The incidence of cancer is increasing, and a number of scientific papers indicate that a similar situation will continue in the future. Humanity needs to find a way to reduce the number of victims of this disease. One such method is nuclear medicine. If earlier, within its framework, the necessary parts of the body were irradiated from the outside, now more and more often, pointwise radioactive substances are used from the inside. There are similar advances in the field of diagnostics. How much will this help and does "atomic" medicine have any other important occupations?
After all, there are other threats: not so loud, but "long-lasting", stealing a huge number of lives annually. From cancer in 2018, according to WHO estimates, 9.6 million people died. So, every sixth death on the planet is from this disease, and this share is doomed to growth.
Today, humanity is captured - regardless of its will - by one major medical topic: the coronavirus. This is not surprising: in the last three months alone, almost half a million people have died from it. But still, no matter how strong the new coronavirus is, its influence will last for years, while humanity may never get rid of some diseases.
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In 2018, a group of Swiss scientists, in an article in the peer-reviewed scientific journal BMC Cancer, showed that the risk of cancer (and indirectly of death from it) has a strong relationship with fertility. In those families where there are fewer children (or no children at all), cancer will be more frequent, and the gap can reach two or more times. In 1990-1995, worldwide, the average number of children per woman in her life was 3.02, while in 2010-2015 it was only 2.22.
In other words, the incidence of cancer should have increased over the past decades. A number of studies claim that this is so, although it is difficult to reliably find out: the quality of diagnosis has changed markedly over the past decades, and today tumors are detected more reliably.
More importantly, cancer will become more frequent in the future, and the proportion of people with it in middle and young age will increase even more than in the general population. Actually, the process has been on the way for a long time: people aged 25-39 years ago in the United States had cancer very rarely, but today the risk of this for them has grown by one and a half times and is increasing.
The states are important here precisely as an example: with a high probability, the same processes should go on all over the world, but for most countries, including Russia, the decline in the average age of cancer patients is still not monitored.
Again, the increase in the incidence of cancer itself does not mean an inevitable increase in mortality: thanks to more and more effective means of diagnosis and treatment, only the incidence of cancer is increasing, but the total number of deaths from it is increasing there rather moderately. And if we take into account the aging of the population, then it even gradually decreases. Similar trends can be seen around the world (see graph). A serious question arises: what to do about it?
A cancer cell is a mutated cell of a sick person, so it is impossible to create a vaccine from it. About one in eight people encounter cancer throughout their lives. In developed countries more often (in Great Britain, according to local scientists, every second), in developing countries - somewhat less often.That is, at least a billion individual vaccines will need to be developed (after all, in each case, the patient's cancer cell line will become unique). Obviously, this is an overwhelming task.
Maybe poison the cancer cells of human tumors with some kind of antibiotic analogue? Alas, they are so similar to our normal, healthy ones that it is extremely difficult to find a medicine that would only kill cancer cells. And it is often very difficult to restrict the spread of the drug introduced into the body throughout the body.
Many chemotherapy drugs inhibit the division of healthy cells in the body, and those that divide more often than others, as a result, dramatically decrease their numbers. Hair loss begins, a sharp decrease in immunity and a drop in the number of blood cells.
As a result, treatment turns into a process where both the patient's body and the tumor are harmed. Therefore, a panacea from chemotherapy does not work, although in a large number of cases (including when other types of therapy are inapplicable) it saves human lives.
Contact therapy: first steps
In Russia, the All-Union Scientific Research Institute of Radiation Technology (until 1989), now NIITFA, was the main developer of the equipment used in nuclear medicine, as well as the conductor of its introduction into clinical practice.
It was his development in 1970 that became the world's first serial device for contact radiation therapy (AGAT-B). Then several generations of similar systems were developed there (AGAT-VT, S, P, PM1, B, B3). Cobalt-60 and iridium-192 were used as radiation sources in them.
In general, the equipment met the level of development of technologies of its time. The source of radionuclides was not injected directly into tissues located deep inside the body: it was normally sent into one of the patient's body cavities (for example, into the vagina when treating cervical cancer).
