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Advances in emerging field of ‘theranostics’ are a game-changer Millions of patients around the globe rely on the regular and timely production of diagnostic and therapeutic isotopes produced in research reactors and accelerator facilities. Image courtesy IAEA. Advances in medical isotope diagnostics and therapy are holding promise for cancer patients, despite challenges facing the nuclear medical field in recent years related to radionuclide production and supply, rising costs, and stricter regulation.

Medical isotopes are radioactive substances used in various diagnostic and therapeutic procedures to treat various types of cancers and other conditions. They are essential for modern medicine, allowing physicians to visualise and target specific organs, tissues and cells in a patient’s body.

Over more than a decade, personalised medicine using nuclear techniques has been gaining pace, allowing doctors to tailor therapies and treatments to the specific needs and physiology of a patient, and to avoid harm to healthy organs or tissues.

According to Sven Van den Berghe, chief executive of Belgium-based isotope producer PanTera, one technique that has seen significant advances is known as theranostics – the term used to describe the combination of using one radioactive drug to diagnose and a second to deliver therapy to treat the main tumour and any metastatic tumours.

In this emerging field of medicine, drugs and techniques are uniquely combined to simultaneously or sequentially diagnose and treat medical conditions.

Experts have said the ability to acquire a diagnosis and administer therapy in one package is a game-changer for medicine. Not only does this offer the opportunity to save time and money, but it also potentially allows doctors to bypass some of the undesirable biological effects that may arise when these strategies are employed separately.

Theranostics is achieved by linking diagnostic and therapeutic isotopes in a single vector such as an antibody or a protein, through a similar molecular structure. The vector is then injected into the patient’s body and used to assess how the cancer will respond to a specific treatment, information which doctors do not always have with alternatives like chemotherapy.

To achieve molecular similarity, practitioners often use different isotopes of the same element alternating between diagnostic and therapeutic features. Examples include iodine-123 and iodine-131, or yttrium-86 and yttrium-90, and various terbium isotopes. But even with isotopes from different elements, theranostics can work effectively as long as they can be attached to the same vector.

The Promise Of Lutetium-177 And Actinium-225

According to Van den Berghe, two medical isotopes that are expected to grow in significance are lutetium-177 (Lu-177) and actinium-225 (Ac-225). Both are causing excitement among researchers who are finding ways to use them to target cancers while avoiding healthy cells.

Lu-177 is being used to treat neuroendocrine tumours and prostate cancer. Ac-225 has not been deployed as a medical product yet, but in clinical trials treating late-stage prostate cancer patients, Ac-225 killed the cancer in three treatments. Ac-225 and treatments derived from it have also been used in early trials for leukaemia, melanoma and glioma. Ac-225 is specifically efficient in destroying cancer cells because of its high energy charge and short range of emitting alpha particles.

Van den Berghe, whose PanTera R&D partnership was set up last year to produce Ac-225 at scale, said the first Ac-225-based pharmaceuticals are expected to be commercialised before the end of this decade.

“Lutetium was a huge step forward for nuclear medicine”, said Van den Berghe, “and we expect actinium to be the next breakthrough moment, especially when we saw Big Pharma investing billions in promising clinical trials.”

Ac-225 is produced in accelerators, while Lu-177 is produced almost exclusively in research reactors. One of the challenges in conducting clinical trials is the limited availability of Ac-225, which is almost all generated from the decay of thorium-229, another scarce isotope generated in research reactors. Ac-225 is currently produced in small quantities by the Oak Ridge National Lab in the US, the Chalk Rive Lab in Canada, and Russia’s Institute of Physics and Power Engineering.

Sven Van den Berghe said PanTera sees the production of Ac-225 as viable because of Belgium’s extensive and “uniquely pure” radium reserves, which offer an alternative way to generate the new isotope. Belgium was a pioneer in radiochemical research and maintains radium reserves dating back to the beginning of the 20th century.

Other companies, including Canada’s BWXT Medical, Alfarim in the Netherlands, and US-based TerraPower, Niowave and NorthStar are planning to develop the industrial capacity to produce Ac-225.

The production of Lu-177 isotopes requires reactors with a high neutron flux. These are mainly the BR2 in Belgium, HFR in the Netherlands, LVR-15 in the Czech Republic, Maria in Poland, Opal in Australia, Safari in South Africa, Murr in the US, and the IVV-2 and SM-3 in Russia.

Among these, the BR2 and the HFR are the largest producers of Lu-177. The operators of both reactors supply irradiation services to dozens of companies performing the extraction and purification of Lu-177. Russia’s’ Rosatom is the main producer of the purified stable isotopes serving as inputs for the generation of Lu-177: ytterbium‑176 and lutetium‑176.

