation compared to conventional Xrays (1 CT scan is roughly the equivalent of 200 X-rays).

RIVM: Diagnostiek: trends in aantal verrichtingen (Diagnostics: trends in number of procedures). http://www.rivm.nl/ims/object_document/o19n1101.html, visited november 2008.

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MRI scan

MRI is short for 'magnetic resonance imaging'. The technique is based on the magnetic properties of atoms, especially hydrogen atoms, which are affected by electromagnetic radiation. The technique is based on the fact that protons (especially hydrogen, but also phosphorus protons) have 'spin', i.e. a small magnetic field. When the spins are placed in a magnetic field, they align either with or against the field. There is a difference of energy between these two states, depending on the strength of the external magnetic field. When the hydrogen nucleus is exposed to a pulse electromagnetic radiation with exactly the right energy (radio waves in the case of MR scanners), this causes the spin status to flip. Shortly after the flip, the nucleus returns to its original position while emitting a photon. By applying a gradient to the force of the magnetic field, flipping the hydrogen nuclei and subsequently measuring the amount of radiation of different wavelengths that is re-transmitted by the nuclei that return to their natural state, you can determine the number of hydrogen nuclei at certain locations. By means of receivers and computers, a 3-dimensional image is formed. An MR scanner consists of a movable table on which the patient has to lie down and which can be moved into a hollow, cylindrical magnet, the magnetic field of which (with a strength of 0.5 to 7 Tesla) is induced by superconductive coils. With modern MR scanners, the resolution is approximately 0.3 millimetres. To increase the contrast of the MR scans, a contrast agent may be applied (gadolinium compounds). With MRI, tissues with many hydrogen atoms can be distinguished from tissues with few hydrogen atoms, as a result of which details of the anatomy can be obtained. MRI scans are particularly useful in producing images of soft tissues. One advantage is that no use is made of X-rays or radioactivity, although little research has been done into the consequences of electromagnetic radiation. Its main disadvantage is that due to the very strong magnetic field, it is not suitable for patients with electronic devices in their body (such as a pacemaker). Echography

Echography, also called echoscopy, is a technique that applies ultrasonic sound waves that move through the body and reflect at interfaces between tissues with different density. The ultrasonic waves are directed into the body by a transducer. The ultrasonic sound waves reflected by the body are received by the same transducer (which alternates between transmitting and receiving) and converted into small electrical impulses. A scanning converter converts the echo signals into video images made visible on a monitor. The potential of digitally processing the signal has expanded enormously in the last decades. Based on the echo, the computer can generate an image of the interior of the body. This technique can be used to make a picture of organs to determine their size, structure, and pathological abnormalities, if any. The most common use of echoscopy is during pregnancy check-ups, but it can also be used to measure the blood flow, for instance. The resolution of ultrasonography is approx. 1 mm. The main disadvantage of the technique is its limited range of applications; it is suitable in particular for soft tissues. The advantage of ultrasonography is it does not involve any ionising radiation or radioactivity. Optical imaging

Optical imaging is a technique based on the inference and bending of light emitted from a laser or infrared light source to the body or tissue. Proteins are introduced in the body that are labelled with a fluorescent marker, for instance, after which the fluorescence is detected. Optical imaging can be further classified into diffusive and ballistic imaging systems. Since light cannot penetrate the body that well, optical imaging is not suitable for examining organs, for instance. It is used, however, for neurological research. The resolution (10 micrometer) is much better than the other modalities, but the importance of optical imaging is marginal compared to the other techniques.

Radioisotopes in Medicine

Nuclear medicine

Nuclear medicine is a mainly diagnostic discipline of medicine for imaging metabolism and other functional processes in the human body. To this end, patients are administered a radioactively labelled tracer. The strength of the technique lies in the fact that use can be made of substances, which move to organ systems in very selective ways. The link to radioactive substances (especially technetium) enables imaging of the distribution of the tracer in the human body with a gamma camera or PET scanner. A major advantage is the high sensitivity that enables measuring (several) molecular processes at picomolar level. Three different modalities are available for this process: planar scintigraphy, SPECT (single photon emission computed tomography) and PET (positron emission tomography). ! Planar scintigraphy is the simplest available technique yielding a 2dimensional projection image of the activity distribution of the tracer in the human body. The technique is based on the gamma radiation that is emitted on decay of the nucleus of a radioactive isotope. SPECT (single photon emission computed tomography) provides threedimensional images of the distribution of nuclear activity with a resolution of 0.5 to 1 cm, which is not very high compared to other techniques. Isotopes suitable for SPECT typically have a half-life of a few hours to a number of days. Isotopes such as technetium (Tc-99m) with a half-life of 6 hours are often applied. With longer half-lives, the radiation exposure of the patient is too high; with shorter half-lives, the necessary connection cannot be made quick enough and preserved long enough. SPECT has been developed from planar techniques and is frequently combined with them. Thus, a gamma camera rotates around the patient and acquires a series of planar projections. SPECT subsequently processes them into three-dimensional images representing the distribution of nuclear activity and enables the physician to view the activity distribution in cross sections of the human body. The gamma rays are detected with a photon detector. The detector consists of a scintillating crystal (a sodium iodide crystal for instance) in which a small flash of light is created when hit by a gamma quantum. A series of horizontal and vertical photo detectors along the crystal record the position of this flash of light in the crystal. In front of the detection crystal, a collimator is placed, a sheet of lead with many tiny holes in it so that a gamma quant incoming diagonally wont get through, but one that is incoming perpendicularly to the surface of the crystal usually is. The result is that in the detector crystal, gamma quanta are detected that is known to be coming from a part of the patient vertically below that place on the detector. It cannot be measured, however, from what depth in the patient's body the gamma photon was emitted. PET (positron emission tomography) is an imaging technique with radioactive isotopes (radionuclides) that emits positrons during their decay. When a positron encounters an electron annihilation takes place, producing energy in the form of 2 gamma photons that are detected by a PET camera. When two photons are detected simultaneously by two detectors that are placed opposite to each other (at 180 degrees), they have been generated by the decay of the same positron, which must have been situated on a straight line between the detection points. From the time difference between the detection of both gamma photons, it can be calculated where the annihilation took place on this straight line; however, light travels at such high speed that even modern detector rings have much better angle than distance accuracy. A computer can reconstruct a three-dimensional image from a large number of such decay occurrences together, observed from different directions by a ring of detectors. The three-dimensional image has a resolution of several millimetres. Most