In this case, the acting radionuclide itself was located in a compact attachment - the so-called endostat. Due to the fact that when injected into the human body cavity, the distance to the attacked tumor was sharply reduced, the side effects from such therapy were noticeably less than with standard radiation.
But after Chernobyl, the organization began to "fever": the attitude of society towards nuclear medicine (and in general everything with the word "nuclear") changed dramatically. Initially, the institute was renamed, removing the word "radiation" from the name (for a short time it became the All-Union Scientific Research Institute of Technical Physics and Automation, VNIITFA, then the word "All-Union" was dropped). Nevertheless, as we will see below, work in the field of nuclear medicine did not stop here.
Controlled Destruction: How Radionuclides Became a Critical Line of Defense Against Cancer
The most promising means for fighting tumors today are considered drugs that contain actively fissile substances, but do not irradiate the body from the outside, but are injected directly into it.
Now such drugs around the world are trying to be considered in a single complex: they are called RFLP (radiopharmaceutical drugs), and their number is constantly growing, as well as the frequency of use in clinical practice.
Some of them are used for diagnostics - for example, monitoring the spread of weakly radioactive "tags" allows you to assess problems with blood flow or track the same tumors.
These radiopharmaceuticals contain very low concentrations of rapidly dividing radionuclides, such as fluorine-18. The half-life of the latter is less than two hours, so it cannot have any long-term effect on the organism of the diagnosed person.
Other RFLP are “curative”, and they are divided into two groups: closed and open. In open form, the drug is injected into the body in a non-isolated form and can freely spread throughout it.So, for example, radioactive isotopes of iodine work, selectively accumulating in the thyroid gland and designed to fight tumors in it.
On the contrary, in closed forms - as a rule, these are metal capsules containing radiopharmaceuticals - RFLP remain exactly at the point in the body where the doctor injected them.
Some RFLP in fact combine both diagnostic and therapeutic capabilities. For example, RFLP based on phosphorus-32, on the one hand, makes it possible to track tumors, because cancer-affected cells accumulate more phosphorus than healthy ones, and therefore are clearly visible in the images after administration of such a phosphorus isotope to the patient.
On the other hand, at several high doses, phosphorus-32 will accumulate in the tumor in such an amount that it will begin to destroy it. Because of the half-life of only a couple of weeks, healthy tissues suffer from it extremely weakly: they, unlike tumors that are more "greedy" for this element, simply do not have time to accumulate it in dangerous doses.
The advantageous aspects of RFLP can be called the fact that they consist of isotopes with controlled properties, and due to the correct selection of the required set of radionuclides, the dose received by a patient taking RFLP remains less in the case of diagnosis than with a traditional X-ray.
Likewise, the dose received during anticancer treatment with their use is lower than with standard "long-range" radiation therapy. However, this does not mean that the patient can come to the hospital and ask instead of X-rays for diagnostics or therapy with the use of radiopharmaceuticals.
Among the most promising radiopharmaceuticals is actinium-225, which has recently attracted the attention of scientists (so far at the stage of clinical trials). This is an alpha emitter - that is, when decaying, it emits not gamma quanta (photons with a high penetrating ability typical for these particles), but rather heavy and positively charged alpha particles (helium nuclei). Due to their large mass, they have a very short range in matter, so they lose all their energy at a short distance from the source.
This means that when a drug based on actinium-225 is used to treat a tumor, its cells are severely damaged, but outside of it, practically no. After all, alpha particles can be effectively retained by several centimeters of air or tens of micrometers of dense matter - such as the same tumor tissue - without reaching healthy cells. The half-life of actinium-225 takes only ten days, that is, its use for treating a cancer patient is quite safe: soon after the death of the cancerous tissue, the anemones itself will stop emitting.
Another promising drug of this kind is radium-223. Unlike most other radionuclides, it combines a short half-life (11.4 days) with great similarity to calcium.
Due to this, once it enters the body (it is administered in an "open" form, outside the capsules, through the bloodstream), it easily accumulates in the bone tissue, where it serves as a powerful source of alpha radiation that kills bone tumors. However, during the period of treatment, it can only kill cancer cells - due to the same short half-life.
