RU2313377C2 - Method of realizing of neutron-catch therapy of oncological diseases - Google Patents

Abstract

FIELD: nuclear medicine.

SUBSTANCE: method of realizing of neutron-catch therapy is based upon introduction of medicinal preparation into damaged organ or tissue of human body. Preparation has isotope with high cross-section of absorption of neutrons. Then damaged organ or tissue is irradiated by neutrons of nuclear reactor. Irradiation is performed with ultra-cold neutrons with energy of 10-7 eV and higher, which neutrons are released from cryogenic converter of neutrons of nuclear reactor and are delivered to damaged organ or tissue along vacuum neutron-guide, which neutron-guide has end part to be made in form of flexible catheter. Dosage loads are reduced.

EFFECT: minimized traumatism of healthy tissues of patient.

4 cl, 1 dwg, 1 tbl

Description

FIELD OF THE INVENTION

The invention relates to nuclear medicine, to radiation therapy and can be used to implement neutron capture therapy, which has found application in the treatment of cancer.

State of the art

It is known from medical practice that the available methods of treating cancer are not effective enough - about 50% of cancer patients die from this disease. Cancer mortality is second only to cardiovascular disease. Treatment of patients with malignant neoplasms is one of the priority state and scientific tasks in all developed countries of the world.

Today, three main methods of therapy are used to treat cancer: surgery, radiation therapy, and chemotherapy. Among these methods, radiation therapy alone or in combination with other methods is used in 40-75% of all cases of cancer, and there is a tendency to increase this role in the near future.

One of the promising areas of radiation therapy is neutron therapy. It is preferable to other methods of radiation therapy in cases of locally advanced tumors of the head and neck, salivary glands, and breast cancer. The advantages of neutron therapy have been demonstrated both to cure the primary focus and to overcome the metastasis of malignant tumors. A positive effect is achieved not only through radical radiation exposure, but also due to the transition of the tumor into an operable form with subsequent surgical intervention.

Currently, neutron therapy is known, implemented in two versions - neutron capture therapy (NRT) and fast neutron therapy (TBN). Particularly promising is neutron capture therapy, based on the absorption of neutrons by the stable boron isotope ¹⁰ V (boron neutron capture therapy) or another element with a large neutron capture cross section and the release of significant energy by the reaction products. The effectiveness of NRT is demonstrated by the treatment of brain tumors of various etiologies: 35% of patients were alive for five years after neutron therapy, while conventional treatment increases the life expectancy by only 8-10 months. Five-year survival of patients with multimorphic glioblastoma reaches 50% without noticeable mental and mental degradation, while the best drug treatment gives only about 3% of five-year survival with significant mental degradation [V.F. Khokhlov, K.N. Zaitsev, V. I. Kvasov et al. Development of radiation technology for the treatment of malignant tumors based on neutron capture therapy. // Engineering Physics No. 1, 2000, pp. 52-55].

The essence of the method of neutron capture therapy is as follows. At the first stage, a medical preparation containing chemical elements with a large capture cross section of thermal neutrons, such as, for example, boron, gadolinium, etc., is introduced into the tumor. Then, the tumor is irradiated with thermal neutrons. When a neutron is absorbed, for example, with a ¹⁰ V boron isotope, an α-particle and an ⁷ Li ion are formed as a result of the ¹⁰ V (n, α) ⁷ Li reaction, the path of which in biological tissue is about 10 μm. At the same time, they release 2.3 MeV energy in the redistribution of a cell containing a ¹⁰ V nucleus, which leads to its destruction. This ensures the possibility of selective damage to cancer cells while maintaining normal tissue intact.

One of the most important requirements for NRT is to reduce the radiation dose to healthy areas of the patient’s body and especially to superficial tissues. Focusing a neutron beam, filtering background γ-rays and fast neutrons allows minimizing dose loads. To the greatest extent, the tangential horizontal experimental channels of research reactors satisfy the requirements for reducing the radiation dose of gamma rays and fast neutrons. A feature of such channels lies in the fact that their axis does not pass through the reactor core — a source of fast neutrons and gamma rays, which eliminates the possibility of unscattered radiation entering the channel. The admixture of fast neutrons and γ radiation at the exit from the tangent channel is less than that of the radial channel. The amount of thermal neutrons should remain unchanged if the luminous surfaces are in identical conditions, since the neutron flux in the reflector is isotropic.

As a prototype, a reactor method of NRT implementation using thermal neutron beams extracted from the core of a nuclear reactor, collimated and transported to the site of radiation therapy was selected [Kulakov VN, Khokhlov VF, Zaitsev KN, Portnov A .BUT. Method for neutron capture therapy of malignant tumors and device for its implementation. RF patent 2141860, 02/06/1998]. In this method, a boron and / or gadolinium-containing compound in a prolonged form is introduced into a biological object (a malignant tumor) and then neutrons removed from the reactor are brought to the tumor. The irradiation field is optimized in energy and intensity using a system of filters and collimators.