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PET radionuclides have a very short half-life and are produced in a cyclotron just before they are used. The most common example of such radionuclide is 18F. This radionuclide is used to label FDG (18F-fluordeoxyglucose) for instance, which is used to image the glucose metabolism in the body. Other suitable radionuclides are carbon (11C), oxygen (15O) and nitrogen (13N). The use of PET depends on the nature of the substance that is chosen. That choice is determined by the process and/or tissue of which an image must be made. Compared to SPECT, PET offers a better sensitivity, higher resolution and the possibility of accurately quantifying the examined processes. The application of the PET technique is in particular limited by the infrastructural and logistic preconditions: because of the extremely short half-life (less than two hours to several minutes are not unusual), a cyclotron has to be present on site or at a short distance. The table below (Table 2) gives an overview of the different imaging technologies, their resolution and their advantages and disadvantages.

Table 2 Overview of the characteristics of imaging techniques

Imaging CT MRI SPECT PET Ultrasound Optical Resolution 0.3 mm 0.3 mm 7 mm 4 mm 1 mm 0.01 mm Based on X-rays Magnetism Gamma radiation Gamma radiation Sound Light Advantage Visualisation of abnormalities in bones and organs Good image of soft tissues Metabolism and functional processes Metabolism and functional processes Safe, soft tissues Measurement of activity in the course of time Disadvantage Radiation exposure Costs and magnetism interference (e.g. with pacemakers) Low spatial resolution Costs and availability Limited applicability Very limited penetration depth

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3.1.2 Medical indication of current modalities

The choice of one of the different imaging technologies depends in the first instance on the medical indication that requires diagnosis. In some cases, that medical indication can only be shown by one technology. However, given uncertainty about a particular condition, several techniques are available; most of the time, more than one technology may be used to confirm diagnosis. That is why the overview below contains some overlap. A neurologist, for instance, may use several imaging technologies to identify a defect; the modality chosen usually depends on the expertise of the neurologist himself, the expertise of the hospital's staff and the presence or absence of specific modalities. In addition, the fact that nuclear medicine and radiology are two separate medical disciplines, responsible for SPECT/PET (nuclear medicine) and CT, MR and conventional X-ray and ultrasonography (radiology) respectively is also important. In most hospitals, these departments operate separately, while in a number of hospitals these departments are integrated. In some hospitals, one discipline is stronger than the other, which also changes in time when new staff is hired. The list below of indications must be regarded in the light of these observations. Indications for CT (non-exhaustive) Oncological indications of various sorts, both for staging and follow-up procedures, lung diseases, urinary tract disorders, complex skeleton disorders, bone tumours, check-up of liver shunts, neck disorders, suspect abdominal swelling.

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Indications for MRI (non-exhaustive)

Brain diagnostics, among others in case of tumours, ischemia (lack of oxygen), arteriography (vessels), demyelination (of the nerves), trauma, dementia, infection. Hernia, spinal disorders and bone infections, myocardial infarction, cardiomyopathy (heart muscle disease), heart valve disease, kidney, adrenal gland, pelvis (prostate and uterus), soft tissue swelling and tumours, disorders of soft bone tissue, optic nerve block. Indications for SPECT (non-exhaustive) Localisation and extensiveness of specific tumours, thyroid disorders, skeleton disorders, inflammations or infections, blood flow in the heart muscle, heart function, brain disorders, including Parkinson's disease. Indications for PET (non-exhaustive) Particularly within the context of staging and follow-up of lung cancer and malignant lymphatic disorders, intestinal carcinoma, head-neck tumours, unexplained pulmonary affections, melanoma, oesophagus carcinoma, ovarian tumours, thyroid tumours, cardiology (vitality of cardiac muscle tissue), neurology (dementia).

3.2 Production of radiopharmaceuticals 3.2.1 Current situation

Worldwide, there are approximately 100 research reactors that produce isotopes; however, the majority of these isotopes are not suitable or used for medical applications. Only a handful of reactors dominate the entire molybdenum/technetium supply for the medical market. Table 3 presents an overview of the reactors that produce molybdenum used for medical use (the grey-highlighted lines indicate the European share). The table includes two estimates; one by NRG dated 2002 and one dated 2008 by Nuclear Engineering International. In the European context, the HFR is of essential importance, given that it provides for approximately two thirds of the European demand and more than a quarter of the demand worldwide for technetium (see Table 3). The HFR is a large producer due to the fact that it meets two key conditions. A proper supply system of reactor isotopes for the provision of medical use requires a high number of operational hours and a good infrastructure. Operational hours are important because a fairly constant supply of isotopes is needed, also in connection with the decay rate of molybdenum. Moreover, the infrastructure around the reactor has to be well developed, so that the isotopes can be processed as quickly as possible (according to Good Laboratory Practice guidelines) and transported to hospitals. Molybdenum has a half-life of 66 hours. This requires that the isotopes be delivered to the hospitals within a few days. The HFR, taking into consideration both aspects, is one of the most suitable in the world. Relatively speaking, the HFR has a high rate of operational hours and the Netherlands is a densely populated country with a well-developed infrastructure so that all hospitals are within reach. From an international perspective, the location of the Netherlands in general and that of the HFR in particular (i.e near Schiphol Amsterdam Airport) is an important aspect in the prominent position of the HFR on the European market. Apart from importance of the HFRs production share in absolute terms, it is considered important to have a substantial production capacity in Europe. Firstly, because the isotopes must be within reach considering the decay rates of the isotopes. Secondly, to be self-sufficient as EU in the production of radiopharmaceuticals. Complete dependency on countries outside the EU is deemed undesirable.