Unfortunately, today the use of such materials (actinium-225 and radium-223) both in Russia and in the world is rather limited. Now Rusatom Healthcare, a company of the state corporation Rosatom, has embarked on the first phase of a project to create a modern production of radiopharmaceuticals in accordance with international requirements for the organization of production and quality control of medicines - GMP (good manufacturing practice).
The new radiopharmaceutical plant will be built at the site of the N.I. L. Ya. Karpova in the city of Obninsk (Kaluga region). The launch is scheduled for 2024. It is there that drugs will be produced based on such promising isotopes as lutetium-177, actinium-225 and radium-223.
RFLP in capsules: the weapon of the closest combat
It may seem that the idea of introducing radiopharmaceuticals into the body is questionable. Aren't radionuclides dangerous to the body, is it not believed that they can, in particular, provoke cancer or even radiation sickness?
Oddly enough, the danger of a radionuclide used for medical purposes is really small - and this despite the extremely high "local" doses, up to 12 grays per hour. The thing is that radiation can be completely different.
A significant part of RFLP gives off a large proportion of its energy through electrons formed during beta decay - and they have a very low penetrating power, noticeably lower than that of gamma-ray photons (although slightly higher than that of alpha emitters such as anemones- 225). Therefore, literally a few millimeters of any human tissue is enough to stop the beta-decay products of the same cesium-131, which is part of quite popular radiopharmaceuticals.
Microsources with cesium-131 are intended for implantation into intermediate tissues of selected localized tumors. They are used for the primary treatment of prostate cancer. As postoperative radiation therapy, cesium-131 can be used to treat non-small cell lung cancer and intracranial malignant neoplasms (after surgical removal of the primary tumor).
In addition, microsources based on cesium-131 are used in the treatment of relapses of gynecological and ocular melanoma. The introduction of this radionuclide into medical practice is considered one of the most important innovations in contact therapy over the past 20 years.
In Russia, in recent years, a needle method has been used to introduce microsources with cesium-131 directly into a prostate tumor - inside sealed seed needles.
Until the 1970s, nontrivial tricks were needed to accurately inject capsules with nuclides ("closed" RFLP) exactly where the tumor is located: for example, an abdominal operation to get to prostate cancer and implant a capsule in it.
Such operations not only increase the risk, but can also lead to undesirable consequences: for example, after them, sexual dysfunction is often observed. It was rather difficult to organize the point introduction of needles: for this, first, it was required to find out exactly where the tumor itself is located.
Everything began to change with the emergence of high-precision "eyes" of doctors, allowing to distinguish between soft tissues - first ultrasound, and then computed tomography. They made it possible to accurately "see" the position of the same prostate gland and to introduce a radiation source into it non-invasively.
By the mid-1990s, operations under ultrasound "visual control" became the norm in the West, at the same time another important solution for closed RFLP appeared - polymer thread. Microcapsules with a radiation source began to be placed on a single polymer thread, so that even after implantation, too sharp movement of the patient would not lead to the migration of the capsule away from the cancer.
All this made the use of capsules with a closed RPD of a limited radius of action quite safe - and today this is confirmed by significant experience in relation to how the operation affects the long-term survival of the patient.
Since 2000, the Research Institute of Urology of the Ministry of Health has been actively using "closed" RFLP in capsules for the treatment of prostate cancer. Over the past 20 years, Russia has also managed to accumulate some experience in this area, although so far the frequency of such operations per capita is much lower than in the West. Why?
It is not a matter of the availability of the radionuclides themselves: Rosatom enterprises produce them in noticeable quantities. But so far, the bulk of the materials goes abroad: inside the country, the demand from medical institutions is quite small - also because there are not so many clinics themselves specializing in the use of RFLP, especially outside the capitals.
