Intravenous Radiation. How Radioactive Substances Help to Diagnose and Treat Fatal Diseases

X-ray diagnostics and radiation therapy are based on human body irradiation from external sources. However, radiation can work inside the human body helping to diagnose and treat diseases of various organs. To do this, the patient is injected with a radionuclide in the form of a radiopharmaceutical. The use of radioactive substances for medical purposes is a separate section of medical specialty — nuclear medicine.

The essence of radionuclide diagnostics and therapy is the use of radiopharmaceuticals: pharmaceutical compounds with radionuclides, whose use is authorized by the Ministry of Health according to legislation. In other words, these are radioisotopes combined with organic transport molecules, sometimes only radioisotopes, if they have appropriate biological properties. This structure allows, during natural metabolism, directing them to specific organs, tissues or cells, where they act as labels for imaging (diagnostics) or directly to the focus of pathology (therapy). For example, the thyroid gland absorbs iodine well, and the brain absorbs glucose.

The presence of radiopharmaceuticals in the examination structure represents the main and fundamental difference between nuclear medicine and other radiological methods. To perform any other radiological examination, the system should have two components: a device and an object of examination. Examinations in nuclear medicine, however, have a third component in the system: a radiopharmaceutical, which is a source of radiation recorded by the device. So it is the pharmacodynamics (biochemical effect) of a radiopharmaceutical, which determines exactly where it will be accumulated and which tissues will be examined. It means that only living organisms can be examined using nuclear medicine modalities, and these examinations are of a functional nature.

There is a similar situation with therapy. Traditional techniques of radiation therapy deliver a focal dose from an external source, while radionuclide therapy uses the properties of therapeutic radiopharmaceuticals to be accumulated in the pathological focus and irradiates it from the inside.

In total, about 140 radionuclides are used in nuclear medicine, and 90% of the procedures use ten isotopes, in particular: technetium-99m (which is obtained from molybdenum-99), iodine-131, indium-111, thallium-201, gallium-67, lutetium- 177, fluorine-18, etc.

“The main idea is to irradiate the target with a neutron flux and obtain various nuclides. Thus, nuclear power reactors are not suitable for obtaining radiopharmaceuticals, since in them, neutron fluxes are brought out in another place and just obtaining them from spent fuel will not work, because when fuel is unloaded from a power reactor, short-lived isotopes will simply decay”, Artem Stavenko, nuclear physicist, an employee of the Izotop enterprise, says.

In addition, radionuclides can be produced using cyclotrons (the target is bombarded with protons or ions) or radionuclide generators.

 

Radionuclide Diagnostics

According to the World Nuclear Association, 90% cases of using radiopharmaceuticals in medicine belongs to diagnostic procedures. Radionuclide diagnostics is especially effective for detecting tumors, infectious processes, diseases of bones, kidneys, bone marrow and brain, cardiovascular system, lungs, liver, etc.

In general, radionuclide diagnostics started rapid development since 1950, when industrial production of radiopharmaceuticals and electronic equipment became possible. During a relatively short period, it has become an integral part of the diagnostic process at all stages of disease progress, assessment of the functional state of a healthy body.

Radioisotope examination techniques can have five forms:

1. One-time or multiple radioactivity determination of the entire human body, individual organs or systems to identify a pathological condition under irregularities of the kinetics of radiopharmaceuticals involved in metabolic processes;
2. Determination of radiopharmaceutical speed in certain areas of the cardiovascular system to study hemodynamics;
3. Study of spatial radiopharmaceutical distribution in the human body for imaging of organs, pathological lesions, other anatomical and physiological systems;
4. Evaluation of dilution degree of a radiopharmaceutical in body fluids;
5. Study of the interaction of labeled compounds with constituents of biological media of the organism.

The examination can be carried out without radiopharmaceutical injection into the human body (in vitro):  under radioimmunoassay (RIA). RIA is a type of immunochemical analysis based on the competitive interaction of the antigen-antibody complex labeled with a radioactive isotope. This method is used to determine the concentration of hormones (insulin, thyroxine, thyroid-stimulating hormone (TSH), cancer-embryonic antigen (CEA), alpha-fetoprotein, chorionic gonadotropin (CGT), etc.) and tumor markers, since this method is highly sensitive to compounds in such low concentrations.

