RU2141860C1 - Method and device for treating malignant tumors by applying neutron-catching therapy - Google Patents

Abstract

FIELD: medicine; medical engineering. SUBSTANCE: method involves injecting boron- and/or gadolinium-containing substance in prolonged action medicinal form into a biological object 5 min before exposure to radiation. The biological object is irradiated with heat neutron beam of 20-150 mm diameter and 5•10⁸-10⁹ th/cm²•s tn/γ with background gamma-radiation power in the beam being not greater than 0.14 R/s during 15-60 min. The device has horizontal channel with graphite scattering unit positioned tangentionally to the active zone of the water-type nuclear reactor and closed with aperture of 10 to 150 mm diameter at its exit to working chamber. System for producing neutron beam has five gate rings with conic collimator unit mounted into three central rings having divergence angle α=1.8-2.0 deg and manufactured from high pressure polyethylene which density ρ = 0.97 g/g/cm³. Filter from polycrystalline bismuth with density ρ=9.75 g/g/cm³ is mounted in the third gate ring when moving in the beam propagation direction which ratio l to distance to diaphragm L is l/L=1/(30-40). Lead and polyethylene bushings are placed in the first gate ring. Biological protection of the operation chamber has movable unit connected with desk which surface has steps coupled with steps on the internal surface of the operation chamber. Stationary biological protection of the operation chamber is built from steel carcasses filled layer-by-layer with 5-6 mm thick layer of lead and boronized polyethylene. Two frames are mounted on the desk in parallel to each other. The first of which has fixing members in front of the aperture for fixing biological object or head phantom. The second frame has tuning concentric rings spaced over polymethyl metacrylate plate attached to the frame for directing neutron beam and mounting dosimetric detectors. EFFECT: high therapeutic effectiveness. 2 cl, 6 dwg

Description

 The invention relates to medicine, radiation therapy with the preliminary introduction of drugs into the body, and can be used for neutron capture therapy of malignant tumors using gadolinium and / or boron-containing drugs.

 There is a method of treating malignant tumors, in particular brain tumors, by introducing metal clips into the tumor, which during radiation therapy reduces the exposure dose of radiation by the amount of additional scattered radiation by ≈1.5 times. Excluding surgical intervention, complex compounds of radioactive isotopes are used, which are able to accumulate in tumor cells and destroy them by the action of their radioactive radiation. However, the process of accumulation in tumor cells is very long (several hours), which is accompanied by irradiation of healthy body tissues during the migration of the drug to the organs and tissues of the body.

A known method of treating malignant tumors by neutron capture therapy. The method consists in preliminary accumulation in the tumor of compounds with stable ¹⁰ B or ¹⁵⁷ Gd isotopes, followed by irradiation of the tumor with a thermal neutron flux. In this case, ¹⁰ B atoms absorb neutrons with the emission of secondary radiation of α-particles and low-energy γ-quanta, which is completely absorbed by the tumor cells, which leads to their death. The radiation dose absorbed by the tumor is proportional to the product of the flux of thermal neutrons in the cross section for their capture by ¹⁰ B atoms. When using ¹⁵⁷ Gd, secondary γ radiation, conversion electrons, and Auger electrons appear in the tumor. The thermal neutron capture cross section ¹⁵⁷ Gd is 66 times larger than the ¹⁰ B capture cross section, which increases the number of interaction events per unit volume of the tumor. This technical solution used to treat melanoma is taken as a prototype.

 A device for radiation therapy containing a nuclear reactor with biological protection; horizontal radial channels in which filters of heavy metals are placed: W, Pb, Bi to form the necessary flow power. This device allows you to irradiate biological objects with three types of radiation: fast neutrons, thermal neutrons and positrons. A complexly organized core is installed in the reactor, on the outside of which are two movable moderator rings containing a liquid composition with various absorbers. The device contains 4 radial channels connecting the active zone with the working chambers, and the rotary rings of the moderator provide a given exposure mode. However, for neutron capture therapy, the movable moderator rings do not provide the necessary reduction in the flux density of fast neutrons and gamma rays in radial channels.

