July 27, 2009

Caution — Lack of Imaging Isotopes May Be Hazardous to Patients
By Beth W. Orenstein
Radiology Today
Vol. 10 No. 14 P. 14

It was somewhat ironic that this year’s SNM annual meeting was held in Toronto because Canada is home to one of five aging reactors worldwide that supply molybdenum-99 (Mo-99), the material needed to produce the technetium-99m (Tc-99m) generators used in 80% of all nuclear medicine studies. The Chalk River reactor in eastern Ontario supplies about 30% of the world market.

As the SNM meeting was under way, its members knew that Chalk River had been offline since May to repair a water leak. People were talking about how the 52-year-old reactor was likely to be down for quite a while. “No one was dissuading us from that notion,” says Robert Atcher, PhD, MBA, of the University of New Mexico/Los Alamos National Laboratory, chair of SNM’s isotope (Mo-99) task force, and the society’s immediate past president. “No one was saying it would be fixed faster than a few months.” Some were speculating it may not be fixed at all, which would affect 50% of the U.S. market.

The timing of the Chalk River shutdown couldn’t have been worse. The world’s other major Mo-99 supplier, the Petten reactor in the Netherlands, was scheduled to be down for several weeks starting this month. “That means their capability to make up for part of the outage in Canada was going to be offline as well,” Atcher says. Like Chalk River Laboratories, Petten also supplies about 30% of the world market, including the other 50% of the U.S. market.

20 Million Exams
SNM estimates that about 20 million nuclear medicine procedures are performed in the United States annually, approximately 60% of those exams in cardiology and oncology. Most commonly, radioisotopes are used in myocardial perfusion imaging for coronary artery disease and in bone imaging to detect the spread of cancer to the bones. Nuclear imaging is also used to diagnose and evaluate diseases of the kidney, liver and biliary system, lungs, brain, and gastrointestinal tract.

Of those 20 million studies, 80% use Tc-99m, which is produced from the decay of Mo-99. “That’s 16 million procedures that depend on the Mo-99 generators for the radioisotopes we use in the imaging study,” Atcher says. With the two major producers of Mo-99 offline, supplies of Tc-99m are short, and hospitals and imaging facilities are making decisions to delay or cancel some procedures or use alternate studies that are not as good.

It’s not just a matter of getting the reactors up and running again. Built in the 1950s and 1960s, the reactors are aging and face continued scheduled and unscheduled shutdowns, Atcher says. Adds Michael Graham, MD, PhD, director of nuclear medicine at the University of Iowa Carver College of Medicine in Iowa City and the recently elected SNM president, “Long term, replacing the large reactors throughout the world needs to be addressed because all of them are at least in their 40s. The one in Canada is 52 years old, and it’s not surprising they’re having problems because they’re really reaching their expected lifetimes.” The reactor in the Netherlands is scheduled for another multimonth shutdown in 2010.

In addition to age, another issue is that the Chalk River, Petten, and three other large reactors in France, Belgium, and South Africa use highly enriched uranium. In today’s world where terrorism is a huge threat, that makes some people uncomfortable. A primary objective of the National Nuclear Security Administration’s Global Threat Reduction Initiative is to minimize proliferation risks by phasing out the use of highly enriched uranium in civil commerce. Recently, Lantheus Medical Imaging, Inc, which specializes in processing isotopes for medical use, announced that it has finalized an arrangement with the Australian Nuclear Science and Technology Organisation (ANSTO) to receive Mo-99 produced from its low-enriched uranium targets in ANSTO’s new OPAL reactor. This supply arrangement makes Lantheus, which had relied heavily on Chalk River, the first company to supply Tc-99m derived from low-enriched uranium to the U.S. market. The arrangement also helps diversify the Mo-99 supply chain, according to the company.

Increasing Domestic Production
Plans to convert research reactors to Mo-99 production or build new ones are on the table. One plan is to convert a research reactor at the University of Missouri, Columbia into a medical isotope producer. In January, engineering firm The Babcock & Wilcox Company in Lynchburg, Va., announced that it had an agreement with Covidien, another major U.S. supplier of isotopes for medical use, to develop technology for the manufacture of Mo-99 using low-enriched uranium. The companies said the project has the potential to supply more than 50% of U.S. demand for Mo-99. “There are people in Congress pushing hard for the U.S. to shift to low-enriched uranium targets that can’t be weaponized,” Atcher says. “It will involve some research and development. We have to do it in a way so that we aren’t harming our ability to produce molybdenum-99.”

Graham believes the Missouri project is one of the most promising. “There is considerable enthusiasm among the nuclear medicine community to convince Congress and the Department of Energy to provide significantly more funding. This is the most realistic near-term solution to the problem. If they are able to upgrade that facility, it could supply about 50% of the Mo-99 in the U.S.,” he says. However, the project will take at least two to three years even if it receives adequate funding and will more likely take seven to eight years, he says. With current economic conditions, it’s hard to predict what will happen. It is possible that stimulus money could be used to support the project.

