The clock is ticking. From the minute the intimidatingly named 18F-FDG is created, doctors have less than two hours to administer the radioactive substance to their patient before it becomes ineffective. With it, the doctor will be able to map their patient’s cancer and be better equipped to treat it.
At the iThembaLABS facility, outside Cape Town, vast energies are pumped into a cyclotron — a machine that accelerates protons and neutrons, the building blocks of matter, and smashes them into a material.
The machine creates beams of these particles that bombard a target substance, creating fluorine-18 [18F], which is mixed with fluorodeoxyglucose (FDG). It is quickly packaged and driven to the nearest hospital — somewhere in the Western Cape — and injected into a waiting patient’s blood stream.
South Africa is one of the world leaders in medical radioisotope production, with production sites at iThembaLABS and the Nuclear Energy Corporation of South Africa’s (Necsa) Pelindaba campus in the North West, near Hartbeespoort Dam. They bring in nearly R1-billion in local and international radiopharmaceutical revenue, according to their annual reports.
“Most international flights that leave OR Tambo International Airport contain one of these medical isotopes, encased in a special container. The container can be compared to the black box on the plane — it’s that hardy,” Elliot Mulane from Necsa previously told the Mail & Guardian.
The facility at iThembaLABS, which stands for the iThemba Laboratory for Accelerator-Based Sciences, is one of the two public entities producing medical isotopes on a large scale in Africa and is the starting point of the race against time.
18F-FDG is a substance that behaves like glucose when ingested into the body, but it cannot be metabolised. This means it will pass harmlessly through the system once it has done its work. Although most of it will be excreted after consumption, after 12 hours it will be in effect untraceable in your body.
It is especially useful in creating 3D pictures of malignant cancer cells, which consume high levels of glucose. It would be difficult to isolate glucose in the body, but this radiopharmaceutical mimics it and can be identified because it is radioactive.
Last year, research published in medical journal Lancet Oncology predicted that global incidences of cancer would increase by 75% from 12.7-million in 2008 to 22.2-million in 2030.
Led by Dr Freddie Bray of the International Agency for Research on Cancer in France, the study also said that developing nations might see a larger growth in cancer cases.
A radioisotope is an atom that has an unstable nucleus, which means that it will emit radiation and decay in an effort to become more stable. It is the raw product that can be created using either a cyclotron or a nuclear reactor. Sometimes, other substances are added to the radioisotope. Once it has undergone regulatory testing and is safe for humans, it is called a radiopharmaceutical, which is what the patient will consume.
Its decay is measured by its half-life, which is the time it takes for half of the substance to decay. 18F-FDG has a half-life of 110 minutes and after that time it is not effective, which is what dictates the stringent deadlines to get the radiopharmaceutical from the lab into the patient. Despite these restrictions, it is in demand because it is a noninvasive way to visualise cancer, making the transportation challenges worthwhile.
Dr Zeblon Vilakazi, the director of iThembaLABS, says that isotope production at the facility is mainly for cost recovery.
“In the late 1990s, we hit a financial crunch, and we had to reformulate our business model, where isotopes became a large part,” says Vilakazi.
“You cannot run an independent business from isotopes, but they cover the shortfall in funding allocations.”
According to iThembaLABS’s 2011-2012 annual report, it received a core state grant of R132-million. The facility, operated by the National Research Foundation, is home to a number of particle accelerators, and its main focuses are research and training.
Radioisotopes are just one part of its activities, which include nuclear and materials research, and proton and neutron therapy — in which cancer patients’ tumours are bombarded with beams of protons or neutrons created in the cyclotron in an effort to kill the cancerous cells.
iThembaLABS produces 18F-FDG through an agreement with Necsa’s subsidiary, NTP Radioisotopes, mainly because the distance between Hartbeespoort Dam and the Cape would render the product ineffective.
Until last year, 18F-FDG was produced using iThembaLABS’s 66MeV cyclotron, in which charged particles are accelerated in a spiral. However, last year an 11MeV cyclotron was purchased for dedicated 18F-FDG production. Mega-electron volts are a unit of energy.
“It is a joint effort between iThembaLABS and NTP to produce fluorine-18 for the Western Cape market,” Vilakazi says. However, the main cyclotron is still used to prepare other radioisotopes.
The head of radionuclide production at iThembaLABS, Dr Clive Naidoo, says 18F-FDG is produced five days a week for 48 weeks of the year. Speaking about the facility’s radioisotope production in general, he says: “We service over 25 nuclear medicine departments in hospitals and clinics, both in the private sector and the public sector.”
He mentions hospitals that include the state’s Tygerberg and Port Elizabeth Provincial hospitals and the private Greenacres and Claremont Mediclinic facilities. According to its annual report, iThembaLABS’s radioisotopes “contributed to the patient management of over 70?000 nuclear medicine patients”.
Professor Annare Ellmann, head of nuclear medicine at Tygerberg hospital and the University of Stellenbosch, says: “We try as far as possible to buy locally. FDG is a PET tracer, and most of our FDG comes from iThembaLABS or from [NTP Radioisotopes at] Pelindaba.”
PET stands for positron emission tomography, and is a medical imaging technique that produces a three-dimensional image of a specific area in the body. In a PET scan, the scanner picks up on the radiation that is being emitted by the radiopharmaceutical that the patient has ingested, and constructs an image of radioisotope concentration.
The problem with 18F-FDG is that a PET scanner is required to create an image of it. These are expensive but are becoming popular as a way to diagnose and monitor cancer.
Last year, the Western Cape Academic PET/CT [Positron Emission Tomography/Computed Tomography] Centre was opened at Tygerberg Hospital, with NTP donating the PET/CT scanner.