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Table 3 Overview of the production capacity worldwide of molybdenum-99. European reactors are highlighted in grey.
NRG, 2002 Reactor NRU (Ca) HFR (EU/NL) Safari-1 (SA) BR2 (Be) HIFAR (Aus) OSIRIS (F) FRJ2 (D) 9 Others Share 45 % 27 % 9% 8% 2% 2% 2% 5% Reactor NRU (Ca) HFR (NL) Safari-1 (SA) BR-2 (Be) Rest of the world NEI, 2008 Share 38% 26% 16% 16% 4%

NRG, 2002 & L. Kid, Nuclear Engineering International, 2008 Currently, the HFR is of great importance to both the Netherlands and the rest of Europe for maintaining the current production capacity of isotopes for medical purposes and safeguarding the availability of sufficient reactor isotopes for medical imaging10.

3.2.2 The future

In the last ten years, the use of technetium has increased by 50% and is expected to increase in the years to come11. NRG expects a moderate increase in the European sales for the coming years. Outside Europe, NRG also anticipates an increase in the use of Technetium, especially outside the United States. The growing prosperity in developing countries will result in a higher demand for nuclear imaging and therefore in a higher pressure on the world market for technetium. Although NRG expects the relevant countries to become self-supporting in time, they anticipate an extra high purchase in the transitional phases (between increasing use and the set-up of production facilities). In this light there is a risk of a shortage of medical isotope-producing reactors in the long term. This is already clear at present now that the existing reactors are (more and more) shut down due to maintenance operations. The current top 4 of reactors that account for 96% of the molybdenum production are old. They came into operation in the fifties or sixties of the previous century12. In all probability, these reactors will reach their end of life in the near future. Safety considerations require regular maintenance, and these reactors will eventually be closed down.
9

The Forschungsreactor Jlich is now closed. Report on the consequences of the (longer) shut down of the high flux reactor in Putten for the supply of radioisotopes for medical applications. Dutch Healthcare Inspectorate, 2002. 11 L. Kid, 2008. Curies for Patients. Nuclear Engineering International. 12 NRU: http://www.nrureactor.ca/html/index.html Safari-1: http://www.igorr.com/home/liblocal/docs/Proceeding/Meeting%208/ouo_06.pdf BR2: http://www.sckcen.be/SCKCEN_Information_Package_2007/CDROM_files/NL/Info_NL/p dfs/2_Installaties_De_BR2_Reactor.pdf
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Furthermore, there is no great increase in suitable new reactors. There is no new construction planned in North America. In the United States, exploratory research is carried out into the possibility of building a few reactors for the production of small amounts of technetium13. In France, the construction of the Jules Horowitz reactor has started; commissioning is planned for 2014. The reactor will be able to produce approximately a quarter of the amount of technetium currently used in Europe, and thus will not produce enough to meet demands and counterbalance the loss of the current reactors. For more information about the production of radiopharmaceuticals, please refer to the research report of the Reactor Institute Delft, commissioned by VROM and carried out at the same time as this report, or international publications14,15,16.

3.3 Use of radiopharmaceuticals by the respondents

Paragraph 3.1.2 indicated the suitability of the different modalities for medical applications. It is not clear from this overview, however, what are the key modalities for specific disorders. By means of the survey, respondents were asked what imaging technique they used for certain disorders. Respondents were asked to distribute 100% over the modalities for use within the following categories: cardiology, oncology, neurology, bone scanning and other organ imaging. The modalities that use reactor isotopes are planar nuclear technology, SPECT and multi-modal17 imaging techniques that combine SPECT with another modality. To estimate the relevance of reactor isotopes in each disorder domain, the relative contribution of planar nuclear technology and SPECT modalities have to be summed. They will be singled out in the following paragraphs. It is important to note in respect of the data presented in the following paragraphs that the picture drawn does not necessarily is representative for the use of reactor isotopes in the total Dutch medical practice. Our group of respondents mainly consists of prominent physicians/researchers from university or top hospitals. In general, these respondents have more modalities at their disposal than an average peripheral hospital. Thus, they can dispose of a PET scanner with personnel that can operate this scanner more often than in the average Dutch hospital. In addition, there is more expertise in these hospitals regarding imaging techniques, which will affect the choice for certain modalities. Furthermore, the group of respondents is made up of a relatively high number of nuclear medicine physicians, as a result of which a high share will be assigned to these technologies in particular. The expert committee assesses that technologies that are already in use for a longer time and require less expertise, will be better represented when a picture is drawn of the total use in the Netherlands. These particular technologies are echoscopy, CT, MRI, planar technologies and SPECT. However, we have chosen the respondents precisely because of their understanding of and experience with imaging technologies in clinical practice and research.

13

Advanced Molecular Imaging and Therapy, 2008 Preliminary Draft Report of the SNM Isotope Availability Task Group 14 Advanced Molecular Imaging and Therapy, 2008. Preliminary Draft Report of the SNM Isotope Availability Task Group 15 Triumf, 2008. Making Medical Isotopes. 16 L. Kid, 2008. Curies for Patients. Nuclear Engineering International. 17 Multi-modal scanners are imaging devices that combine different modalities in one device.