Today in Russia the number of cases of treatment with the introduction of RFLP into the body reaches a couple of thousand a year, and in some of them there are already many years of tracking the fate of those who underwent surgery many years ago. The survival rate of such people was 98% for ten years after the course of treatment. Even among those in whom the disease was detected at a late stage - that is, among the most difficult patients - the ten-year survival rate after the introduction of RFLP reached 79%
It should be repeated: in our country, the frequency of RFLP treatment is still very moderate. In the United States, there are up to fifty thousand such cases a year. And the situation is only partially explained by the fact that in the United States, up to 40% of all cancer cases in men are in the prostate gland. It is estimated that in 2020 there will be more than 190 thousand cases of it with 33 thousand deaths.
In Russia, the frequency is still noticeably lower: only 38.3 thousand in 2016 with 12.5 thousand deaths. The main explanation is still different: American medicine often uses this type of drugs.
Until 2014-2015, almost all microscopic sources of such a widespread RFLP as iodine-125, used to treat prostate cancer, were imported from abroad.
In general, this is nothing new: before the blockade of the Crimean War cut off imports of Dutch herring for Russia, it was considered an expensive imported delicacy and was available only to the richest. The blockade, however, within a matter of months forced the Russian population to discover that herring is found in the Caspian Sea no worse than the Dutch, after which its production began - then this fish became a dish of the poor and lost its "aristocratic" status.
Something similar happened to RFLP after 2015: they began to be made on the spot much more often. And it quickly became clear that in the production of a titanium capsule of 4.5 millimeters by 0.8 millimeters, nothing is impossible. Each of them, in addition to silver iodide, where iodine is represented by the radioactive isotope iodine-125, also contains a marker strip of gold (to make it easier later to make sure that it is correctly placed on the x-ray). In total, no more than 75 such capsules are used during one typical therapy session using this radiopharmaceutical.
Of course, RFLP "closed" in capsules and needles are used not only in the case of localized prostate cancer, but also in cases of tumors in the uterus, breast and skin cancers. They are also promising for some types of brain and eye tumors - including because the treatment of tumors in the eyes surgically leads to a sharp drop in vision (due to tissue removal), and when using RFLP (based on ruthenium-100), the organ itself is preserved
Alas, this type of treatment is not a panacea: a number of types of cancerous tumors cannot be suppressed by a point effect, since their cells are actively spreading throughout the body. Although RFLP allows you to "burn out" the tumor quickly and even without long-term hospitalization (they are often applied to outpatients who only visit the hospital), they cannot completely cure cancers spreading through the bloodstream.
Protons, electrons and other "long-range" radiation therapy
The key difference between "long-range" radiation and contact radionuclide therapy "close-range" is in the form of radiation exposure. Radiation therapy often uses high-strength X-rays.
It is much easier for photons of the X-ray part of the spectrum to penetrate into living tissues: their waves are longer than that of gamma quanta (photons of the gamma range). Compared to electrons from beta decay, the penetrating capabilities of X-ray photons are even higher.
Today, the bulk of radiation therapy devices in Russia are imported. However, since 2017, all at the same NIITFA (now part of Rusatom Healthcare) have been developing their own apparatus of this kind - Onyx (aka KLT-6).
The energy of the electrons emitted by the Onyx accelerator is from 2.5 to six megaelectronvolts.To "see" the tumor, particles with lower energy will be used (due to them, the cone tomograph included in the "Onyx" works), but photons with an energy of six megaelectronvolts are used for treatment.
The new installation is fundamentally different from the previously used sources for radiation therapy - based on cobalt-60, with the energy of gamma quanta in 1.2 megaelectronvolts - or from conventional X-ray sources with photon energies up to 0.4 megaelectronvolts.
In contrast, photons that kill tumor cells are generated here due to the bremsstrahlung of electrons. This is the name given to the radiation generated by the deceleration of an accelerated particle (in this case, an electron) in an electromagnetic field.
This means that the Onyx accelerator itself does not need a large amount of radionuclides, but at the same time it generates a flux of X-ray photons with energies up to six megaelectronvolts, which is several times higher than that of the previous types of installations.
Due to the significant energy of photons generated by the electron accelerator, the required number of sessions of anticancer therapy for Onyx patients will be noticeably reduced. In order to guarantee accurate damage to tumors by radiation, a special tungsten set of "petals" is used: they will move, exactly repeating the shape of the tumor and at the same time protecting normal human tissues.