Last year, Canadian nuclear operator Bruce Power announced pilot Lu-177 production would begin at the Bruce-7 nuclear plant, a Candu reactor at the commercial Bruce nuclear station. Candu heavy water reactor designs are the only commercial electrical power production reactors which have sufficient neutron flux to efficiently produce isotopes.

A graph showing a wide range of isotopes used for diagnostics (blue) and therapy (orange) of various cancers and other pathologies. Courtesy of Nuclear Medicine Europe.

Big Growth Seen In Nuclear Medicine Market

Market watchers have estimated the value of the global nuclear medicine market in 2022 at $5-$10bn (€4.6-€10.1bn). By 2030, this could grow to about $20-$25bn. The market for Lu-177 was estimated at around $700-$800m in 2020 and is expected to almost double as the end of the 2020s approaches.

Estimates for the Ac-225 market are less reliable, but global needs are estimated as more than 300 curies (Ci) per year by 2027 and potentially more than 1,000 Ci per year by 2032, enough to server one million patients annually. For comparison, demand for Mo-99 is currently estimated at about 500,000 Ci per year, while demand for Lu-177 is expected to reach a similar level after 2025.

Despite the recent introduction of novel radioisotopes, the workhorses of nuclear medicine around the globe are still molybdenum-99 (Mo-99) and its decay product – technetium-99m (Tc-99m), which is “milked” from Mo-99-based generators in hospitals.

According to the Dutch nuclear industry group Nuclear Netherlands, Tc-99m, with its approximately six-hour half-life, is used in about 80% of nuclear medicine procedures in hospitals globally. This means about 40 million of the nearly 50 million nuclear diagnostic procedures carried out annually require Tc-99m.

Overall, about 50% of global production of Mo-99 is almost equally spread between the Dutch HFR and Belgium’s BR2 research reactors. Other leading producers include South Africa’s Safari, Poland’s Maria, Australia’s Opal and the Czech Republic’s LVR-15 research reactors, with between 10-12% global share each.

The success of nuclear medicine and its promise for patients depends on the reliable supply of these isotopes. Over the last decade there have been a number of disruptions in production which led to shortages.

“The supply chain for Mo-99 is extremely fragile at the moment,” said Van den Berghe, who previously directed the department of the Belgian Nuclear Research Centre SCK CEN operating the BR2 reactor. “The Petten HFR and BR2 are currently too important in the chain and if either of them goes out of service for whatever unexpected reason, there is an immediate supply crisis.”

In January 2022, operators found technical faults at the Petten reactor and it had to be shut down until March 2022, causing strain on global production. The gap was filled by the Maria and BR2 reactors.

Another problem arose in October 2022, when the BR2 reactor had to be closed unexpectedly for about three weeks. South Africa’s Safari reactor was used to partially compensate for lost capacity.

Earlier, in 2009, there was a supply crisis for Mo-99 when the NRU research reactor in Canada was shut down because of a technical malfunction. This hit hospitals around the globe and caused delays in diagnosis and treatment for patients.

The crisis resulted in closer international coordination between research reactor operators to avoid supply shortages. By 2020 security of supply had improved, despite the permanent shut down of the NRU in 2018. In 2012, the European Union set up the European observatory on the supply of medical radioisotopes to coordinate and monitor the supply Mo-99 specifically.

The World’s Ageing Research Reactors

The problem remains that the world’s research reactors are rapidly ageing and no bullet-proof solution seems to be in sight.

With the NRU no longer in operation and France’s Osiris reactor – another key producer of isotopes – also shut down, production capacity has to be met by fewer facilities. With the exception of Germany’s FRM-II and Australia’s Opal, all the reactors used to produce life-saving isotopes have been operating for longer than 40 years. Many could reach the end of their operation before 2030.

There are only a handful of research reactors being built in Europe to replace capacity which will eventually be retired, or can support isotope supply in the event of unexpected supply chain disturbances.

A map showing research reactors around the world capable of producing Mo-99 and their final operating date (in brackets). Courtesy of US National Academies Press, 2020.

A material testing reactor, the Jules Horowitz Reactor, has been under construction in southern France since 2007 and is expected to be online in the early 2030s, though the project has seen both delays and cost overruns. The reactor is focused on supporting the commercial nuclear power industry, but medical isotope production is one of its objectives.

The Pallas reactor project in the Netherlands recently received a construction licence and will help replace retiring isotope production capacity. It is expected to be online in 2026 and in 2030 will fully replace the HFR on the same site, which is to be retired.

In South Korea, the Kijang research reactor is to be built by the Korea Atomic Energy Research Institute with target deployment in 2027. It is expected to play a role in Mo-99 production, but deployment has been pushed back several times.