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3.3.1 Cardiology
Figure 3 shows the results of the survey regarding the preferential use of imaging technologies in cardiology. The dominant modalities in this domain are SPECT and echoscopy. According to the expert committee, this is consistent with the most common medical practice regarding prevalent heart conditions such as myocardial infarction or ischemia. To a lesser extent, planar nuclear technology is also relevant in cardiology, just like MRI and CT; these last two are used especially for the diagnosis of heart failure. PET modalities are not common yet in cardiology. Among the respondents, modalities are used in 50% of the cases that depend on reactor isotopes, of which 10% planar nuclear technology, 32% SPECT and 8 % SPECT/CT.

Figure 3 Relative use of modalities in cardiology. Technologies that require reactor isotopes are included in the red box.

Source: survey Technopolis Group. n=16

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3.3.2 Oncology
Figure 4 shows the relative use of preferential modalities in oncology. The most dominant modality is by far the CT scan. MRI, PET, PET/CT and nuclear planar technology are also important. CT is still preferred regarding a first diagnosis in case cancer is suspected and in the procedures to follow up treatment. Subsequently, for further research, a nuclear medicine technique is used to determine the activity of a tumour. This is possible with SPECT, but our group of respondents often opt for a PET modality already in this stage. Planar nuclear technology is the preferred choice in the determining bone metastases. Modalities that use reactor isotopes represent approximately 23% of cases for our respondents: 14% planar nuclear technology, 8% SPECT and 1 % SPECT/CT.

Figure 4 Relative use of modalities in oncology. Technologies that use reactor isotopes are included in the red box.

Source: survey Technopolis Group. n=16

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3.3.3 Neurology
Figure 5 shows the relative preferential use of modalities in neurology. MRI is the dominant modality here, and to a slightly lesser extent, CT. Of the other modalities, only SPECT is applied regularly as well. This picture corresponds with the usual preference in indications for brain diagnostics. The fact that MRI plays an important role is consistent with the fact that brains are soft tissues. The contribution of SPECT is explained by the use of this modality in diagnosis of Parkinson's and related diseases, and also of dementia. The respondents use reactor isotopes in 22% of the cases with the following distribution over the modalities: SPECT (15%), planar nuclear technology (6%) and SPECT/CT (1%).

Figure 5 Relative use of modalities in neurology. Technologies that require reactor isotopes are included in the red box.

Source: survey Technopolis Group. n=19

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3.3.4 Bone scans

For bone scans, planar nuclear technology is the dominant modality; the respondents use it in 43% of the cases (see Figure 6). Other relevant modalities are MRI, CT and SPECT. SPECT is used mainly to determine the exact location of bone metastases and for applications in orthopaedics and sports medicine. The results may overlap with the result for planar technology in the oncology domain, thus leading to an overestimation of the total share of planar nuclear technology. MRI is used for diagnostics of joints, the soft tissues between the bones. CT is the present-day technology, like x-ray was in the past. Reactor isotopes are used in 55% of the cases, especially in planar nuclear technology and to a much lesser extent in SPECT (10%) and SPECT/CT (2%).

Figure 6 Relative use of modalities for bone scans. Technologies that use reactor isotopes are included in the red box.

3.3.5 Source: survey Technopolis Group. n=15

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Scans of other organs For the rest of the organs, planar nuclear technology is the preferred technology as well; it is applied in 57% of the cases (see Figure 7) involving mainly determination of functional aspects of organs such as kidneys and liver. Other important modalities are echoscopy and SPECT. There may be a certain amount of overlap with SPECT results in the cardiology domain, thus probably leading to an overestimation of SPECTs total share. Reactor isotopes are also important for the other organs. In 74% of the cases, the respondents use modalities that require reactor isotopes.

Figure 7 Relative use of modalities for the other organs; the technologies that use reactor isotopes are included in the red box.

Source: survey Technopolis Group. n=14

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3.3.6 Therapy
It is estimated that more than 90% of the medical reactor isotopes are used for imaging procedures. The remaining part is used for therapy (see Figure 8 for a list of isotopes for therapeutic use). Although this domain is relatively unimportant in quantitative terms, it is of vital importance to the quality of medical care in general and to the quality of life of a smaller group of patients in particular. There is no alternative, for instance, for iodine-131 treatment of patients with thyroid cancer. Reactor isotopes are also very important in palliative therapy (therapy directed at symptom relief): they are used for pain relief in patients with bone metastases where morphine is the only alternative.

Figure 8 Reactor isotopes for therapeutic use

Isotope Iodine-131 Strontium-89 Iridium-192 Samarium-153 Rhenium-186 Iodine-125 Yttrium-90 Lutetium-177 Holmium-166

Source: NRG, 2002; adapted by Technopolis Group

3.3.7 Findings
Reactor isotopes are of great importance in the current medical imaging practice of the respondents in cardiology (50%), for bone scans (55%) and for the other organs (74%). In oncology (23%) and neurology (22%), reactor isotopes are of less importance. As already mentioned above, these results might not be entirely representative for the average Dutch situation, but provide a picture of the current situation in university and top hospitals (STZ hospitals18). However, many patients visit these hospitals. In the general Dutch situation, conventional technologies (including CT and planar nuclear technologies) are bound to have a greater share. The results presented in this report describe the situation in the clinical practice in the hospitals that fulfil a leading role19.

18

STZ hospitals: Hospitals affiliated with the Dutch association of tertiary medical teaching hospitals. 19 A complete picture of the use of the different modalities at present (and in the past) can only be obtained by asking all Dutch hospitals for the production figures of the departments of radiology and nuclear medicine, subdivided in figures per modality.