The closest technical solution adopted for the prototype of the proposed device is a device for irradiating the tumor, including the reactor core, a horizontal channel with a graphite diffuser, a filter, a collimator of variable cross section, a working chamber with a table for placing the biological object inside the biological defense. This device provides an increase in the power of the neutron flux with energies up to 0.4-0.8 MeV while reducing the fraction of thermal neutrons with energies below 0.4 MeV to reduce the thermal damage to healthy tissues. The technical level of the pressurized water reactor in the standard version provides the following characteristics of the radiation fields: thermal neutron flux density - 3 • 10 ⁸ tn / cm ² • s, fast neutron flux density - 1.2 • 10 ⁷ bn / cm ² • s doses of background γ radiation of 1.2 R / s. These parameters do not ensure the effectiveness of neutron capture therapy, since the thermal neutron flux density is small and its use lengthens the exposure time, which, due to the high power of the background γ radiation, leads to radiation damage to the biological object.

The single technical task to which the group of inventions is directed is to increase the efficiency of neutron capture therapy by creating a high concentration of ¹⁰ B and ¹⁵⁷ Gd atoms in the tumor tissue, increasing the thermal neutron flux density with a decrease in (power) of background γ-radiation.

This problem is solved by the fact that in the method of neutron-capture therapy of malignant tumors in an experiment, which includes introducing boron and / or gadolinium-containing preparations into a biological object, irradiating the object with a neutron flux and evaluating the effectiveness of therapy, according to the invention, boron and / or a gadolinium-containing compound in a prolonged dosage form and then it is irradiated with a beam of thermal neutrons with a diameter of 20-150 mm with a flux of 5 • 10 ⁸ -10 ⁹ t / cm ² s with a dose rate of background γ-radiation in the beam not greater its 0.14 R / s, for 15-60 minutes As a biological object, small laboratory animals are used with transplanted tumors or a phantom of the human head, with flat polyethylene containers filled with prolonged dosage forms of boron and / or gadolinium-containing compounds, and boron and / or gadolinium-containing compounds in the form of prolonged dosage forms are injected directly into the tumors 5 minutes before irradiation with a neutron flux.

This problem was also solved by the fact that in a device containing a nuclear reactor with a channel connecting the active zone and the working chamber, with a movable stage for placing a biological object and with biological protection, as well as a neutron beam formation system with a scatterer, a filter, a collimator of variable cross section, according to the invention therein, a horizontal channel with a graphite diffuser is placed tangentially to the core of a water nuclear reactor and is closed by a diaphragm with a hole diameter at the outlet to the working chamber from 20 to 150 mm; the neutron beam formation system consists of five slide rings, in the three central of which a cone-shaped collimator with an angle of divergence α = 1-2 ^° inserted from high-density polyethylene with a density ρ of 0.97 g / cm ³ is inserted, with 3- m along the beam, a polycrystalline bismuth filter with a density ρ - 9.75 g / cm ^{3 is} installed in the gate ring, the ratio of which l to the distance to the diaphragm L is l / L = 1 / (30-40); at the same time, lead and polyethylene bushings are placed in the first slide ring, and the biological protection of the working chamber is equipped with a movable unit connected to the table, the surface of which is made in the form of ledges mating with similar ledges of the inner surface of the working chamber; stationary biological protection of the working chamber is made of steel frames filled with layers of lead and borated polyethylene with a layer thickness of 5-6 cm. At the same time, two frames are mounted on the table in parallel, on the first, in front of the diaphragm, clamps are made for attaching a biological object or head phantom to the second frame, on which a plexiglass plate is mounted, alignment concentric circles are applied to orient the neutron beam and install dosimeter detectors.

 The claimed group of inventions meets the requirement of "unity of invention", since the proposed device is designed to implement the method, and both objects are aimed at solving the same problem with obtaining a single useful result.