The Babcock & Wilcox/Covidien project is also several years from completion. “The most optimistic projections I’ve heard is four years,” Atcher says. “I’m a nuclear chemist by training, and I think that’s way too optimistic. We’re estimating five to seven years before that technology could be brought online.” Also, he says, the project faces not-in-my-backyard opposition when it comes to finding a site for the reactor.

While government, industry, and the nuclear medicine community seek long-term solutions to shortages of Mo-99, hospitals and imaging facilities have to deal with the immediate problem. Lantheus and Covidien say they are doing what they can to supply their customers. In addition to its agreement with ANSTO, Lantheus has new agreements with NTP Radioisotopes (Pty) Ltd, a subsidiary of the South African Nuclear Energy Corporation, to manufacture and supply an ongoing volume of Mo-99 from its Safari reactor.

Rick Lytle, vice president and general manager of Covidien’s Imaging Solutions-North America, says knowing that the Petten reactor would be down for several weeks starting in July, it attempted to secure more Mo-99 from the remaining three reactors. Lytle says Covidien was also in communication with its customers, so they could adjust their patient schedules while the isotope was in short supply. Standing-order customers are given priority, he says. “We consider first and foremost our standing-order customers, our existing customers,” he says. “Our non–standing-order customers are served after we serve our standing-order customers.”

Juggling Procedures
Graham says that some facilities have had to delay or reschedule nuclear medicine procedures because of the short supply of the isotopes. Others have had to use alternate procedures, which, he says, are not as high quality as those using Tc-99m, and he is concerned that patient care will suffer while the world resolves its radioisotope supply problems.

Graham says how a facility copes with the shortage depends largely on who its main supplier is. “At the University of Iowa,” he says, “we had Lantheus and we had a major problem for a while, but it has slowly gotten better.” One solution, he says, was to inject less of the isotope into the patients, which meant imaging the patients for longer. “In other cases,” he says, “we postponed and rescheduled studies.” How do providers determine which ones can be postponed until supplies are back to full speed? “We don’t have any strict rules,” he says, “but certainly the truly elective cases we could postpone more than anything that was more emergent.”

Because of the shortages, some physicians have returned to doing cardiac perfusion imaging with thallium-201. Knowing that’s the case, Lantheus has ramped up production of thallium in its cyclotrons at its site in Billerica, Mass., and Covidien has ramped up production of thallium in its cyclotrons at its site near St. Louis. “We are currently operating at expanded capacity to meet the demand for this alternate cardiac imaging agent during the Mo-99 shortage,” Lytle says.

Thallium had been used until Tc-99m agents came along. However, Tc-99m has better decay characteristics, so the images are clearer, Atcher says. The catch is that Tc-99m has been on the market long enough now that there’s a generation of nuclear medicine technologists and some physicians who are not that experienced with using thallium, he notes. “They’re going to have to brush up on their skills because it’s a little different,” he says. “You’ve got to set the imaging instrumentation up a little bit differently. Patients have to be handled a little bit differently. If you’re using thallium again, you really need to refresh your memory in terms of what you need to do with thallium vs. imaging based on technetium compounds.”

Having to delay or reschedule some nuclear imaging studies could mean some patients will undergo more costly procedures, Atcher says. For example, he says, a nuclear cardiac imaging study for a patient is about $1,500. If the physician doesn’t have the radioisotope, he may have to do a cardiac catheterization, which is about $15,000.

Oncology Questions
Atcher is particularly concerned about the alternatives physicians may be forced to rely on when it comes to oncology applications. “The other imaging modalities are not nearly as sensitive as nuclear medicine to detecting the spread of cancer to the bone,” he says. “You’ll see it but see it at a much later stage when the bone has actually been destroyed rather than seeing changes associated with increased blood flow and changes in terms of what’s going on with the bone in that area. That’s a big worry.”

Reimbursement is another issue. Bone scans can be done alternately using F-18 sodium fluoride PET. SNM and the Academy of Molecular Imaging have asked the Centers for Medicare & Medicaid Services (CMS) to reconsider its coverage decision on sodium fluoride PET scans, especially in light of the Mo-99 shortages. The CMS opened a 30-day comment period in June to review evidence, according to Atcher. The outcome was not known at press time. Bone scans play an important role in terms of staging patients with breast, prostate, or lung cancer, Atcher says, and he is concerned that some patients won’t receive proper treatment if they don’t undergo such scans.

Yet another concern, he says, involves those cases where physicians have no alternate imaging procedures. “There are a number where we don’t have an option,” he says, noting that’s where patient care may suffer the most.

Atcher says it’s also ironic that the United States does not have any reliable domestic supply of Mo-99, as the country is more reliant on nuclear medicine imaging than most. “The reliance is, in part, because of the way our healthcare system is set up, but also there are important considerations in terms of patients,” he says. “We use nuclear medicine studies because we’ve determined they generate the best information for us in terms of diagnosing and staging patients. The alternatives almost always involve some combination of less accuracy, higher radiation dose, higher cost, or more invasive procedures.”

— Beth W. Orenstein is a freelance medical writer based in Northampton, Pa. She is a regular contributor to Radiology Today.