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Although therapy only accounts for a small share in the total use of reactor isotopes, it plays an important role in terms of quality. The expert committee endorses the above picture of the use of reactor isotopes. CT is common in oncology, and PET is increasing; MRI is frequently applied in neurology, SPECT is used to determine the functionality of tissues, where PET is emerging as well, and planar nuclear technology is commonly used for bone scans. CT and MRI are generally used at every radiology department, while in nuclear medicine planar techniques and to a lesser extent SPECT are dominant. Reactor isotopes are consequently of great importance to medical imaging at present, especially in the fields mentioned above. Moreover, they are even more important in hospitals that do not dispose of a PET scanner. In a limited number of medical centres (including VUmc, UMCG, ErasmusMC, UMC St. Radboud in Nijmegen and St. Antonius in Nieuwegein), a lot of research is done currently into PET applications. PET use is frequent in 10 hospitals. Apart from that, another 35 hospitals in principle have access to PET technology. The distribution of the use of various modalities for certain conditions already shows that more than one modality can be used for the same disorder. As already mentioned in 3.1.2, within the imaging domain further choices for a particular modality are made on medical grounds, or dependent on the preference or expertise of the physician and the radiological technologists. In paragraph 4.1.2, we will address the decisive factors that determine the preference for a specific modality in more detail.

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4. Explorations into the future use of radiopharmaceuticals in medical practice

Radiopharmaceuticals are currently of great importance in the medical practice, especially in diagnostic imaging. This chapter will deal in greater detail with the experts future expectations in this area. The central question here is to what extent reactor isotopes will be important in the future; in other words: will the modalities that use reactor isotopes (SPECT, planar, and multi-modalities) still be used in 2015 and 2025?

4.1 Modalities 4.1.1 Trends

Based on the interviews, a few important trends were identified that in relation to the range of modalities and that might bring about some shifts. The following trends are important for substitution effects: Improvement of current modalities. The current modalities are still improved incrementally. These are in particular technological improvements, such as the increase in sensitivity and resolution, the further development of software to process the data and combine parameters. Eventually, the quality of the scans will increase as a result of these improvements and better diagnoses can be made, or the use of a specific scanner can be expanded. PET is a good example of a technology that is still developing rapidly. Experts still expect a considerable advance in this area, for instance through discovering, testing or experimenting with new tracers, as a result of which the PET scanner can be applied for a wider range of procedures. But also 'older' modalities, such as SPECT, are still developing. Currently, new crystals are being tested and used, which will improve the resolution of SPECT. Some experts anticipate that as a result SPECT will equal the resolution of PET in time; others take the opposite view. Our interviews show that PET is one of the fastest growing modalities. Some of the interviewees in this study, as well as a Canadian expert panel20 expect that PET will expand more rapidly than, for instance, SPECT. It remains to be seen, however, if this will lead to large shifts in applications that are now conducted with planar nuclear technology and SPECT to PET. Many developments will be focused on extending the possibilities for medical science, as a result of which the diagnosis in specific cases is improved and PET will function as an add-on. The interviewees also point out that so far, no modality has ever disappeared from the total range of technologies. Combinations of modalities. Parallel to the improvement of the modalities, one of the most important developments is the combination of modalities into one device. The biggest advantage of the so-called multi-modal scanners is that they can generate information about metabolism as well as spatial information (location). When measuring metabolism with a SPECT scan for instance, it is less clear where the metabolic abnormalities are located. This information can be better obtained with a CT scan. Combining these modalities is combining the 'best of both worlds'. At present, the PET/CT scanner is a well-selling multi-modal

20

See Triumf, 2008.

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scanner. Other combinations are still under development, such as the SPECT/CT, PET/MR, and SPECT/MR scanners. Combinations of modalities require further technological developments, in particular in the area of integrating two devices. Apart from developments in physics, mechanical engineering, and the like, significant developments in software are also required given the fact that two datasets have to be combined with each other. Development of new tracers. The detection of certain processes (metabolism) or substances (e.g., particular proteins) requires tracers which attach themselves to the right place in the body and which can subsequently be represented by means of a modality. New tracers function as 'enablers' for a modality, they expand its possibilities. At present, many tracers are developed, in particular for PET; however, also for other modalities expectations for new tracers are high. Nanotechnology and bionanotechnology hold promises for new tracers and markers, for instance for optical, MR or other modalities. Although new tracers could lead to shifts between modalities, it is not yet clear what modalities will be stimulated as a result. In the recently started Center for Translational Molecular Medicine (CTMM), the research into biomarkers and imaging technologies is combined. Development of new therapies. Although reactor isotopes are mainly used for imaging purposes, they are also of qualitative therapeutic importance. Reactor isotopes already play an important role in thyroid and prostate cancer therapy and palliative therapy for bone metastases. Therapeutic applications seem to be gaining importance rapidly. For instance, a few years ago, Lutetium-octreotate was administered to patients for the first time. This isotope is given to patients with neuroendocrine tumours (they are mainly located in the stomach, intestines and pancreas and may produce spreading harmful amounts of hormones). The beauty of such applications lies in the fact that the administered substances can be targeted to the process under treatment; this is not possible with external radiotherapy, where the surrounding tissue is also exposed to radiation. Furthermore, treatment with lutetium results in an increased life expectancy of patients with 4 years with a relatively good quality of life. 21 Development of new devices/modalities. Although at present there is no prospect of a totally new modality, this scenario of 'unforeseen circumstances' has to be taken into account in a foresight. In the survey, we investigated the length of time required for a new finding to develop from the laboratory to preferred clinical use (see Figure 9). According to the respondents, the average duration of the initial research phase to obtain clinical evidence is approximately 8 years. From that point onwards preferential use takes at least another ten years. Therefore, if options are overlooked in this explorative study because they are only in an early stage of development, it will last at least 18 years before they become a preferred modality in clinical practice. Although the estimates of the experts differ greatly, the averages are confirmed in the interviews with the experts from the industry and medicine, as well as by the expert committee.