At the opening event, NTP executive director Mapula Letsoalo said: “The need for an additional scanner was imminent as the use of [18F-FDG] grew by 109% in 2009-2010 compared with 2008-2009 [figures]for Tygerberg alone.”
NTP also produces F18-FDG, but the cash cow is a substance called molybdenum-99 [Mo-99], which is produced in the Safari-1 reactor at Pelindaba.
The 48-year old Safari-1, which stands for South African Fundamental Atomic Research Installation, was provided by the United States as part of its Atoms for Peace programme. The 20MW reactor is used for materials testing, not electricity generation such as at Koeberg nuclear power station.
“The NTP Group achieved sales of R842-million … [It] remains one of the world’s leaders in the supply of medical isotopes and the only company in the world that produces Mo-99 using a fully low-enriched uranium-based process,” Necsa says in its 2012 annual report.
South Africa is the only country in the world to have willingly halted its nuclear weapons programme, which hinged on uranium enrichment for warheads. This was carried out at “Valindaba”, which is on the Pelindaba site.
“We don’t want highly enriched uranium, which is why we have closed Valindaba. We’re trying to remove all the technology associated with highly enriched uranium,” Necsa spokesperson Elliot Mulane has said.
Unlike 18F-FDG, Mo-99 has a longer half-life of 66 hours and is not consumed by the patient. It breaks down into technetium-99, which is the radiopharmaceutical. Because technetium-99 only has a half-life of six hours, it is difficult to transport over long distances, which is why Mo-99 is ordered by doctors in what is called a technetium-99 generator, or a “moly cow” because the Mo-99 is “milked” for technetium.
“We call it the cow,” says Ellmann from Tygerberg Hospital. “There is molybdenum inside the cow, and you get out technetium. That’s actually what we use. We regularly buy NTP’s molybdenum-technetium generators, [in fact we have a] delivery once a week. It is the backbone of what we use in nuclear medicine.”
She refers to the use of technetium as “ordinary” nuclear medicine, because the patient does not need a PET scan to image it.
Although the technetium can be used on its own, it is often more useful to make it organ specific through the use of a labelling kit, which is mixed with the technetium. This is injected into the patient’s blood stream.
If a doctor is, for example, looking for an image of thyroid cancer, the kit they use will contain iodine, because iodine collects in the thyroid. This means that the technetium-iodine mixture will accumulate in the thyroid and in the tumour.
Professor Willie Vangu, the head of nuclear medicine at Donald Gordon Medical Centre and Wits University, says: “Molybdenum is our bread and butter.”
“About 95% of what we use is produced at Pelindaba,” he says, adding that the most commonly used radiopharmaceutical is technetium, but that use of 18F-FDG is increasing.
In 2009, a problem at a radioisotope production facility in Canada saw South Africa become the world’s leading medical radioisotope producer as it addressed the lack of supply. Today, the NTP’s radioisotopes and labelling kits have customers in 60 countries on six continents, according to the Necsa report.
Ellmann said that last year Tygerberg Hospital performed more than 9?000 procedures on more than 4?000 patients.
“There are more procedures than patients because one patient could have a bone scan, then a PET scan, then something else,” she says, adding that Tygerberg’s nuclear medicine department was “very busy”.
Before the Western Cape Academic PET/CT Centre at Tygerberg, only about 12 patients could be scanned each week, Professor James Warwick, who is in the nuclear medicine department at Tygerberg, told the online newspaper Engineering News at the facility opening. About 100 patients could be scanned per week with the new scanner.
Ellmann says that the hospital treats both private and public patients. Using 18F-FDG, it costs “approximately R8?000 to R9?000 for a full private patient (a patient whose treatment is not subsidised by a medical aid). If it’s public, it depends what category they’re in — they pay according to income.”
Vulnerable patients such as children and pregnant women are treated for free.
For “ordinary nuclear medicine”, which does not include PET scans, “it varies between R200 and R3?000 to R10?000, depending on the cost of the [labelling] kit, then the patient outpatient consultation.”
Repeated attempts to get comment from Necsa were unsuccessful.
Radioisotopes are good business
What medical radioisotopes does South Africa produce?
• For export, iThembaLABS and Nuclear Energy Corporation of South Africa subsidiary NTP produce generators — radioisotopes that decay into products that can be used to treat patients.
This is because transport times depend on the products’ half-lives, or the time it takes for half of the radioisotope to decay.
iThembaLABS’s germanium-68 [68Ge]/gallium-68 [68Ga] generator “is shipped to over 40 clients worldwide, predominantly to Europe, Australia, the United States, Canada, Mexico, Singapore, Malaysia, India and China,” says Dr Clive Naidoo, head of the radionuclide department. 68Ge has a half-life of 271 days, whereas half of 68Ga decays after just over an hour [68 minutes]. “iThembaLABS provide[s] one third of the world’s demand and a shipment leaves [the facility] once a month,” says Naidoo.
The total income for the 68Ge/68Ga was R4.9-million in 2011-2012.
• The research facility also exports strontium-82 [82Sr] to Canada, but this is a radioisotope in its raw form.
“When it arrives in Canada, they produce a radiopharmaceutical, rubidium-82,” iThembaLABS head Zeblon Vilakazi says. In 2011-2012, the total income for 82Sr was more than R5-million. Rubidium-82 is used to detect myocardial infarction, or heart attacks, in patients.
• Necsa last year said NTP would be looking to produce a new radio-isotope, lutetium-177 [177Lu], which is used to identify neuroendocrine tumours. NTP executive director Mapula Letsoalo said that NTP was not “manufacturing it locally yet, but we’re setting up a facility”.
It was not expected to rival Mo-99, but “represented a high-value-added product in the port-folio mix”.