A useful result is that a thermal neutron flux with a density of 5 • 10 ⁸ -10 ⁹ tn / cm ² • s was obtained in a standard reactor, which is higher than in the prototype (30 times), with a dose rate of background γ-radiation in a beam of 0.14 R / s (reduced by 8 times). In combination with the proposed device, the use of prolonged dosage forms of boron and / or gadolinium-containing compounds allows to obtain a high therapeutic effect of neutron capture therapy of malignant tumors (about 80%).

The manufactured experimental setup was mounted on the basis of the IRT pressurized water reactor. The dosimetric measurements showed that the installation parameters are fully consistent with the requirements specified in the invention and the requirements of the current NRB and OSP. The facility is capable of working using small laboratory animals or a head phantom as biological objects. The prepared prolonged forms of boron and / or gadolinium-containing compounds are characterized by delayed absorption from the injection site and the malignant tumor, which ensures the maintenance of the necessary neutron-capture therapy at concentrations of ¹⁰ B and ¹⁵⁷ Gd during the entire exposure. The present invention, both in part of the device, and in the part of dosage forms is used in experimental studies. Thus, the proposal of the applicant meets the criteria of the invention of "industrial applicability".

 A search by the authors for patent and scientific and technical sources did not reveal analogues for the method and device of the claimed group, characterized by features that are identical in their properties and the result obtained in their totality to the essential features of known technical solutions in this field, which allows us to consider the proposal of the applicant in accordance with the criteria of the invention "inventive step". The individual elements of the device and the materials for their manufacture are known, however, their use for neutron capture therapy in the aggregate indicated in the invention is not known and is practically not used. Similarly, prolonged dosage forms of boron and gadolinium-containing compounds are not known.

 When comparing the applicant’s proposals with prototypes, it was revealed that the method differs in the nature of the biological object, the dosage forms of boron and gadolinium-containing compounds and the characteristics of the neutron flux, and the device differs in the geometric arrangement and channel structure for generating the thermal neutron flux, experimentally selected materials and the geometry of the main elements of the device, which allows us to consider the proposal of the applicant in accordance with the criteria of the invention of "novelty."

The essence of the invention lies in the fact that for the formation of a thermal neutron beam by the proposed method on a standard 2.5 MeV IRT water reactor, it was necessary to create a horizontal channel tangent to the core, located 395 mm from its center, which made it possible to reduce the fraction of fast neutrons and γ radiation in the beam. A 400 mm long graphite diffuser is installed in the tangent channel in the A3 plane, which, depending on the thickness and material, increases the contribution of thermal neutrons in the flux. In this case, the number of fast neutrons decreases by 20 times, and γ radiation - by 50 times (in the case of using graphite with a thickness of 150-200 mm) (Fig. 1 and 5). To form a thermal neutron beam in a tangent channel, a high pressure polyethylene collimator is installed in the three central gate rings. The choice of high-pressure polyethylene is due to the presence in it of the maximum number of centers scattering γ-radiation in comparison with other brands of polyethylene. It was experimentally established that the collimator divergence is α = 1.8 - 2.0 ^° , which ensures focusing of thermal neutrons and a decrease in the fraction of fast neutrons and γ radiation in the beam. The collimator is a truncated cone with an inlet diameter of 126 mm and an outlet diameter of 60 mm. High-pressure polyethylene, with a selected density ρ - 0.97 g / cm ³ provides an additional collection of thermal neutrons.

To attenuate the γ \ radiation flux emerging from the channel, a filter made of polycrystalline bismuth is installed along the neutron beam in the 3rd gate ring. Of the various materials — uranium, molybdenum, lead, bismuth — polycrystalline bismuth with a density ρ of 9.75 g / cm ³ was selected (Fig. 2), which slightly reduces the amount of thermal neutrons, but effectively absorbs γ radiation. The choice of polycrystalline bismuth is also due to the fact that it has the desired crystalline structure and is an available material. It was experimentally established that the optimal placement of the filter is determined by the following formula:
l / L = 1 / (30-40),
where l is the thickness of the filter, L is the distance between the filter and the diaphragm, 30-40 is an experimentally selected coefficient.