21

http://www.nrg-nl.com/general/nieuws_nl/cms/2008/200801161635.html

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Figure 9 Expert estimates of the length of the innovation process in years from initiation of research to clinical proof incl. clinical trials (red) and the length from clinical evidence to preferential use in years (black). Average values: research phase: 8 years; implementation: 10 years

Source: survey Technopolis Group. n=32

4.1.2 Expectations regarding the use of modalities

In the survey, we asked the respondents about their expectations regarding the use of the various modalities in clinical practice. By means of the interviews we identified all the possible modalities that might play a more prominent role in future. Subsequently, the respondents were asked to indicate what share they expected a particular modality to have in the number of scans in their clinical practice in 2008, 2015, and 2025. The respondents could assign 100% in total to all modalities; Figure 10 shows the results. Note that the figures express the share of one modality relative to the other modalities, rather than absolute numbers.

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Figure 10 Expert estimation of the relative use of modalities in 2008, 2015 and 2025.

Source: survey Technopolis Group. n=23

Based on these expectations for the future, the following conclusions can be drawn regarding the proportion between the modalities. Our respondents expect: A relative decrease in the CT in the procedures they perform, which is significant (more than 10% in the period from 2008-2025) A slight decrease in the number of single MRI procedures (less than 3%) A slight decrease in the number of ultrasounds (approximately 4%) An equal number of PET procedures A fairly substantial decrease in the share of SPECT (approximately 7%) A fairly substantial decrease in the other modalities (in particular planar, optic). These are the modalities that were expected to have a share of a few percent only (approximately 4%) A fairly substantial increase in the share of PET/CT (approximately 7%) A fairly substantial increase in the share of SPECT/CT (approximately 7%) Sharp increase in PET/MRI (more than 10%) After 2015: growth of the SPECT/MRI (approximately 2.5% from 2015 to 2025)

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To single out the trends in modalities that use reactor isotopes, in Figure 11 the percentages of the multi-modalities have been added up to the single modalities. The share of PET/CT has been added up to both PET and CT and the share of SPECT/MRI to both SPECT and MRI. As a result, a picture is created of the total use of the single base modalities, even though the total number of scans exceeds one hundred percent.

Figure 11 Share of the number of scans according to base modalities

Source: survey Technopolis Group. n=23 Figure 11 shows that the respondents expect a strong increase in the combined use of PET, as well as MRI,. The decrease in the number of PET and MRI is substituted by the use of multi-modalities. The combined use of CT will increase fairly substantially at first, followed by a slight decrease at the expense of MRI multi-modalities. The share of SPECT modalities will remain more or less unchanged. The considerable decline in the share of SPECT (see Figure 10) is substituted by the use of multimodalities: initially by SPECT/CT and after 2015 by SPECT/MRI. Since SPECT is the modality that uses reactor isotopes, the share of SPECT is broken down in Figure 12. Figure 12 is a break-down of figure 11; it shows the substitution effects of the SPECT multi-modalities: the use of SPECT will decline strongly, the use of multi-modalities including SPECT will increase strongly.

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Figure 12 Break-down of the shares of SPECT modalities

Source: survey Technopolis Group. n=23

4.1.3 Innovation dynamics

The implementation of innovative technologies is driven by technological and nontechnological factors. One of the technological factors in this case is the resolution. Non-technological factors that are related to nuclear technology are the logistic and infrastructural problems around isotopes. As for reactor isotopes, they have to be refined and purified according to GLP and transported to hospitals; as for PET radionuclides, the infrastructure has to meet certain requirements for production in the cyclotron and transport to hospitals, and well-trained staff is required who can work with these radionuclides. Furthermore, in the medical domain and in hospitals, various human aspects play an important role, such as the skills and expertise of the radiological technologist and convenience of use, but also costs, contracts and efficiency22. To determine what technological or non-technological factors are decisive in choosing a particular modality in the clinic, the interviewees were asked to indicate which of those factors are (very) important or unimportant. Figure 13 shows that to a greater or lesser extent, the respondents find nearly all factors important.

22

PET Gepast gebruik(t), ZonMW Doelmatigheidsonderzoek, januari 2007 (Efficiency study regarding the use of PET scanners, carried out by the Netherlands Organisation for Health Reserach and Development)

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Figure 13 Factors that determine the choice for a certain modality (1= very unimportant, 2= unimportant, 3=neutral, 4=important, 5= very important)

Source: survey Technopolis Group. n=21 The only factor that is considered less decisive is dependency on contracts. Of the 4 factors that on average score higher than 4 (important), only higher resolution is a technological driver. Two factors are related to human aspects: the skills of the radiological technologist (this is connected in part with the expertise of the radiological technologist) and human resources in general. The latter mainly refers to the highly specialised staff required for PET modalities. Finally, infrastructural problems are regarded as important. This can refer to the problems with the delivery of technetium as well as to the infrastructural organisation of cyclotrons in hospitals. In summary, we may conclude that a higher resolution is a technology driver, but that the human factors are the ones that largely determine the success of that technology. In this case it also means that the pace at which the PET applications will be expanded mainly depends on sufficient qualified personnel and infrastructure. Incidentally, the decisive factor 'costs' has not been further defined; it may refer to the costs of a single procedure as well as to investment costs of a hospital when acquiring the technology.