If a radiopharmaceutical is injected intravenously or orally (in vivo), its radiation is recorded by measuring equipment, so an image of radiopharmaceutical distribution and kinetics can be obtained. There are several methods of radionuclide diagnostics, which differ in principles of operation, equipment, radiation type and quality of obtained images.

Method	Radiation	Equipment	Radionuclides	Image
Positron emission tomography (PET) + computed tomography (CT)	beta	PET scanner + computer tomograph	18F, 11C, 13N, 15O, 68Ge/68Ga, 13А, 124І, 82Sr, 82Rb half-life: from a few seconds to an hour	Three-dimensional
Single-photon emission computed tomography (SPECT)	gamma	SPE-tomograph with several gamma-cameras /+ computer tomograph	99Mo/99mTc, 201Tl, 123I, 111In, 67Ga half-life:  from a few minutes to a day
SPECT/CT
Scintigraphy (single organs or whole body)		Gamma-camera		Two-dimensional

Scintigraphy was the first technique of radionuclide diagnostics. The principle of this method: gamma quanta in the crystal of the gamma camera detector cause scintillations (light flashes that occur in substances under the influence of charged particles), which are transformed into an electrical pulse and transmitted through the system of photomultiplier tubes to the diagnostic image collection station.

The received image information is displayed on the computer monitor for processing and obtaining a two-dimensional or three-dimensional image. Scintigraphy visualizes the functioning tissue of the myocardium, brain, lungs, thyroid gland, skeletal bones, kidneys, liver, other organs and systems.

A further improvement of this technique was single-photon emission computed tomography (SPECT), which allows forming images in three-dimensional projection. In combination with computed tomography, SPECT has become the most common imaging technology today, it allows not only to determine the functional state of the organs under examination, but also to accurately localize pathological changes.

A relatively new and more advanced technique is positron emission tomography (PET). It uses positron-emitting radiopharmaceuticals synthesized by the cyclotron method. After fixing in certain tissues, during physical decay, a radionuclide emits a positron, which is combined with the nearest electron (annihilation of positron-electron pairs) that provides simultaneous radiation of two gamma quanta in opposite directions. They can be accurately identified by two detectors that significantly improves the quality of a diagnostic image.

Nowadays, a PET scanner almost always complements a computer tomography that, due to the combination of two image types improves diagnostic accuracy by an average of 30%. Due to this, PET-CT is considered the most accurate non-invasive technique for detecting and assessing most cancer types, as well as a unique tool to diagnose numerous diseases from dementia to cardiovascular diseases.

Radionuclide diagnostics gives doctors another advantage over X-ray radiography: with a single injection of radiopharmaceutical, an image of the whole body can be obtained without increasing radiation exposure of a patient.

A diagnostic radionuclide should have as short half-life as possible to minimize the harmful radiation effects on humans, and at the same time sufficient to deliver a radiopharmaceutical from the reactor (cyclotron) to a hospital.

The most common radioisotope for diagnostics (scintigraphy, SPECT) is technetium-99m used for the synthesis of radiopharmaceuticals, which are generally applied in 80-85% of visual radionuclide examinations (70-100 thousand scans per day in the world).

The range of applying radiopharmaceuticals based on it is wide: localization of tumors in the body, monitoring the functional state of the heart and kidneys, mapping blood movement in the brain, and determining target organs during surgery. A short half-life and absence of high-energy beta radiation (^99mTc is a gamma emitter) provides a small dose of patient exposure, and the rest of the radiopharmaceutical is quickly excreted from the body naturally.

The half-life of ^99mTc is 6 hours, therefore, technetium generators and not finished products are supplied to medical institutions: lead containers, which contain an ion-exchange column with the parent isotope. It is molybdenum-99 generated at the reactor, which decays to technetium-99m in the generator. It is removed from there by washing out with a solvent: salt solution (elution process). After two weeks or less, the generator is returned to the manufacturer for recharging or recycling.

Technetium-based radiopharmaceuticals are prepared from the so-called cold kits. They are called so because they are not a source of radiation until a radioactive technetium molecule is attached to this label.