 The dependence of the thermal neutron flux density and the intensity of the background γ radiation and their ratio on the position of the bismuth filter are shown in FIG. 6 and 7.

 In the first slide ring located near the diaphragm, polyethylene and lead bushings are installed, which determine the final power of the background γ-radiation, equal to 0.10-0.14 P / s.

 Thus, each element of the device contributes to the preservation of the thermal neutron flux near the biological object and reduces the level of fast neutron flux and the power of the background γ radiation in the beam. At the same time, the values of the last two correspond to the requirements of the current NRB and OSB.

 The diameter of the diaphragm forming a beam of thermal neutrons is set in the range of 10-150 mm, which corresponds to the geometry of a biological object - laboratory animals with transplanted tumors or a phantom of the head.

 The working chamber, which houses a table with a biological object, is surrounded by biological protection (Fig. 3 and 4). Protection consists of stationary and four movable blocks connected to the table. The castle configuration of stationary and moving blocks in a closed working chamber avoids direct shots of neutrons and γ-radiation. Stationary blocks are made of monolithic reinforced concrete. Movable blocks consist of layers of lead and neutron-stop-borated polyethylene 5-6 cm thick.

 Two parallel plexiglass frames are installed on the table. A biological object is fixed on a frame 6 cm apart from the diaphragm. The second frame is 30 cm away from the first and equipped with a replaceable Plexiglas plate with concentric circles deposited on it in increments of 1-2 cm (depending on the size of the biological object), the center of which coincides with the axis of the thermal neutron beam. The circles are intended for beam alignment and placement of dosimeter detectors.

 An example implementation of the method.

Experimental studies on neutron capture therapy were carried out on laboratory animals - mice and rats in the amount of 250 pcs. and head phantom. The head phantom is a plexiglass ball with channels equipped with cells for inserting plastic bags with prolonged dosage forms of boron and gadolinium-containing compounds and plate radiation detectors (Fig. 4). The prepared prolonged dosage forms of boron and gadolinium-containing compounds were injected directly into the transplanted tumor 5 minutes before the animals were irradiated with thermal neutrons. The experiments were performed on the sarcomas of Jensen, Walker and S45. The use of prolonged dosage forms provides a ¹⁰ B content in the tumor at a level not lower than 35 μg / g and ¹⁵⁷ Gd - not lower than 180 μg / g for 50-60 minutes. The obtained results of experimental verification of the proposed method and device for neutron capture therapy of malignant tumors in laboratory animals are shown in the table, and using phantoms in FIG. 8.9. In FIG. 8a shows the deep dose distribution in a homogeneous rat phantom, where 1 is the thermal neutron flux; 2 - dose of γ radiation along the axis of the radiation beam of the reactor; 3 - thermal neutron flux (x20); 4 - dose of γ-radiation (x10) for a normal section at a distance of 70 mm to the right of the beam axis. In FIG. 8b shows the dose distribution in a rat phantom with a tumor model containing gadolinium at a depth of 0.6 cm from the surface, where 1 is the neutron kerma; 2 - dose of γ radiation. In FIG. 8c is the same as in FIG. 8b, but to localize the tumor model at a depth of 1 cm from the surface. In FIG. 9 shows the deep dose distribution in a homogeneous phantom of the human head, where 1 is the neutron kerma; 2 - dose of γ radiation.

 The following survival rates were obtained on animals with other transplanted tumors: 80 ± 4% (Walker sarcoma) and 82 ± 5 (S45 sarcoma).

 The device is depicted in FIG. 1-4, where in FIG. 1 shows a General view of the device; in FIG. 2 - placement and device channel for the formation of a beam of thermal neutrons; in FIG. 3 - a movable table for placing a biological object with protection units; in FIG. 4 - phantom of the head.

