публикация №1637423864, версия для печати


Дата публикации: 20 ноября 2021
Автор: Alexander CHERNYAEV, Sergei VARZAR, Maria KOLYVANOVA
Публикатор: БЦБ LIBRARY.BY (номер депонирования: BY-1637423864)
Источник: (c) Science in Russia, №4, 2014, C.28-35

by Alexander CHERNYAEV, Dr. Sc. (Phys. & Math.), Prorector of Lomonosov Moscow State University (MGU); Sergei VARZAR, Cand. Sc. (Phys. & Math.), Associate Professor of the Physics Department (MGU); Maria KOLYVANOVA, junior research assistant, Physics Department (MGU)


The paper presents a brief history of creation of accelerators and other nuclear-physical technologies in medicine since detection of X-rays. Specialists put emphasis on description of basic inventions stimulating development of "X-rays" therapy and nuclear medicine, and offer their analysis of the current medical application of nuclear facilities.




Charged particle accelerators are one of the examples how a sophisticated invention of a "profound" science, which is open to a very practical insignificant number of scientists, can become an indispensable element of many current technologies. According to most people they are still needed only for a narrow circle of specialists, are of enormous sizes and require great expenses. But the actual situation of the development trends of accelerating equipment looks somewhat differently. Though they were intended for perception of the microworld, today only 3-4 percent of all existing accelerators operate in fundamental science. A major part of them is used for practical purposes. They are used in production of car tyres and polymer pipes, cable insulation, rubber articles, packing film and many others. At present researchers have already developed technologies using accelerators for such processes as wine age test, color changes in semi-precious (and precious) stones, liquefying of associated gases, etc. Accelerators are more and more widely used in public health, where they are used in sterilization of single-use syringes and other medical tools along with X-ray therapy and nuclear medicine.


Meanwhile, nowadays the total number of accelerators (about 1,000 new facilities are put into operation annually in the world) in use on the whole planet is estimated

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Accelerators in medicine.


at about 40,000. About 1,200-1,500 accelerators out of the above figure are used for fundamental research in nuclear physics and elementary particle physics, and above 25,000 operate in industry. More than a half of all electron accelerators (about 12,000) or almost a third of all existing ones and also about 1,000 ion and proton accelerators* operate in X-ray therapy and nuclear medicine (without regard of X-ray tubes which can be considered the simplest low-energy electron accelerator).




Meanwhile, the application methods of accelerators in medicine can be divided conventionally into several stages. The first stage is conditioned by the origin of new sections of physics which study laws of the subatomic world and necessary hardware. Scientists link traditionally its start-up with a series of discoveries at the end of the 19th century, most of which won the Nobel Prize: in 1895--discovery of X-rays by the German physicist Wilhelm Roentgen (the first Nobel Prize winner in physics in 1901); in 1896--discovery of natural radioactivity of uranium salts by the French physicist Antoine Becquerel; in 1897--discovery of electron (first subatomic particle) by the British scientist Joseph Thomson; in 1898--separation and studies of radium and polonium properties by Marie and Pierre Curie; in 1899--discovery of positively charged alpha-particles and negatively charged beta-particles in radiation from uranium salts by the British physicist Ernst Rutherford; in 1900--discovery of gamma-radiation by the French physicist and fellow of the Paris Academy of Sciences Paul Villard.


Actually simultaneously with the discovery of new types of radiation there started also approbation of their medical application. For example, as early as the end


See: A. Tyurin, S. Ivanov, "Proton Accelerator and Its Mission", Science in Russia, No. 3, 2010.--Ed.


of 1896, scientists proved a damaging action of X-ray radiation on a human skin, and in November of that same year the physician Leopold Freund (1868-1943) carried out the planned radiation of a hairy nevus of a 5-year girl. In 1901 Henri-Alexandre Danlos (1844-1912) used radioisotopes in the treatment of a tubercular patient, and in 1903 the American scientist Alexander Bell (1847-1922) offered to dispose radium sources in the tumor or nearby.




Let's point out that the potential of new "rays" was not ignored by national physicists and physicians. As early as the beginning of 1896, Wilhelm Roentgen sent out copies of his article to his colleagues in several countries including the privat-docent of physics at the Moscow University Pyotr Lebedev (1866-1912). At the end of that month Lebedev delivered a lecture "On the X-rays Discovered by Roentgen" and accompanied it with demonstration of X-ray pictures made by him. In February of 1896 at the Petersburg University Ivan Borgman (1849-1914) presented a paper and demonstrated two X-ray pictures, and at the Medico-Surgical Academy Vladimir Tonkov (1872-1954) made a report on the X-ray examination of bone growth. That same year the experiment of the aforesaid Becquerel was reproduced at the Military Medical Academy in Petersburg*.