Application of technetium-based radiopharmaceuticals for planar scintigraphy and SPECT

Radiopharmaceutical	Diagnoses the following
99mTc-pertechnetate	Diagnostics of diseases of the thyroid and salivary glands, diagnostics of tumors of soft tissues and brain (meningiomas, gliomas, glioblastomas, astrocytomas)
99mTc-DTPA (diethylenetriaminepentaacetic acid)	Assessment of filtration and excretory function of the kidneys, glomerular filtration rate, number of functioning parenchyma
99mTc-DMSA (dimethylene – succinate acetyl)	Assessment of defects of the cortical substance of the kidneys, diagnosis of temporary and permanent kidney damage
99mTc-MAG3 (mercaptoacetyltriglycine)	Assessment of secretory-excretory function of the kidneys, renal plasma flow, prognosis of viability of the transplanted kidney
99mTc-EC (ethylene dicysteine)	Assessment of secretory-excretory function of the kidneys, renal plasma flow, detection of true or false obturation of the urinary tract, vesicoureteral reflux
99mTc-HAG3 (hydroxyacetyltriglycine)	Assessment of secretory-excretory function of the kidneys, renal plasma flow
99mTc- glucoheptonate	Assessment of defects of the cortical substance of the kidneys, diagnosis of temporary and permanent kidney damage, determination of glomerular filtration rate
99mTc- phosphates (pyrophosphate, methylenediphosphonate)	Diagnostics of the presence of primary or secondary damage of the skeletal system, assessment of severity of inflammatory changes in the kidneys, identification of areas with necrosis in the myocardium
99mTc-MIBI (methoxyisobutylisonitrile)	Study of myocardial perfusion, identification of myocardial ischemia zones, diagnosis of parathyroid adenoma, breast cancer
99mTc- tetraphosmin	Diagnostics of breast cancer, assessment of treatment effectiveness
99mTc- colloid	Assessment of morphofunctional state of the cells of the reticuloendothelial system, identification of primary and secondary liver damage
99mTc-XIDA (imidodiacetic acid)	Assessment of the secretory-excretory capacity of hepatocytes, functional capacity of the gallbladder, determination of biliary dyskinesia type
99mTc-MAA (macroaggregate of human blood serum)	Assessment of pulmonary perfusion, diagnosis of tumor lesion, its prevalence, diagnosis of pulmonary embolism (PE)
99mTc-ceretec (HmPAO)	Assessment of cerebral perfusion, identification of ischemic areas, diagnosis of ischemic strokes
99mTc-DMSA (V)	Determining localization of anonymous tumors, metastases
99mTc- depreotide	Diagnostics of lung tumors, pulmonary embolism
99mTc-IgG	Identification of hidden inflammation areas
99mTc-nanocoll	Identification of the first lymph node that is metastatic in breast cancer
Source: Kundin, V., Radionuclide Diagnostics: Current State and Near-Term Prospects

Rubidium-82 (half-life is 1.3 min) is obtained from strontium-82 for PET using a similar principle. However, the main radiopharmaceutical for PET (PET-CT) is fluorodeoxyglucose (FDG) with fluorine-18 as a label. Fluorine-18 has a half-life of 110 minutes and is very suitable to study cell metabolism, because it easily penetrates cells without decay.

Thallium chloride-201 or technetium-99m is used for myocardial perfusion imaging: a type of SPECT to diagnose coronary artery disease.

Non-technetium-based diagnostic radiopharmaceuticals

67Ga labeled gallium citrate	Abscesses and infections, cancer, tumors
111In labeled  indium oxyquinoline	Blood volume tests, abscesses and infections
51Cr sodium chromate decahydrate	Blood volume tests, bone marrow disease, red blood cell disease, spleen disease, intestinal and internal bleeding
13N – ammonia	Diseases of blood vessels of the brain, liver disease, heart attack, heart diseases
123І iodoamphetamine	Diseases of blood vessels of the brain, diseases and tumors of the brain
133Xe, 127Xe	Lung diseases
18F sodium fluoride	Bone diseases, cancer, tumors
59Fe labeled iron citrate	Disorder of iron metabolism and absorption
Radioiodoalbumin	Blood volume test
18F labeled fluorodeoxyglucose	Cancer, tumors, diseases and tumors of the brain, heart diseases, heart attack, thyroid diseases; thyroid cancer; liver disease
111In labeled pentetreotide	Diseases and tumors of the brain, cancer, tumors; thyroid diseases; thyroid cancer
11С labeled methionine	Cancer, tumors
Yobengguan labeled with a iodine radioisotope	Cancer, tumors, thyroid diseases; thyroid cancer
57Co labeled cyanocobalamin	Malignant anemia; impaired absorption of vitamin B12 from the intestine
111In- pentetate	Disorders of cerebrospinal fluid circulation in the brain
82Rb	Heart diseases, heart attack
201Tl labeled thallium chloride	Heart diseases, heart attack, parathyroid diseases
Kr81m	Lung diseases
131І labeled sodium iodide	Thyroid diseases; thyroid cancer
131I labeled sodium hyppurate (iodohyppurate); 123I labeled sodium hyppurate	Kidney diseases
Source:  Mayo Foundation for Medical Education and Research