Another project is Belgium’s Myrrha, but as a fast reactor, it will not be able to produce isotopes such as Mo-99 and Lu-177 in commercial quantities.

In February 2023, Darlington, another commercial Candu plant in Canada, announced it is now ready to produce Mo-99, marking what would be a world’s first at a commercial power plant.

The problem for securing future replacement capacity for ageing facilities lies in the fact that the production of medical isotopes was historically not the primary goal of a research reactor, but rather a by-product. All of the world’s research reactors were built for scientific, experimental, or material testing purposes at times when the commercial nuclear power industry was experiencing rapid growth.

For years, the financing of nuclear research facilities and research reactors in the western world has been a problem for governments and state research institutions. According to Van den Berghe, maintaining the supply chain of critical medical isotopes is not a motivation enough for investment in costly nuclear research facilities because of the market conditions.

“There is no business case in the production of molybdenum-99 for example,” he said. “One has to keep in mind that many of the reactors producing these isotopes have been built with and are maintained thanks to the money of taxpayers in a handful of countries, while the whole global supply depends on them.”

Nuclear Medicine Europe (NMEU), a Brussels-based association for the nuclear medical industry, outlines four main challenges facing Europe’s nuclear medicine sector: secure and reliable supply, regulation, support for innovation and research, and raising public awareness.

Cost transparency should be boosted by closer monitoring of radiopharmaceutical prices – in cooperation between healthcare providers, health insurance companies and governments.

The organisation of healthcare systems also needs to be reevaluated to address the skills needed for nuclear medicine, including the development of an expert workforce of oncologists, radiotherapists, nuclear medicine physicians, radiologists, and radio-pharmacists.

According to the NMEU, nuclear medicine is often ignored in EU health policies because of its low visibility compared with other medical disciplines.

A 2018 position paper by research reactor operators and developers CEA (France), NCBJ (Poland), NRG (Netherlands), Pallas (Netherlands), RCR (Czech Republic), SCK CEN (Belgium), and TUM (Germany), called for the production of isotopes to be made economically viable.

Industry Needs ‘Full Cost Recovery’

To encourage investment, the industry needs full cost recovery in the production chain. This would mean an increase in the price paid for the providers of irradiation services.

“Based on the experience of the past it is acknowledged that reserve capacity of at least 35% is needed to avoid a supply shortage and this has to be paid for,” says the position paper. Such reserve capacity is not there, nor is it covered by the pricing of isotopes.

According to a 2019 Nuclear Energy Agency (NEA) study, the central problem is that nuclear research reactors have high fixed costs while the marginal costs of irradiation are low. The reactor operators are captive to local processors and have little choice but to continue supply even at prices that are too low, while government funding sustains their operations. Downstream, price competition creates a disincentive for processors and generator manufacturers to increase prices unilaterally.

The inability by reactor operators to increase prices sufficiently for full cost recovery, combined with insufficient reserve capacity – in the event of a reactor outage, for example – at various steps of the supply chain, leave security of supply vulnerable and the market economically unsustainable.

The NEA said a phased and coordinated discontinuation of government funding of irradiation-related costs for nuclear research reactors could catalyse price increases. This could be accompanied by policies ranging from increased price transparency to price regulation. Funding of irradiation by end-user countries could be an alternative option.

“However, no single policy can be recommended as the preferred solution and each option has strengths and weaknesses,” the NEA said. “Governments need to coordinate their efforts and evaluate options in more depth in cooperation with all stakeholders to identify the most acceptable solutions in their respective jurisdictions.”

Operators have also called for improved standardisation of targets, transport containers, while equipment and transport licensing, they say, will improve efficiency and further increase the security of supply within Europe.

Alternatives To Research Reactors Under Development

In recent years, companies like US-based Shine Medical and NorthStar, Canada’s Triumf, and Russia’s Rosatom, have been looking into the possibility of commercialising the production Mo-99 using particle accelerators, which would not depend on the neutron flux of a reactor system.

NorthStar announced in January it had successfully produced Mo-99 at a recent accelerator facility in Wisconsin, using an external neutron source. However, no such commercial facilities have yet operated at scale.

Van den Berghe warned against betting on the accelerator alternative. The technology has not been proven commercially, he said, and failure to deliver on the promise or sustain it would leave little time to deploy research reactors to secure global supply.

“It is a gamble when you know that building a research reactor is not something you do in just two years,” Van den Berghe said. “Not all isotopes currently produced in research reactors can be produced by these novel technologies, but research reactors also cannot survive just on those, which means some specific cancer treatments using less common isotopes may no longer be available”.

Date: Friday, 14 April 2023
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