There are 120 of them in total, with a thickness of five to ten millimeters - for comparison, in Western counterparts such as Elekta Axesse there are still less than 100 of them. It is assumed that the serial production of "Onyx" will begin in 2021.
Long range is the main advantage of the ray method, but it is also its main weakness. By themselves, malignant tumors cannot occupy a really large volume in the body of a living person.
Therefore, for example, the introduction of RFLP into the body - especially in a "closed" form - destroys tumor cells, but does not affect the surrounding tissues and causes moderate harm to the body. Because of this, radiopharmaceuticals are considered the most "targeted" of the existing anticancer therapies: in the overwhelming majority of cases, it is more selective and safer than both chemotherapy and surgery.
But radiation therapy must "get" to the tumor through the layers of normal, healthy cells. Consequently, some of them may die from X-rays or gamma rays, which undoubtedly inflicts a noticeable blow on the patient.
This chance is especially great because most of the X-ray radiation is absorbed in the very first centimeters of their path through any medium (except vacuum). This means that if we need to irradiate a tumor in an internal organ, then the main blow will be inflicted by radiation therapy on the healthy tissues that cover this organ, close to the skin.
There is a natural desire to get rid of the disadvantages of external beam radiation therapy - to achieve the same selectivity as when using radiopharmaceuticals. At the same time, it would be nice to keep the flexibility of radiation therapy: after all, it allows you to act not only on cancerous tumors localized at one point, but also on those located in different parts of the body.
It may seem that we are faced with a typical "But if I could attach a mustache of Nikita Vladimirovich to Ivan Ivanovich's nose." Indeed: if the stream of particles can penetrate into the body and treat the tumor in its different parts, then it must also pass through healthy tissues, which means that side effects cannot be avoided. But, in fact, everything is not so bad: nuclear physics knows a way to obtain combinations, sometimes seemingly impossible.
It's all about the so-called Bragg curve: this is the name of the graph describing the probability of ionization of a target depending on the distance traveled by a particle in it. For a number of atomic nuclei - for example, a proton (the nucleus of a hydrogen atom) - the probability of ionization of a target particle directly depends on its own energy.When the energy of the atomic nucleus falls below a certain threshold (it gradually loses it, moving through the medium), the probability of ionization jumps up sharply: the proton stops, at once giving up almost all of its energy to the target.
Based on this physical effect, so-called proton therapy is based, combining the flexibility of radiation therapy and the safety (for healthy cells) of radiopharmaceuticals. For it, a source of protons is taken, which allows them to set their energy so that they release it at a precisely set depth - exactly where the tumor is located, with an aim of up to several millimeters.
As with radiopharmaceuticals, today this method is only part of widespread medical practice in Russia: there are not so many sources of proton radiation. It should be noted that the rapid development of this area is still ongoing. In recent years, an approach has been tested to destroy the tumor with overclocked ions derived from ordinary carbon atoms. Such particles have two notable advantages over protons.
First, they are heavier and more severely hitting the target tumor than relatively light protons. Secondly, the size of carbon ions is so large (in comparison with protons) that they can break two DNA strands at once, and not one, like the same proton or X-ray photon. This is extremely important: a human cancer cell is noticeably more tenacious than an ordinary one, therefore it can often survive even after the destruction of one of the two DNA strands.
One- and two-photon eyes of doctors
Until the 21st century, the ability of doctors to track what was happening in soft tissues was rather limited. X-rays often could not clarify the situation, because their radiation "flew" too quickly through such tissues and did not provide detailed information. The resolution of ultrasound diagnostics left much to be desired, and it did not suit all organs equally well.
The situation began to change dramatically with the advent of two nuclear medicine technologies: single-photon emission computed tomography and positron emission tomography.
With the word "emission" everything is clear: both methods are based on the properties of weakly radioactive isotopes launched into the body to emit particles. But why “single-photon” and how does it differ from “positron”?
There is nothing complicated here. Single-photon tomography directs fluid with low-level radioactive labels that emit gamma quanta (gamma photons) into the patient, one photon at a time. But for positron tomography, particles that emit positrons are used. The very word positron means "positive electron" - that is, it is the antiparticle of an ordinary electron.