By the way, the Russian inventor of radio Alexander Popov was among the first to study radioactivity in Russia and as early as 1902 he invented an instrument for measurement of "voltage of atmospheric electrical field by ionization action of radium salts". The next year professor of physics of the Moscow University Alexei Sokolov studied radioactivity of the Caucasian mineral


See: Zh. Alferov, E. Tropp, "St. Petersburg--Russia's Window on Science", Science in Russia, No. 3, 2003.--Ed.

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waters. Later on he organized the first training workshop on radioactivity in the country.


The start of radioisotope application in national medicine was also attributed to the Moscow University. In the autumn of 1903 there was set up a Moscow Oncological Institute (today the Moscow Research Oncological Institute named after P. Herzen). The institute was actively engaged in treatment using radium preparations presented to the institute by the well-known scientists Marie and Pierre Curie. The first large monograph Radium in Biology and Medicine (1911) devoted to radio-biology and medical radiology was written by the Russian pathophysiologist Yefim London (1869-1939).




Meanwhile, the natural radioactive preparations and X-ray tubes remained the only sources of ionizing radiation for almost 30 years. The origin of ideas of production of artificially accelerated particles was probably conditioned by the experiments conducted by Ernst Rutherford in 1919. Soon after specialists suggested methods which in the project should provide the main advantages of accelerators as compared with natural radioactive preparations: greater particle energy, direction and high intensity of the beam, possibility of proton and ion acceleration. But the first operating facilities which employed these methods appeared only at the end of the 1920s.


For several years the researchers were working on facilities based on the direct method of acceleration (accelerators of Van de Graaf, 1929, and Cockroft-Walton, 1932), and resonance accelerators (linear, 1928, and cyclotrons, 1929). The idea of betatron (cyclic but not resonance electron accelerator with fixed equilibrium orbit, in which acceleration takes place by means of vertical electric field) was patented in 1922 by the American physicist Joseph Slepyan (1891-1969), but the first operating betatron was created only in 1940 by the American physicist Donald William Kerst (1911-1993). It is notable that in the same year the experimental physicist and member of the American National Academy of Sciences Luis Walter Alvarez (1911-1988) was the first in world practice to accelerate ions of carbon C+6 to energy 50 MeV, thus having laid the foundations for studies of interaction of multi-charged ions with the substance. Intensity of an accelerated ion beam on a cyclotron end radius made up then 500 ions per minute.


The first medical electron accelerator for treatment of cancer patients was put into operation in 1937 at the St. Bartholomew's Hospital in London. The plant sizes reached 10 m, and the beam energy did not exceed 1 MeV. Somewhat later, in the 1940s, in the USA and Canada scientists began to use high-voltage accelerators of the transformer type in radiation therapy and also accelerators of Van de Graaf with maximum energy of bremsstrahlung photons up to 1-4 MeV and betatrons with energy up to 13-25 MeV.


Interest in construction of linear accelerators for radiation therapy came to show since the 1950s. For example, in 1953 at the Hammersmith Hospital in London the physicians developed and put into operation the first commercial linear accelerator for medical purposes. By the middle of the decade only several linear medical accelerators existed all over the world. Just then the scientists faced the problems of reducing accelerator sizes, providing operating reliability and safety, increased accuracy of getting by the beam into the target.




The achievements of accelerating physics created a base for a wider application of radioactive isotopes. In the early 1930s, the American physicists Ernest Orlando Lawrence (1901-1958), the Nobel Prize winner of 1939, and Milton Stanley Livingston (1905-1986) showed a possibility of cyclotron radioisotope production. It was by means of cyclotrons that most radioactive isotopes were discovered, which found commercial application in nuclear medicine and radiation therapy, including 60Co received in 1938 by two Americans, the physicist John Livinhood and the chemist and nuclear physicist Glenn Theodore Seaborg (1912-1999). It is commonly accepted that the accelerator constructed at the clinic of the Washington University in Saint Louis in 1940 was the first cyclotron designed for medicine. But low intensity of the beam remained an evident disadvantage of cyclotrons in those years; therefore the start of a wide thera-

стр. 30


Accelerators in medicine.



peutic utilization of isotopes was connected with appearance of nuclear reactors in the 1950s.


The first apparatus for radiation therapy with the 60Co source was launched in Canada in 1951. Gamma-therapeutic apparatuses had intensity and energy comparable with accelerators but their dimensions were much smaller. They were especially widely employed at the American Oncological Institute in Toronto, where 137Cs sources were used along with 60Co sources and attempts were made to introduce 192Ir with a half-life period of only 74.5 days into medical practice.