4.1.4 Summary of findings

Based on the identified trends (4.1.1) and the proportions of modalities (4.1.2) it may be concluded that the experts anticipate a significant increase in PET modalities. The interviewees from both the industry and the group of users indicate that this modality, at present, is showing the biggest growth. The multi-modal developments seem to stimulate the growth of PET. The share of SPECT modalities will remain more or less unchanged. The number of SPECT scans will decrease in the years to come; however, the share of multi-

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modalities that combine SPECT with other modalities will increase. The industrial interviewees indicated that many efforts are put into the development of a SPECT/CT scanner, and the survey shows that the clinical practice foresees a substantial share for this scanner. As for the mix of modalities, it has become evident that reactor isotopes will continue to be of great importance. Based on the unchanged share of SPECT scans, it can be concluded that the relative demand for reactor isotopes (in proportion to the total number of scans) will remain more or less the same. The implementation of a technology is determined by both technological and nontechnological factors. When choosing a particular modality in the clinic, it appears that although higher resolution is shown to be a technology driver, human factors are the ones that determine the success of that technology to a large extent. In this case it means that the pace at which the PET applications will be expanded mainly depends on sufficient qualified personnel and infrastructure. In paragraph 4.2 we will discuss the expectations of the experts regarding the use of technetium in the clinic in more detail.

4.2 Future use of technetium 4.2.1 Total number of scans

The total number of scans in medicine is expected to grow in the coming years. Increasing prosperity results in a higher standard of living, better medical science and a higher life expectancy. As people are getting older and the ageing population increases, the number of medical procedures will increase as well. Moreover, medical technology will be used more frequently as a result of a higher standard of living. Combined with a growing population figure, this will lead to an increasing number of imaging procedures. This trend has already started, and the total number of scans will continue to increase especially due to the ageing population and population growth. This picture is supported by the estimates of the experts. They almost unanimously anticipate an increase, and even a significant one, in the total number of scans over time. Figure 14 shows the experts' expectations for the total number of scans in 20082010, 2010-2015 and 2015-2025.

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Figure 14 Expert expectations of the total number of scans for medic use

Source: survey Technopolis Group. n=33 Figure 15 shows the same results as Figure 14, however represented as the weighted averaged of the respondents' answers. Nearly all experts foresee an increasingly certain growth of the total number of scans in the future. On average, the experts anticipate an increase; for 2015-2025, 60% of the respondents anticipates a significant increase.

Figure 15 Weighted average of the expert expectations on the total number of scans in 2008-2010, 2010-2015, 2015-2025. (1= large decline, 2= decline, 3= unchanged, 4= increase, 5= large increase)

Source: survey Technopolis Group. n=33

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4.2.2 Probability that scans using technetium will be substituted by other

technologies The survey also asked for the probability of technetium-based procedures being replaced by modalities that do not require the use of technetium. Figure 16 shows how likely it seems to the respondents that technetium will be substituted in the period till 2010 (red), from 2010-2015 (black) and from 2015-2025 (grey). Figure 17 shows the weighted average of these results.

Figure 16 Expert estimations on the probability of the substitution of technetium

Source: survey Technopolis Group. n=33

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Figure 17 Weighted average of the expert estimates of the substitution of technetium. (1= certainly not, 2= probably not, 3= neutral, 4= probably, 5=certainly)

Source: survey Technopolis Group. n=33 Sixty-five per cent of respondents do not consider it probable that technetium will be partly replaced in the period up to 2010. For the period from 2010-2015, still 30% of the respondents consider this unlikely, although the same percentage gives a neutral answer. Further into the future, the respondents expect an increasing chance of technetium replacement. On the one hand, this can be explained by an increasing uncertainty: in future forecasts there are always unknowns and uncertainties. This is shown by the increasingly diverging responses to the question of time: the spread for the period 2015 - 2025 is markedly greater than for earlier periods (see Figure 16). However, the weighted average of the substitution shifts from 'probably not' for 20082010 to 'neutral' for 2010-2015, with a slight tendency towards 'probably' for the period 2015-2025. The average value shifts from 2.0 for 2008-2010 to 3.2 for 20152025 (see Figure 17). From the interviews it has become clear that this shift can be explained in particular by the estimation that other modalities will have higher functionalities in this period (see also Figure 10). Nuclear physicians anticipate important developments especially for PET. Experts from other fields of medical imaging expect breakthroughs regarding MRI, as a result of which this technology may also be used for the imaging of metabolisms. There is no consensus on these matters. In general, experts do not have a total view of all these future developments. The average estimate shows, however, that the use of technetium will slightly decline as time goes by.

4.2.3 Future use of technetium

The probability of substitution was examined in greater detail in the survey by means of a quantitative estimate of the future use of technetium. The experts were asked in the survey to give an estimate of the use of technetium in the future compared to 2008. Figure 18 shows the distribution of the estimates of the experts in percentage points.

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Figure 18 Expert estimates on the use of technetium in 2010, 2015 and 2025, as a percentage of the current use (2008).

Source: survey Technopolis Group. n=29 Figure 19 shows the weighted average of these answers. This indicates the total estimated use of technetium in 2010, 1015 and 2025, compared to 2008.

Figure 19 Weighted average of the expert estimates on the use of technetium use 2010, 2015 and 2025 (reference year: 2008).

Source: survey Technopolis Group. n=29 In the short term (2008-2010, red), 90% of the respondents expect the use of technetium to slightly increase or remain unchanged (Figure 18). Overall, the experts expect the use of technetium to grow with 5% by 2010 (see Figure 19). After that, in

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the period from 2010-2015 (Figure 18, black), the number of respondents that think of a decrease in use increases, but the use, on average, is the same as the use now. Figure 19 shows that the weighted average of the use in 2015 is estimated to be 99% of the use of 2008. For the period from 2015-2025 (Figure 18, grey), the spread in responses is significant. However, the weighted average results in a slight decline in the total use of technetium till 92% of its current level. The answers to this question match the expectations regarding technetium substitution.

