The solution to a looming shortage of the medical isotope technetium-99 may lie in the basements of many hospitals, according to Canadian scientists.
The answer: cyclotrons.
Researchers associated with Vancouver's TRIUMF nuclear physics research center say machines that are widely used to make other imaging isotopes can be modified to make technetium-99, the substance at the heart of the isotope crisis.
The process is relatively simple to implement and can produce commercial quantities of technetium-99 at a reasonable cost, they said. Best of all, it uses equipment that is a lot cheaper than a nuclear reactor, currently needed to make the isotope.
"We don't think there are any show-stoppers here at all," said Tom Ruth, PhD, who is principal investigator for the two-year, $6-million project.
"We've demonstrated it all works and it's feasible and within the economic realm of being competitive," he told MedPage Today.
But there remain a few hurdles that still need to be cleared, according to Robert Atcher, PhD, of the University of New Mexico in Albuquerque, who is past president of SNM and chairman of the molecular imaging society's isotope committee.
Among them are regulatory issues, he told MedPage Today, such as does the technetium-99 produced by the cyclotrons meet medical safety standards, and does the production process itself meet nuclear safety guidelines?
Atcher pointed out that cyclotron production may work well in the Canadian health system but he's not convinced it's suitable for the U.S.
Isotope Insufficiency
If one possible solution to the isotope crunch lies in Canada, the root of the problem is also there.
Canada's aging NRU reactor in Chalk River, Ont., is the main source of technetium-99 in North America. It has been in and out of service for the past several years, and the Canadian government says it will get out of the medical isotope business entirely by 2016.
That's a problem because technetium-99 is used in about 85% of all medical imaging procedures, and the remaining facilities that produce it -- reactors in the Netherlands, Belgium, France, Australia, and South Africa -- are unlikely to be able to take up the slack left by the Canadian shutdown.
The reactors don't actually make technetium-99. Instead they make molybdenum-99, a radioactive substance that decays into technetium-99.
The molybdenum-99 is packed into "generators" and distributed to hospitals, where nuclear medicine specialists can draw off the technetium-99 as needed for about a week.
The cyclotron process is more direct, Ruth said. For between three and six hours, the machine sends a stream of high-energy protons at a target of molybdenum-100, a nonradioactive isotope of the element, converting some of its atoms to technetium-99.
At the end of that time, a half-hour chemical processing step removes technetium-99 from the target and it's ready to be used in imaging procedures, he said. Unlike nuclear reactors, the machines that are needed are in wide use.
The downside is that the technetium-99 has a half-life of only about six hours, meaning it can't be stored for a long time or shipped long distances, Atcher said.
In Canada, where a large fraction of the population lives in urban centers, that may not matter, he said, as a dozen cyclotrons could probably handle the country's needs.
But in the U.S., the distance factor might mean that rural areas would be left out, Atcher said.
As well, the short half-life might make it more difficult to get technetium-99 on an emergency basis -- at night, for instance, or on weekends -- where specialists currently can simply draw off a little more from their generators.
"You can't equal the convenience of the generator," Ruth conceded. "That's why they've lasted so long."
So some generator production will probably continue, but the cyclotron process is "a piece of the puzzle," he said.
The researchers made a point of using machines similar to those now in use. In particular, of the three machines they modified to make the substance, two were 16 MeV machines made by GE, which are in common use around the world. At least in Canada, one of the regulatory hurdles -- establishing nuclear safety -- is under way, Ruth said. The Canadian Nuclear Safety Commission, the equivalent of the U.S. Nuclear Regulatory Commission, was involved in and approved the modifications to the test machines.
The second hurdle, establishing medical safety, will require clinical trials. Ruth said he and his colleagues hope to have a phase I study running this fall to show that their isotope is both safe and efficacious.
The technetium-99 they produce, he said, is identical structurally to the substance produced by molybdenum-99 generators. But the cyclotron process also introduces some other technetium isotopes -- less than 1%, the researchers calculated -- and those might have some unforeseen toxicity.
Ruth said Health Canada, the government department that has equivalent safety jurisdiction to that of the FDA, has also been aware of the research from the beginning. Technetium Tussles Another issue is cost, Atcher said. Given that the Canadian reactor is going out of business, there was pressure in Canada to find other sources of isotopes, even if they cost more. But whether the U.S. market would pay more is another question, he said. Ruth told MedPage Today he thinks the cost per dose will not be much higher, as least according to his group's preliminary calculations. But complicating the picture are the subsidies that underlie the current price of technetium-99. All of the reactors in the business, including Chalk River, are primarily research machines that get substantial support from their respective governments -- in essence, a subsidy for the isotope business. But there is currently a push to use molybdenum-99 made in reactors that use low-enriched uranium, unlike the highly enriched uranium used in current machines. Those facilities may not get similar support, so that the cost of generators would rise, Ruth said. The U.S. Department of Energy has been supporting efforts to develop a domestic source of isotopes. Two groups had been trying to develop a reactor-based technology, but one of those -- led by General Electric -- has recently dropped the project. As well, there are two projects based in Wisconsin that do not use reactors. Madison-based NorthStar Medical Radioisotopes is hoping to have commercial production of molybdenum generators this year, while Middleton-based Phoenix Nuclear Labs is also developing a production process. Because of that work, Atcher said he is more optimistic that the isotope market can become more stable than it has been. "But when we have a hard deadline of 2016, you always wonder what can go wrong in terms of technical development," he added. Bench to Bedside Technical development aside, it's also important to get products from the lab to the clinic, Ruth said. His group has done the scientific spadework and is now trying to find commercial partners to make and distribute cyclotron-produced technetium-99. Ottawa-based Nordion, the current commercial intermediary between the Chalk River reactor and the clinic, said it's discussing the issue with TRIUMF. In a statement, the company said it considers the cyclotron process to be something that would supplement reactor-based production. For clinicians, Ruth said, the key question is reliability -- can they depend on having enough isotope? That is a matter of how the cyclotrons are distributed and what other demands are placed on them. For example, the machine they tested in Vancouver could probably supply the needs of the Greater Vancouver Area, with a population of about 2.1 million. That device, at the B.C. Cancer Agency, has other functions, Ruth said, but a similar machine dedicated to making technetium-99 could probably serve all of the people in the province, some 3.5 million. Similar calculations would have to be made anywhere the process is used, he said. On the other hand, clinicians are used to some isotopes with a short half-life, such as fluorine-18, so that the distribution channels should not be a major issue. "We think we've dotted all the i's and crossed all the t's," he said. But "time will tell," Atcher noted.
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