At the end of the first half of the 20th century two new fundamental ideas became decisive for the development of radiation medicine. In 1948, the Swedish professor of neurosurgery Lars Leksell (1907-1986) suggested a diagram which allowed to direct a multitude of beams practically to one point. Since 1951 this method has been assumed as a basis of stereotaxic radiosurgery using 60Co radioactive sources without cephalotomy. Leksell's activity resulted later in the creation of a facility named "Gamma Knife"*.


Another idea concerned a possibility of using heavy particles in radiation therapy. It was a question of protons, whose deep radiation dose distribution is characterized by a sharp growth of values at the end of the route of the particles. Their use in radiation therapy was suggested


See: A. Golanov, M. Zotova, V. Kostyuchenko, "Stereotaxic Radiotherapy and Radiosurgery", Science in Russia, No. 5, 2010.--Ed.


by the Nobel Prize winner in physics (1927) Scotsman Charles Thomson Rees Wilson (1869-1959) in 1946.


Thus, already in early 1950s, there was a multitude of new ideas and technologies in radiation therapy, which could successfully substitute natural isotopes and X-ray tubes.




The second stage in the development of radiation technologies in medicine characterizes a wide introduction of gamma therapeutic apparatuses and electron accelerators into clinical practice. In the 1960s-1970s cobalt units became a basic tool in radiation therapy. They numbered above 15,000 in the world and competed with betatrons and linear accelerators. According to IAEA by 1970 the total of 306 electron accelerators including 157 betatrons, 118 linear accelerators, 22 Van de Graaf's accelerators and 9 resonance transformers were used for the needs of medicine in the world. But the role of accelerators was growing steadily, and by the end of the 1980s they become a dominating tool in radiation therapy.


The main ideas during the second stage of the electron accelerator development were attributed to attempts of physicists to enhance efficiency of target irradiation. The methods of particle acceleration remained the same but the design of apparatuses reached a brand new level. Scientists tried to generate beams of heavy currents and worked on reduction of sizes and increase of stability of facilities. For better supprssion of deep-seated tumors

стр. 31


they increased energy of an electron beam and, consequently, of photons emerging in the process of electron inhibition. Herewith the maximum of a dose distribution shifted inward from the tissue surface, and the dose decreased deep-down more slowly. In its turn, it led to the necessity of a more exact consideration of heterogeneities of the human organism and the absorbed dose quantity received by the critical organs and tissues.


The methods of irradiation from several directions, which were also developing, required rotation of the patient or a beam around him. As it turned out, in the first case extrusion of the patient's viscera could take place, which decreased the target accuracy, while in the second case the beam control could become complicated. The facility created for supplying an accelerating beam from different directions was named "gantry".


At the second stage the specialists realized an advantage of the deep distribution of a heavy charged particle dose. They turned attention to efficiency of carbon nuclei application in radiation therapy and started to develop methods of radiation therapy using beams of heavy particles such as protons, deuterons, alpha-particles, carbon nuclei and pi-mesons. For example, the first experiments on cancer patient therapy by proton beams were carried out in Berkeley (USA) in 1954 and at the Uppsala University (Sweden) in 1957. In Russia the medical proton beams were produced in 1967 at the Joint Institute for Nuclear Research (Dubna, Moscow Region)*, in 1969 at the Alikhanov Institute of Theoretical and Experimental Physics (ITEF, Moscow) and in 1975 at the Petersburg Institute of Nuclear Physics named after B. Konstantinov (Gatchina, Leningrad Region). But all facilities for heavy charged particles were essentially larger and more complex than electron accelerators.


Meanwhile, in the 1960s the Swedish scientists, professor of neurosurgery Lars Leksell and physicist Bjorn Larsson developed the first model of the Gamma Knife with 179 cobalt sources, and in 1968 in Stockholm they were the first to perform an operation using this method. The advantage of this facility is that the focused dose exceeded many times a dose on the surface of the human


See: A. Sissakian, "Dubna's Worldwide Glory", Science in Russia, No. 2, 2006.--Ed.


body. The tumor was subjected to 10 Gy dose while in healthy tissues it remained within permissible limits. The Gamma Knife allowed treatment of vascular neoplasms and brain tumors including metastases without surgical intervention and long-time radiation.


Today around 265 Gamma Knives operate in the world, and two thirds of them are in the USA (~ 107) and Japan (~48). Above 400,000 patients in the world underwent therapy using the Gamma Knife in forty years after this method was introduced. Currently only two similar facilities operate in our country.