Recently, world radionuclide diagnostics tends to use radiopharmaceuticals with radionuclides produced at cyclotrons, since PET and PET-CT become more common. However, short life of isotopes requires location of medical facilities within a two-hour reach of the cyclotron, and this constrains the rate of diagnostic method spread.

Technetium-99m or molybdenum-99 can be produced at cyclotrons or linear accelerators, but in small quantities yet, and this is 3-10 times more expensive than at reactors. Technologies that would allow mass production of these isotopes not at reactors are still being developed. 

 

Radionuclide Therapy

The property of radionuclides to be accumulated in a certain type of tissue is the basic principle of therapeutic use of radiopharmaceuticals. Radionuclide therapy is often called systemic radiation therapy and less often — molecular therapy.

It is effective in the treatment of a number of benign and malignant tumors, diseases of the thyroid gland, musculoskeletal system, and the neuroendocrine system. Therapeutic radiopharmaceuticals are labeled mainly with beta radiation isotopes (which provides therapeutic effect): strontium-89, samarium-153, aurum-198, phosphorus-32, strontium chloride-99, iodine-131, rhenium-186 and rhenium-188, tin-117, strontium-90/ytterbium-90, tungsten-188/rhenium-188, lutetium-177, palladium-103. However, radiopharmaceuticals with alpha emitters, such as actinium-225/bismuth-213, radium-223 are also used.

Main radionuclides for radionuclide therapy
Radionuclides	Half-life	Application
Phosphorus-32	14.3 days	Bone tumors
Scandium -47	3.4 days	Tumors of internal organs
Cuprum-67	61.7 hours	Tumors with monoclonal antibodies (MCAT)
Yttrium-90	64.1 hours	Tumors of different localization
Palladium -103	17.0 days	Prostate tumors
Argentum-111	7.47 days	Lymphatic systems
Cadmium -115	53.5 hours	Arthritides
Iodine -131	3.0 days	Tumors of the thyroid gland, kidneys, liver
Samarium -153	46.7 hours	Tumors and bone metastases
Gadolinium-159	18.5 hours	Tumors of various localization
Holmium -166	26.8 hours	Rheumatoid arthritides
Europium-169	9.4 days	Rheumatoid arthritides
Thulium -170	128.6 days	Leukemia
Ytterbium -175	4.2 days	Tumors of different localization
Lutetium -177m	160.0 days	Tumors with MCAT
Rhenium -186	90.62 hours	Bone tumors
Rhenium -188	17.0 hours	Brain carcinoma, bone metastases
Aurum-198	2.7 days	Tumors of different localization
Astatine-211	7.2 hours	Ascitic tumors
Fermium-253	20. 5 days	Therapy of leukosis with MCAT
Bismuth-212	60. 6 minutes	Therapy of myeloid leukemia with MCAT
Source:  Anokhin Yu. N. Nanotekhnologii i Nanomaterialy Dlia Vizualizatsii i Terapii Zlokachestvennykh Opukholey // Uspekhi Sovremennogo Yestestvoznaniya. 2014. № 5-2. S. 14-25 (Anokhin Yu., Nanotechnologies and Nanomaterials for Imaging and Therapy of Malignant Tumors// Achievements of Up-to-Date Natural Science, 2014, No. 5-2, p. 14-25)

Systemic radiation therapy is most widely used in the treatment of bone metastases: strontium-89, samarium-153 (oxabifor) or phosphorus-32 passes by healthy bones and accumulating in damaged areas affects cancer cells. Moreover, taking iodine-131 treats thyroid cancer or thyrotoxicosis (radioiodine therapy). Injections of lutetium-177, indium-111, yttrium-90, etc. combined with the analogs of somatostatin receptors treat neuroendocrine tumors: this method is called peptide receptor radionuclide therapy.