On tomography, marker radioactive particles in the patient's bloodstream emit positrons, and they collide with ordinary electrons of the human body and annihilate, emitting not one but one pair of photons at once - which distinguishes the picture they receive from that of a single-photon tomograph.
Yes, you heard right: antiparticles. This is not science fiction of the last century, humanity has really learned to use antiparticles to its advantage - and those who are treated thanks to this, as a rule, do not even know that this is happening with the help of antiparticles.
We do not think this is entirely coincidental. The popularization of difficult-sounding scientific facts is often opposed by doctors themselves. Let's remember: after 1986, nuclear magnetic tomography was universally renamed into magnetic resonance imaging, although the essence of the method did not physically change (by the way, despite the name, it does not apply to nuclear medicine).
Why did you have to undertake such a strange renaming? Because in 1986 the significance of the accident at the Chernobyl nuclear power plant was, to put it mildly, somewhat exaggerated - mainly by the media and activists of a number of public organizations such as Greenpeace.Most likely, this is why single-photon emission tomography is called so, and not "single-photon gamma-tomography" - as it would be more accurate and more honest. Likewise, positron imaging would be a little easier to understand if it were called “two-photon gamma imaging,” but pop culture myths seriously interfere with this honesty.
In fact, despite the use of gamma radiation in the operation of these systems, there is nothing dangerous in them. The fact is that a lot of its own radioactive decays constantly occur in the human body, including the emission of gamma quanta (photons of the gamma range).
This is especially true for those of us who eat a lot of fish, bananas, or nuts (however, fried potatoes also produce a lot of decay per minute). Unfortunately, all this "noise" of natural decays is insufficient for the operation of tomographs. But the use of low-level radioactive labels can solve the problem.
What does all this give? To begin with, a real three-dimensional picture of what is happening inside a person, which is very difficult to obtain by means of the same classical radiography. But not only that.
Take positron tomography: the most actively used radiopharmaceutical is fluorine-18, an isotope with a half-life of only 110 minutes (then it turns into completely safe oxygen, which is utilized by the patient's body) and very moderate radiation.
Fluorine enters the body in the form of fluorodeoxyglucose, a compound so similar to glucose that the cells of the human body confuse it with it and try to use it as ordinary glucose.
And this is good: after all, the highest consumption of glucose in humans at rest is shown by the brain, liver and … cancer cells. This means that after the introduction of the liquid with its content into the body, it is possible to relatively quickly and accurately identify the places where the cancerous tumor is hiding - and strike it with a targeted blow.
Single-photon emission tomography uses other types of radioactive labels such as technetium-99. It is injected into the tetrafosmin compound, which accumulates in the heart muscle, where it enters from the bloodstream. By comparing the accumulation of the technetium carrier before muscle load (or the corresponding drug) and after, doctors can understand how healthy the median muscle is and whether the patient has coronary heart disease (or, for example, what is its strength).
We emphasize right away: single-photon and positron tomography has many other applications for other diseases, so we will not even try to cover them all in one text. The examples above are among the most massive and most important for patients and in no way claim to be comprehensive.
Nuclear medicine is on the rise, but carefully hides the word "nuclear"
A rather interesting picture emerges from the above. The patient comes to the clinic and often hears not "radiotherapy" but "brachytherapy". Not "gamma tomography", but "single-photon" or "positron". Since the words "nuclear" and "atomic" have become something of a taboo in modern society, nuclear medicine is rarely called nuclear in the presence of patients - especially those who came to the tomography.
But all this does not negate the fact: nuclear medicine saves many lives. One branch of this industry finds cancerous tumors better than many alternatives, while others - both radiopharmaceuticals and promising proton and ion therapies - kill these tumors more efficiently and safer than others.
Undoubtedly, we will not completely defeat cancer even with such an advanced "scalpel" as nuclear technology. But it is also indisputable that in a number of cases, nuclear medicine can give a patient many years of full life.
We are grateful to the State Atomic Energy Corporation Rosatom for help in creating the material.