At the end of the 1970s another line of accelerator application in medicine, i.e. intraoperating electron beam therapy, came into being. This method of cancer patient treatment implies a single application of a high dose of electron beams to a target during a surgical operation. Either the tumor or its bed after operation is irradiated. A special plastic or metal tubule (nozzle) is put in a surgical wound in sterile conditions. The other end of the tubule is connected to an irradiating tip. The tubules not only form a radiation field but also screen tissues and organs outside them from a primary radiation. In Russia intraoperating electron beam therapy developed most actively at the Medical Research Oncological Institute (Moscow), the Medical Radiological Scientific Center in Obninsk and at the Research Institute of Oncology in Tomsk.




The third stage of medical accelerator development began in the mid-1980s and is going on up to now, is connected with new potentials of computer technology and nuclear-physical methods of diagnostics. Today the specialists are developing methods of work with electron beams, which allow to achieve the best coincidence of the target boundaries with an area subjected to a maximum dose (methods of conformai irradiation), for example, irradiation from different sides and variations of beam intensity (IMRT--intensity-modulated radiation therapy). At present multilobed collimators (facilities

стр. 32


Nuclear-physical facilities in medicine.



which produce parallel beams of light or particles) and stereotaxic surgery are actively developing too.


Since the 1980s linear electron accelerators, after improvement of sources of a high-frequency electromagnetic field, decreased essentially in size and became easy to use in radiation therapy. They are gradually replacing cobalt and other types of accelerators. For example, by 2002 the number of electron accelerators in medicine reached 7,500,000, and they were mainly linear.


In the middle of the 1980s the scientists succeeded in development of an alternative to the Gamma Knife based on linear accelerators used in the traditional radiation therapy. In this facility they used the modified linear accelerator LINAC instead of a cobalt source. A stereotaxic frame is used here for providing immobility of the patient and target. This system has two perpendicular rotation axes of an accelerator which is installed on the platform. For radiation purposes inhibition radiation is used, while the photon beam is always directed to one point.


In such systems, contrary to the Gamma Knife, no radioactive material is needed and no radioactive waste is accumulated when they operate. At present it is the most common radiosurgical tool for treatment of intracranial lesions. By the way, attainable distribution of radiation doses in systems with the modified LINAC and that in the Gamma Knife are comparable.


The CyberKnife system for radiation therapy is another alternative to the Gamma Knife. The apparatus was created in 1992 at the Stanford University (State of California, USA) under guidance of John Adler, and the first successful operation was performed in 1999. This system includes two basic elements: a light linear accelerator and a mobile computer-aided robotic arm with 6 degrees of freedom and providing a target radiation from 1,200 possible directions. The facility is based on electron accelerator whose energy makes up 4 or 6 MeV The CyberKnife provides nonisocentric (i.e. such radiation when beams can be concentrated in different points of space) radiation of the target and also nonsymmetrical and highly conformai radiation with accuracy up to 0.5 mm.


Surgical intervention in a patient's body is minimized in this case, which is an objective of oncologists all over the world and is a main advantage of the CyberKnife. The location of tumor and metastases are determined by magnetic resonance, computer-aided and positron emission tomography (PET) correlated with rigid reference points, on the basis of which an individual radiation program is worked out for a specific patient with account of particulars of localization, volume and configuration of pathological areas. After location of the tumor and metastases are determined, physicians radiate them during one session from many directions. It becomes possible to perform due to placement of a light accelerator on a robotic arm.


It should be noted that currently physicians of the Moscow State University set about developing a new generation of the CyberKnife with variations of electron energy. A new facility is being created on the basis of the compact slit microtron, which was first devel-

стр. 33


oped at the Research Institute of Nuclear Physics of the Moscow State University and also the robotic manipulator now under construction at the Research Institute of Mechanics of the Moscow State University.


If the Gamma Knife is used mainly for treatment of brain tumor, the CyberKnife allows radiation of other parts of the human body too. By the end of 2012 the total of 268 such facilities operated with a major part in the USA (144), in the countries of Europe (34), in Japan (23), South Korea (9) and China (10). In Russia only 6 CyberKnives are functioning (or are prepared for operation) as yet. Almost 100,000 patients in the world have already passed treatment on this apparatus, besides, a substantial part of them were considered practically incurable. The course of treatment is 30-90 minutes, and the number of sessions varies from 1 to 5 with an average size of the tumor 1-5 cm.


Since the 1980s combined radiation of malignant neoplasms has also been intensively developing. For example, patients are exposed to irradiation simultaneously with application of a magnetic field at the Medical Radiological Scientific Center (Obninsk), and the intra-operating (during operation) radiation therapy in combination with a remote radiation therapy is used at the Tomsk Institute of Oncology since 1989.