 The device (Fig. 1) contains an active zone 1 with a horizontal tangent channel 2, the output of which has a lead diaphragm 3 in the working chamber 4. The channel passes through five slide rings 5. The movable protection units 6 have a locking surface in the form of ledges with stationary protection 7 working chamber. On the movable table 8, frames 9 are installed to fix the biological object for alignment and dosimetry of the beam.

 A graphite diffuser 10 is installed in the channel (Fig. 2) in plane A3. A conical collimator 11 made of high pressure polyethylene is installed in the central slide rings (II, III, IV). A bismuth filter 12 is placed in the slide ring III. A polyethylene 13 and lead 14 bushings are installed in the slide ring 1.

 On the movable table (Fig. 3) there are frames 15, on one of which a biological object 16 is fixed, and the adjustment rings 17 are applied to the other and the dosimeter detectors 18 are installed.

 The operation of the device. The biological object and dosimeter detectors are fixed on a movable stage, after which the stage with protection slides into the working chamber. Sliding rings open, the exposure time is fixed. Irradiation is stopped by closing the gate rings, a table is pulled out, detectors for spectrometric analysis and dosimeters for dose calculation and a biological object (animals) are removed for subsequent observation.

Claims (6)

1. A neutron-capture method for treating malignant tumors in an experiment, comprising introducing boron and / or gadolinium-containing preparations into a biological object, irradiating the object with a neutron flux and evaluating the effectiveness of therapy, characterized in that a boron and / or gadolinium-containing compound is introduced into the biological object prolonged dosage form and then it is irradiated with a beam of thermal neutrons with a diameter of 20 - 150 mm with a flux of 5 • 10 ⁸ - 10 ⁹ t / cm ² • s, with a dose rate of background γ-radiation in the beam of not more than 0.14 R / s, 15 to 60 minutes  2. The method according to claim 1, characterized in that small biological animals with transplanted tumors are used as a biological object.  3. The method according to claim 1, characterized in that the phantom of the human head is used as a biological object, with flat polyethylene containers filled with prolonged dosage forms of boron and / or gadolinium-containing compounds.  4. The method according to claim 1, characterized in that the prolonged dosage forms of boron and / or gadolinium-containing compounds are administered directly into the tumor 5 minutes before irradiation with a neutron flux. 5. A device for neutron capture therapy of malignant tumors, including a nuclear reactor with a channel connecting the active zone and the working chamber, with a movable table for placing a biological object and with biological protection, as well as a neutron beam formation system with a scatterer, filter, and a collimator of variable cross section characterized in that in it a horizontal channel with a graphite diffuser is placed tangentially to the active zone of a water-water nuclear reactor and the diaphragm is closed at the exit to the working chamber a hole diameter of 10 to 150 mm, and the neutron beam forming system consists of five vane rings, three of which are inserted into the central conical collimator divergence angle α = 1,8 - 2,0 ^o, made of a high density polyethylene having a density ρ = 0.97 g / cm ³ , while a filter made of polycrystalline bismuth with a density ρ = 9.75 g / cm ³ , the ratio of whose length l to the distance to the diaphragm L is l / L, is installed in the third slide valve along the beam = 1: (30 - 40), while in the first slide ring on the side of the diaphragm are placed core and polyethylene bushings, and the biological protection of the working chamber is equipped with a movable block connected to the table, the surface of which is made in the form of ledges mating with similar ledges of the inner surface of the working chamber, and the stationary biological protection of the working chamber is made of steel frames filled with lead and boronized in layers polyethylene with a layer thickness of 5 - 6 cm.  6. The device according to claim 5, characterized in that two frames are installed in parallel on the table, on the first in front of the diaphragm, clamps are made for attaching the biological object or phantom of the head, on the second frame, mounted on it a plexiglass plate, alignment concentric circles are applied for neutron orientation beam and installation of dosimeter detectors.

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