4.2.4 Summary of findings

All experts unanimously anticipate a significant to very significant increase in the total number of diagnostic imaging scans in the future. This outcome is connected to the ageing population and population growth. As for the expectations regarding the substitution of imaging modalities that use technetium, major changes (substitution) are not expected for the time being. For the period after 2015, the experts are divided in their opinion; the average, however, shifts from 'probably not' to more or less neutral, with a slight tendency towards 'probably' in 2025. The same trend can be observed in the total use of technetium: in the coming years, the use of technetium will certainly not decrease, but rather slightly increase. For the period from 2015-2025, the experts foresee that the use of technetium will slightly decrease (<10%), but the spread in responses is high.

4.3 Therapy
As for the use of reactor isotopes for therapy, the results of the survey are unequivocal (see Figure 20). The current use of iodine and iridium is not expected to increase a great deal (indicated with o). However, the experts do expect an increase, in the use of lutetium-177 and ytrrium-90 and this increase will start now and continue until past 2015 (indicated with +). The use of holmium-166 and samarium-153 will also increase, but that will start after 2010. In this area, the expectations of the experts coincide with the results of the interviews and the literature, which without exception point out the developments in radiopharmaceuticals for therapy.

Figure 20 Expert expectations for the application of therapy with reactor isotopes. ( -- = large decrease, - = decrease, o = unchanged, + = increase, ++ = large increase)
2008-2010 Iodine-131 Strontium-89 Iridium-192 Samarium-153 Rhenium-186 Iodine-125 Yttrium-90 Lutetium-177 Holmium-166 o o o o o o + + o 2010-2015 o o o + o o + + + 2015-2025 o o o o o o + + 0

Source: survey Technopolis Group. n=22

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5. Conclusion
The Ministry of VROM commissioned this study. It sets out to answer the following research questions: 1. What is the expected volume of imaging technologies for medical purposes in the future, i.e. from now till 2025 and what will be the relative share of technetium-based imaging in these technologies?"

2. "What new or upcoming imaging technologies in medicine may affect or displace the technetium-based imaging technology in the period till 2025, both in terms of quality and quantity?" The following conclusions may be drawn on the basis of interviews, the results of an online survey and validation by an expert committee. Current developments There is a range of imaging modalities available at present (CT, MRI, SPECT and PET) each of which has a specific application in the medical domain. Technetium is used for SPECT and planar technology; these modalities are preferentially applied in bone scans (including bone metastases in oncology) and organ scans (including measuring of blood flow and heart muscle function in cardiology). Multi-modalities that combine nuclear and radiological techniques in one device are emerging. For the future, shifts are anticipated in the use of the modalities, foreseeing a decrease in the single modalities in favour of the multi-modalities. At the moment, there is no new technology that might affect the use of technetium. If there were one, the experts think that it would take at least 18 years before its use would be preferred in clinical practice. Furthermore, 'old' techniques usually do not disappear. Although an important technological driver for imaging modalities is a high resolution, the human factors determine the success of a technology to a substantial extent.

Expectations A significant increase in PET modalities is expected, especially in combination with CT or MRI. Partly due to the high resolution, the current applications of PET will be expanded, but probably not at the expense of the total share of SPECT modalities. The rate of the developments related to PET also depends on the development of new radiopharmaceuticals, required infrastructure and expertise. The relative share of SPECT modalities probably remains unchanged, but the single SPECT will be replaced in time by SPECT/CT and later on by SPECT/MRI (not available yet). The experts are convinced that the total number of scans will show a (significant) increase in the future. This increase already started in the last few years. Furthermore, the experts consider it unlikely that technetium-based imaging will be replaced by other technologies in the medium term (till 2015); it might slightly decrease in the period from 2015-2025. This also becomes clear from the expectations for the total use of technetium: It remains unchanged for the time being, but will slightly decrease (<10%) in the period from 2015-2025. A number of experts also indicate that to date, no imaging modality has ever been replaced,

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even the conventional x-rays are still used; the total range of possibilities has only been further increased in the course of time. Summarising, the conclusion can be drawn that the demand for radiopharmaceuticals that are produced in nuclear reactors will continue to exist till 2025. In the field of nuclear medicine, the experts anticipate that the current accelerated development of PET will continue, which will cause a relative decline in the use of reactor isotopes. However, due to the low costs and relative simplicity of SPECT and planar nuclear imaging, these technologies will continue to exist and, in absolute terms, will be used just as much.

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Appendix A
Consulted individuals

A.1. Expert committee

Expert

Institute

Prof. Dr. H.G.M. Rooijmans Professor emeritus Psychiatry, former chairman of the Raad voor Gezondheidsonderzoek (RGO Health Research Council) Prof. Dr. Ir. M.A. Viergever Professor medical imaging Prof. Dr. A.A. Lammertsma Professor clinical physics Dr. A. Verzijlbergen Chairman Dutch Society of Nuclear Medicine Image Sciences Institute (ISI), UMC Utrecht Nuclear medicine & PET research, VUMc Amsterdam Department of Nuclear Medicine, Sint Antonius Hospital, Nieuwegein

A.2. Interviews
Name H.G.M M.A. A.A. H. F. P. R. A. A.M. B. A. Rooijmans Viergever Lammertsma Hofstraat Gerritsen Luijten Diericx Verbruggen Van der Schaaf Paans Institute Former chairman of the RGO Health Research Council UMCU VUMc CTMM, UMC Philips and TU Eindhoven CTMM, UU, Philips RUG KU Leuven NRG UMCG

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Technopolis Group The Netherlands Herengracht 141 1015 BH Amsterdam The Netherlands T +31 20 535 2244 F +31 20 428 9656 E info.nl@technopolis-group.com www.technopolis-group.com