Until GE found a better way to produce and deliver I123, most nuclear medicine labs had to make do with an isotype that produced an inferior image
This edition of Tomorrow’s Medicine highlights neuroblastomas and pheochromocytomas — two different tumors that affect widely differing age groups but share several characteristics.
Most people do not associate newborns with cancer, but one cancer in particular can occur at birth — the neuroblastoma. In fact this tumor is occasionally discovered on prenatal ultrasounds. This highly malignant cancer has its origin either in the adrenal gland, in nerve cells in the abdomen, or in the ganglia of the nervous system.
About 650 children will be diagnosed with neuroblastoma this year and the incidence is about one in 100,000 children — making it the second most common pediatric cancer after leukemia and other lymphoproliferative diseases.
About 50 percent of cases are diagnosed in children less than 2 years old. By the time of diagnosis, 70 percent of patients have metastatic disease. It is one of the few cancers that secrete hormones, mainly epinephrine and norepinephrine (NE).
There are no data to support routine screening for neuroblastoma. Parents who find a lump in the abdomen of their child typically are the first to notice a neuroblastoma.
Occasionally it can occur behind the eye and cause a proptosis or bulging of the eye. High blood pressure, diarrhea, rapid pulse, abnormal sweating, or uncontrollable eye movements can accompany it. If the tumor originates in the paraspinal ganglia, paralysis can occur as the tumor compresses the spinal cord.
Treatment consists of surgical removal with follow-up chemotherapy and radiation therapy used to attempt to destroy cells not removed by surgery.
First described in 1886, the pheochromocytoma is a predominantly benign tumor originating in the medulla of the adrenal glands that, like the neuroblastoma, also secretes excessive amounts of catecholamines. It is diagnosed in approximately 1,000 people each year in the United States and occurs mainly in young or middle-aged adults. In about a quarter of cases it is familial. It might be suspected when symptoms of a hyperactive sympathetic nervous system are present, such as rapid pulse, sporadic resistant elevation of blood pressure, palpitations, sweating, anxiety, headache, and elevated blood glucose. About 10 percent of pheochromocytomas are malignant. Surgical resection of the tumor is the common treatment.
Analyzing urine and blood samples for the byproducts of the secreted hormones helps with the differential diagnosis for both of these tumors. Tests that determine the levels of catecholamines or their metabolites — dopamine, homovanillic acid (HVA) and vanilly mandelic acid (VMA) — are usually undertaken.
A variety of imaging studies are used to diagnose and localize both neuroblastoma and pheochromocytoma, including ultrasound, computed tomography (CT) scans, magnetic resonance imaging (MRI) tests and nuclear imaging using radioactive labeled agents. Making the diagnosis is difficult and typically requires more than one imaging modality, but suffice it to say that nuclear imaging is one of the mainstays. More than three decades ago, researchers discovered that these tumors had a tendency to secrete hormones related to neurotransmitters.
If an analogue of NE were tagged with a radioactive isotope, the analogue would be taken up by the tumor. This allows the tumor to “light up” with the released radiation from the radioisotope.
Iobenguane was the analogue chosen, as it is a rather inert compound similar in structure to the neurotransmitter NE. Iobenguane is subject to the same uptake and accumulation pathways as NE, accumulating in adrenergic nerve terminals, presynaptic storage vesicles, and all adrenergically innervated tissue.
By labeling iobenguane with a radioactive isotope of iodine, the uptake of iobenguane allows scintigraphic images to be taken of the organs and tissues in which the radiopharmaceutical accumulates.
This process of labeling iobenguane with radioactive iodine has been a mainstay of imaging neuroblastomas for decades.
But recently a development has occurred that has significantly improved the process by which this radiopharmaceutical is made available to physicians. To understand this, a little background is in order.
Because of the radioactive nature of radiopharmaceuticals, nuclear medicine isotopes are highly regulated, not just because of the safety concerns for the patients and medical personnel who use these drugs, but also because of heightened security issues since 9/11. They can be created and used only in licensed facilities.
Transporting these compounds is controlled by a variety of federal and state laws and regulations.
These compounds also have very different properties than other pharmaceutical products in that they expire in a very short time after manufacture because of the relatively short half-life of the radioisotopes used in human diagnostic procedures.
Most people reading this column understand that some radioactive compounds are by their very nature unstable and highly dangerous because they emit high-energy particles that can damage human cells, can remain in the environment for years and sometimes millennia, and have been associated with both acute and chronic human disease. But radioactive agents vary considerably in both their energy release and their half-life. Some radioactive agents last a fraction of a second and others last for thousands of years.
The holy grail of nuclear medicine has been to find radiopharmaceuticals that balance the biology of the agent with the physical decay of the radioisotope.
An ideal radiopharmaceutical used for imaging would emit radiation for a very short time at the proper “strength” of energy, exhibit rapid and specific uptake into the desired organ, and demonstrate rapid elimination from the body to minimize the radiation exposure to the patient. It must also accurately and precisely depict the target organ. Using an agent with just the right amount of energy allows for a better picture of the target organ.
Labeling iobenguane with iodine has been done for decades, but the most convenient isotope, I131, was an agent with a relatively long half-life (eight days) that released a relatively high energy level of 364 kiloelectron volts (keV).
A better iodine isotope is I123, which has a shorter half-life of just 13.2 hours and has an energy release of just 159 keV. The lower energy released by I123 requires less lead in the nuclear camera and produces better images.
The crux of the problem is that local radiopharmaceutical producers do not create their own radioactive isotopes and must rely on outside sources.
The major source of I123 in North America is a company in Canada. The company ships the radioactive material to the local pharmacy (of which there are about 300 in the United States). The pharmacy then compounds the isotope with iobenguane and ships it to the hospital’s nuclear medicine department for eventual patient use.
All of this takes time, adds expense, and produces a non-FDA approved product lacking consistency in the manufacturing process and quality. In addition, since the availability of pharmacies that are capable of creating this diagnostic agent is not geographically uniform and the process is difficult, many physicians and hospitals could only use the easier-to-produce I131 version of this product because of its longer shelf life.
A recent FDA approval has solved this. General Electric understood that to provide a highly consistent I123 labeled iobenguane that could be made available to any nuclear medicine practice in the United States, it had to be able to manufacture this isotope at will. The company also had to control the precise manufacturing time to ensure that the rapidly decaying isotope was still fresh, and to deliver it to the nuclear imaging laboratory in a highly controlled and choreographed manner.
Since I123 is created in a cyclotron, the company built one in centrally-located Illinois, allowing for rapid transport to the entire country.
The product, AdreView, is an orphan drug indicated for use in detection of primary or metastatic pheochromocytoma or neuroblastoma as an adjunct to other diagnostic tests.
The safety and efficacy of AdreView was studied in an open label, multicenter, multinational trial of 251 subjects with known or suspected pheochromocytoma or neuroblastoma. Patients ranged in age from 1 month to 88 years.
Diagnostic efficacy was determined by three independent experts who compared the increase in radionuclide uptake and who were blinded to the clinical data presented on planar scintigraphy.
An overview of the entire FDA submission is beyond the scope of this article, but physicians now have for the first time an FDA-approved product that is available for use throughout the United States and that is manufactured in a consistent and predictable high-quality manner.
Pricing was not available from the manufacturer, but because of the nature of the prior process of manufacturing, which required multiple vendors and several transportation events, the price is likely to be similar to or even less than unapproved substitutes.
The use of I123 will enable production of improved images that are likely to allow a more reliable reading and diagnosis.
AdreView again reinforces the view that technology, backed by a large nationally recognized corporation, is capable of providing improved diagnostic options for Tomorrow’s Medicine!