During therapy, patients take radiopharmaceuticals orally, by inhalation, putting drops in an eye or by catheter injection.

The therapeutic use of radiopharmaceuticals has shown significant success in the treatment of obstinate diseases with low toxicity as a side effect. Usually, the patient receives a dose of 20-60 Gy during the procedure, although radionuclides with high activity can be used, for example, ¹³¹I for ablation (destruction) of residual thyroid tissue after surgical removal of the thyroid gland and treatment of distant metastases.

The radiation dose is entirely directed to the pathological focus without damaging the surrounding tissues. This possibility of the targeted delivery of radiopharmaceuticals makes this technique one of the most effective at the early stages of cancer with minimum side effects.

Radioisotopes, which provide beta radiation with a small amount of gamma rays that allow imaging, are the best for therapy. One of them is lutetium-177, which is generated by irradiation of ytterbium-176 and decay of ytterbium-177. In addition, yttrium-90 is used to treat cancer, especially non-Hodgkin’s lymphoma, liver cancer, and arthritis. Lutetium-177 and yttrium-90 become the main radionuclides for radionuclide therapy. Phosphorus-32 controls red blood cell production in polycythemia (Vaquez disease).

However, alpha-emitting isotopes are also increasingly being used for therapeutic purposes, and this new type of therapy has significant potential, especially in the treatment of tumor micrometastases. Indeed, unlike beta-radiation, alpha particles do not penetrate so deeply into tissues (50-90 microns), but they have a much greater linear energy transfer than beta particles. Thus, radiation energy is directed at cancer cells, since the carrier, for example, a monoclonal antibody, delivers the radionuclide to the focus of the disease. Radionuclide therapy with alpha emitters is called targeted (alpha) therapy (TAT), or radioimmunotherapy (RIT).

The main radionuclide for TAT is bismuth-213, which is obtained using a technology similar to the production of technetium: elution from the actinium-225/bismuth-213 generator. ²¹³Bі has a half-life of 46 minutes and is obtained from ²²⁵Ac during three alpha decays. Actinium-225, respectively, is the end product of the decay chain of thorium-232 —uranium-233 — thorium-229 — radium-225. Actinium-225 is also produced by Th-229/Ac-225 generator. Actinium can be used directly or in combination with protein or PSMA (glutamate carboxypeptidase-II) antibody to treat prostate cancer.

TAT using plumbum-212 is of key importance for the treatment of pancreatic, ovarian cancers and melanoma. ²¹²Pb (half-life of 10.6 hours) is obtained using ²²⁴Ra/²¹²Pb generator systems. The therapeutic principle of this isotope is plumbum-212 decay (combined with a monoclonal antibody), bismuth-212 formation (half-life of 1 hour), and formation of polonium-212 from bismuth-212, respectively. Alpha decay of ²¹²Bi and ²¹²Po destroys cancer cells within hours.

RIT is also used to treat oncohematological diseases. For example, in the USA with the help of Zevalin (⁹⁰Y labeled ibritutomab tiuxetan: monoclonal antibody that affects the CD20 antigen), obstinate slow B-lymphocytic non-Hodgkin’s lymphoma or its relapses are treated.

Boron neutron capture therapy is a further improvement of the TAT technique. It consists in the injection of boron-10-based radiopharmaceuticals into the tumor followed by its irradiation with thermal neutrons or protons. Boron isotopes tend to capture neutrons that results in a nuclear reaction, and high-energy alpha particles destroy cancer cells. This method has proven to be effective in the treatment of malignant brain tumors. Methods based on the use of radiopharmaceuticals with gadolinium-157 are at the experimental stage.

Ukrainian Reality in Nuclear Medicine

The circle of manufacturers of radionuclides for radiopharmaceuticals is rather small. The largest players in the world market are the USA, Canada, France, Belgium, Poland, South African Republic, Australia, Russia, the Netherlands, Germany, Czech Republic, and China.