Nuclear medicine is another extensive domain in which accelerators are actively used. The first application of radioactive isotope 131I (symbolizing the origin of nuclear medicine) for diagnostics of a thyroid gland disease is ascribed to the end of the 1930s. To this period specialists refer the diagnostic and therapeutic methods using radioactive isotopes. The latter numbering above 50 are produced for medical purposes by cyclotrons with 4-30 MeV energy or reactors.


Gamma-ray chambers became the first medical instruments created for registration of photons from isotopes administered to a human body. Physicians started to use them in clinical practice from the middle of the 1960s. Their more sophisticated modification providing a three-dimensional image of an object was called "single-photon emission computed tomograph" (SPECT).


The positron emission tomography (PET) became a truly unique nuclear-physical method in medicine. In 1931, the German biochemist and physiologist Otto Heinrich Warburg (1883-1970), Nobel Prize winner in physiology and medicine of 1931 for discovery of the nature and mechanism of action of respiratory ferments found out the following: malignant tumors are distinguished for an increased level of glucose intake. In 1977, Louis Sokolov suggested measurement of a local level of glucose metabolic intake in a rat brain by means of deso-xyglucose, labeled by radioactive carbon isotope. In 1979 Michael Phelps proposed measuring of the same parameter in people by means of desoxyglucose labeled with radioactive fluorine isotope 18F (fluorodesoxyglucose). It is a reminder that fluorodesoxyglucose (FDG) is an analog of glucose at several stages of its metabolism but in contradistinction to it metabolism of FDG stops prematurely and its product accumulates in tissues. This research work laid a foundation for positron emission tomography.


The physical principle of positron emission tomographs is based on using of 18F or other artificial isotopes decaying with positron emission. Such positrons pass a distance equal to 1-3 mm in the surrounding tissues, and then they annihilate with electrons. In the process of annihilation there are formed twin photons with 0.511 MeV energy, flying out in opposite directions. Recording of photons allows to determine their formation point and consequently an isotope accumulation place.


Recovery of radioactive isotopes is performed on proton accelerators, in particular, cyclotrons. The typical energy of cyclotrons used in PET is 7-18 MeV.


In modern medicine PET is widely used not only in oncology but also for diagnostics of other diseases such as neurological and cardiovascular disorders. The PET method provides an early diagnostics of structural changes in tissues, which improves essentially the prognosis and quality of treatment.




By the way, by 2010 nuclear-physical facilities were used in more than 70 countries of the world. The greater part of them (about 98 percent of the total number!) op-

стр. 34



Accelerators in Russia. Comparative table of application.


erate in the USA, Canada, countries of Europe, Japan, China, India and Russia.


Altogether about 73,000 units of medical equipment based on ionizing radiation excluding X-ray apparatuses and electron microscopes are used now. They include accelerators, cobalt units, CyberKnives, Gamma Knives and also their modifications, reactors, gamma-ray chambers and their versions (SPECT), computer tomographs, PET tomographs and scanners. Accelerators account for about one third. Linear accelerators are used mainly in radiation therapy and cyclotrons in nuclear medicine.


The USA is a leader in the development of medical nuclear-physical technologies (there one medical accelerator falls on 70,000 citizens). In the European Union countries this parameter corresponds to approximately 170,000 and in Japan to 140,000 citizens. Russia unfortunately falls behind as yet. Today there are about 120-150 medical electron accelerators in our country. To reach the mid-European level we need around 1,000 electron accelerators.




Thus for eighty years accelerators in medicine passed a distance from a thread method to high-technology complexes, which are irreplaceable in conducting of sophisticated methods of treatment and diagnostics, while their abundance can be considered as one of the parameters of the level of medicine development in the country.


According to their potential medical accelerators of last generations reach "cosmic heights", and perspectives of their development look attractive. The future of this field depends in many ways on cooperation efficiency between fundamental science and private companies as the main producers of accelerating equipment.


It appears that in the near future we can expect appearance of technologies directed to decrease the cost of accelerators and operating expenses. As promising in this connection there are permanent magnet microtrons capable to generate higher quality beams as against linear accelerators, while microwave electronics required for their production is considerably cheaper. Substantial progress was made in this field by scientists of the Research Institute of Nuclear Physics where compact 30 and 70 MeV microtrons were developed.


The sharp upswing in proton and ion therapy can be made if superconducting magnet cyclotrons are developed or laser acceleration methods are implemented. Application of synchrotron radiation will facilitate substantially the potential of medical visualization but its wide application requires creation of sources of a smaller size which are now being developed intensively in the USA, Europe and Russia.

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