Ukraine is not included in this list, despite its own research reactors. Our nuclear medicine imports the majority of radiopharmaceuticals from Poland (National Centre for Nuclear Research — Radioisotope Centre Polatom), Hungary (Institute of Isotopes Co., Ltd.) and Uzbekistan (State Enterprise Radiopreparat).

Ukraine today is capable to produce only one liquid radiopharmaceutical consisting of the ¹⁸F radionuclide combined with fluorodeoxyglucose in the Feofaniya Clinical Hospital (Eclipse RD cyclotron manufactured by Siemens, SNRIU license of 2012) of the Kyiv City Clinical Oncology Center (Pet Trace cyclotron manufactured by General Electrik, license of 2013). Both institutions supply radiopharmaceuticals to their own diagnostic PET centers with a maximum activity of 1.5 x 10¹¹ Bq and 2.96 x 10¹¹ Bq, respectively.

¹⁸F is obtained by bombarding a target containing ¹⁸O enriched water (up to 95%) with protons with energy of 11 MeV or 16.5 MeV and proton beam current of up to 40 μA. After irradiation, ¹⁸F is transported through piping to hot shielded chambers of the synthesis laboratory using compressed argon or helium. By the end of irradiation (2 hours), one target accumulates ¹⁸F radionuclide activity of up to 1.48 x 10¹¹ Bq (4 Curies). The maximum possible obtained activity in one irradiation cycle (120 minutes) is 2.96 x 10¹¹ Bq (8 Curies) (at the end of the cycle).

The shielded chambers contain synthesis modules used to provide chemical processes for the synthesis of radiopharmaceuticals labeled with a radionuclide coming from the cyclotron.

“The state did not have the will to establish such an enterprise [to produce radiopharmaceuticals — ed.] based on existing capabilities. The necessary conditions for work and manufacturing products were not provided, as you can see. Although attempts have been made”, Artem Stavenko, an employee of the Izotop, which is the only enterprise in Ukraine that supplies radiopharmaceuticals, says.

Indeed, according to the data presented by Valeriy Shevel, Deputy Chief Engineer of the Institute for Nuclear Research of the National Academy of Sciences of Ukraine, successful experiments on the production of ^99mTc were carried out at the Kharkiv Institute of Physics and Technology jointly with foreign partners. Moreover, the INR itself has a ready developed technology for ⁹⁹Mo production in the channel of the VVR-M research reactor in Kyiv. In addition, the neutron source, which is being constructed at the KIPT, will have the possibility of producing isotopes for radiopharmaceuticals. The institute even has the SNRIU permit to conduct these activities (however, one more permit is required: from the Ministry of Health of Ukraine).

Last but not least, the bureaucratic nature of state registration of the preparation and its high cost prevents the launching own production of the radiopharmaceutical. For example, documents for registration of the radiopharmaceutical should undergo a review at the State Expert Center of the Ministry of Health. If in 2008 the cost of this service was 13,220 UAH, in 2020 – 197,430 UAH, i.e., 14 times as much!

Due to this up-to-date radiotherapy preparations based on Ra²²³, Bi²¹² and Bi²¹³, and others with radionuclides, whose action principle is based on the Auger effect, cannot enter the Ukrainian market.

Another factor that slows down the production of radiopharmaceuticals in Ukraine is the incredible lagging behind not only developed countries, but also the nearest neighbors, in nuclear medicine. According to the assessment of the reference “On urgent issues of nuclear medicine development in Ukraine” (2020) prepared by Izotop experts, regarding the degree of implementing up-to-date techniques of nuclear medicine into medical practice, our state lags behind developed countries by 10-20 years.

The following institutions work currently in Ukraine:

• 64 departments/laboratories that perform radionuclide diagnostic tests with open radiopharmaceuticals 64;
• 9 departments of nuclear medicine for radionuclide therapy, 92 “active” beds;
• 2 PET/CT centres.

In Ukraine, in average, more than 100 thousand radionuclide diagnostic tests are carried out annually; about 3500 patients (iodine, phosphorus, strontium, and samarium) are treated with open radiopharmaceuticals, although more than 4500 patients require this type of therapy. To reach the European level of diagnostics (one PET unit for 1.5-2 million people), Ukraine needs at least 20 PET/CT systems.

According to the IAEA mission report, when in Ukraine, in general, 339, 000 nuclear medical procedures (diagnostics and treatment) were carried out in 2018, then in the USA — 16, 000, 000 (47 times more, while the population is only 8 times more), Japan — almost 2, 000, 000 (6 times more, while the population is only three times more than in Ukraine). In the neighboring countries of Central and Eastern Europe, the number of diagnostic tests with radiopharmaceuticals is also 10-15 times more than in Ukraine.

Accordingly, due to the high cost of registration of radiopharmaceuticals, the need to meet pharmaceutical quality standards and a small number of nuclear medicine institutions, it turns out that it is more profitable to purchase radiopharmaceuticals abroad. According to Artem Stavenko, radiopharmaceuticals are purchased for a specific patient, upon request. The lots of iodine-131 and technetium-99m are more large scale. These radionuclides are widely used in diagnostics, therefore, a certain stable amount is supplied to hospitals.

The following types of radionuclide diagnostics are available to Ukrainian patients:

• oncology: scintigraphy (brain, kidneys, thyroid and parathyroid glands, liver and biliary tract), osteoscintigraphy, lymphoscintigraphy, mamoscintigraphy and intraoperative detection of sentinel lymph nodes; positron emission tomography
• cardiology: perfusion scintigraphy of the myocardium;
• radioimmunoassays to determine levels of hormones and other biologically active substances.

Thus, Isotope collects applications for relevant radiopharmaceuticals and purchases them, for example, in the National Centre for Nuclear Research in Poland. When the local research reactor has prepared preparations or technetium generators, special vehicles deliver them to Ukraine.

“Products from Poland arrive every week. During this period from Monday to Thursday, you need to have time to submit an application, on Thursday the vehicle should leave in order to arrive on Friday. This maintains a stable flow of imports”, Stavenko says.

Upon arrival to the Isotope transport and warehouse facilities near Kyiv, its employees provide dosimetric monitoring of each vehicle and each unit of products to make sure that preparations have an adequate level of activity. Then they are delivered by Isotope vehicles to the regions from which applications were made.

“Stable demand is provided by Kyiv (Kyiv City Clinical Oncology Centre, institutes of cancer and endocrinology), Lviv, Dnipro, Odessa and Kharkiv (Institute of Medical Radiology)”, Artem Stavenko says. “Sometimes there are deliveries to other regional centers (for example, Mykolayiv, Ivano-Frankivsk), but their amounts are much smaller”.

In total, technetium generators are used by 25 state medical institutions in their practice: healthcare institutions, institutes of the Ministry of Health and National Academy of Medical Sciences of Ukraine. However, the level of radiopharmaceutical import does not meet the needs of the Ukrainian market. The Isotope reference states that the average annual number of ^99mTc-pertechnetate generators over the past 5 years is 258, but 642 are needed. Preparations to treat metastatic tumors are purchased: ⁸⁹Sr-chloride — 1.9 times less than it is needed, ¹³¹Na-iodide — 2 times less and the like. “The list of radiopharmaceuticals supplied to Ukraine has been reduced to a critical minimum”, the document sums up.

This causes a critical situation for Ukrainian patients, when they have to wait months for their turn for treatment. For example, according to the IAEA 2018, about 2000 patients with highly differentiated thyroid cancer undergo radioiodine treatment annually, but this is only a part of those who need it.

Artem Stavenko believes that there is a lack of political will to improve the situation on the radiopharmaceutical market: “I know there were attempts and proposals to reduce the cost of registering radiopharmaceuticals, but, unfortunately, either the management of relevant ministries is not interested or they simply do not understand. We have what we have.”.

In any case, without liberalization of the registration system for radiopharmaceuticals, the expansion of their list, as well as development of own production and investment in the development of radionuclide diagnostics centers, Ukraine will not be able to catch up with nuclear medicine either of its neighbors, or especially of Western countries.

The article was updated on 2 October 2020. Thanks to radiologists Oleksiy Galchenko (Bogomolets National Medical University) and Maryna Satyr (Heart Institute of the Ministry of Health of Ukraine) for the advice and additional information.

Uatom.org Editorial Board