The disadvantages of the method are the adverse spatial distribution of neutrons in the patient’s body at the highest absorbed dose of neutrons on the surface of the body (in the skin), a rapid drop in dose with depth — already at a depth of ~ 2 cm, the neutron flux decreases by 2 times [K.N. Zaitsev, A. A. Portnov, V. A. Sazykin and others. Neutron capture thermal neutron therapy at the MEPhI Institute of Atomic Energy // Atomic energy, vol. 91, issue 4, October 2001, pp. 307-314] and the background of fast neutrons and associated γ-radiation leading to radiation damage to normal patient tissue. This limits the use of the method only to superficial or superficially lying tumors. In addition, it is necessary to apply special measures to suppress the background of fast neutrons and associated γ-radiation.

Disclosure of invention

The problem to which the invention is directed, is to increase the efficiency of the implementation of neutron capture therapy of malignant tumors.

The technical task is to meet the requirements of minimizing damage to healthy patient tissues by reducing dose loads from concomitant γ-radiation and fast neutrons to healthy areas of the body, the possibility of transporting a neutron beam to deep-lying tumors and effective effects on small tumors.

The problem is solved in that the method for the implementation of neutron capture therapy of cancer includes the introduction into the affected organ or human tissue of a medicine containing an isotope with a high neutron absorption cross section, and subsequent irradiation of the affected organ or tissue with neutrons from a nuclear reactor, the irradiation being ultracold neutrons with ^-7 energies below 10 eV, which is withdrawn from cryogenic converter neutron nuclear reactor and is delivered to the affected organ or tissue by vacuum neutron guide, which end portion is formed as a flexible catheter.

In a particular embodiment, ultracold neutrons are delivered to the affected organ or tissue, for example, through the esophagus, oral cavity, bronchi, urinary tract, and rectum.

In another particular embodiment, ultracold neutrons are delivered to the affected organ or tissue using a flexible neutron guide catheter made, for example, of copper, or nickel, or stainless steel.

In another particular embodiment, lithium-6, or boron-10, or gadolinium-157 is used as an isotope with a high neutron absorption cross section.

Ultracold neutrons (UCNs) have a velocity of <10 m / s and wavelengths from several hundred to a thousand angstroms. One of the features of UCNs is their ability to experience complete reflection from the surface of condensed matter at any angle of incidence. The existence of the phenomenon of reflection of neutrons of very low energies and the ensuing possibility of long-term storage of neutrons in special containers was first pointed out in [Ya. B. Zel'dovich // ZhETF, 1959, v. 36, p. 1952]. The phenomenon of complete reflection of UCNs, the possibility of long-term confinement in confined spaces, and transportation through neutron guides were demonstrated in numerous experiments [I.I. Gurevich, V.P. Protasov. Neutron physics. - M .: Energoatomizdat, 1997, p.331-342].

The storage time of UCNs in special containers is determined by the lifetime of a free neutron before β decay and losses due to inelastic scattering or capture during collisions with the walls of the storage volume. The boundary energy of the total reflection of the neutron from the surface at any angle of incidence is determined by the expression:

,

,

where the first term is nuclear, and the second is the magnetic component of scattering;

μ is the magnetic moment of the neutron;

ρ is the density of nuclei;

b is the coherent scattering length;

A is the mass number;

B - magnetic induction;

(±) - for the neutron spin with parallel and antiparallel B. directions

For b> 0, a neutron falling from a vacuum into a medium encounters a positive barrier of height U. For most nuclei (Be, C, Mg, Fe, Cu, Zn, Pb, etc.) b> 0 and only for certain types of nuclei (Li, Mn, Ti, V) b <0. If E <U, the neutron is reflected and does not pass the interface. For almost all substances, E _g ~ 10 ^-7 eV. The values of U and critical velocities for various substances are shown in the table.

Table Substance U (10 ^-7 eV) V _gr , m / s Substance U (10 ^-7 eV) V _gr , m / s H ₂ O -0.146 - Ti -0,500 - Polyethylene -0.070 - Mn -0.680 - Be 2,500 6.90 Fe 3,500 8.20 C (graphite) 1,750 5.83 Stainless steel 1,820 6.05 Mg 0.595 3.37 Cu 1,720 5.70 Al 0.541 3.22 With 1,740 5.76

Traditionally, the problem of producing ultracold neutrons is solved by isolating the low-energy tail of the Maxwell distribution of thermal neutrons at the output of the moderator of a nuclear reactor. In this case, the ability of UCNs to be reflected from the surfaces of materials is used: such neutrons are “locked up” in a closed storage vessel, where they are sent from a nuclear reactor. However, since the fraction of very cold neutrons in the thermal spectrum of the reactor is negligible, the "yield" of ultracold neutrons with this approach is very limited.

There is another possibility of producing ultracold neutrons - cooling neutrons after leaving the reactor moderator when passing through a cryogenic converter (converter) with a low-temperature moderator, for example, superfluid helium, solid or liquid deuterium, and liquid hydrogen. In this case, a fairly efficient transfer of energy from the neutrons of the reactor to phonons (a quasiparticle, which is a quantum of elastic vibrations of the medium) occurs, which significantly increases the proportion of ultracold neutrons. The converter is located outside the neutron reflector and biological reactor protection to reduce the thermal effect of radiation on the low-temperature moderator.

In the first experiments on UCN extraction from the reactor and retention in the vessel, the neutron flux density was ~ 0.1 n / (cm ² · s). Currently, UCN flux density values are five orders of magnitude higher. At the reactor of the Institute. M. Lauet and P. Langevin in Grenoble UCN flows reach values of more than 10 ⁴ n / (cm ² · s). It is expected that due to the improvement of beam extraction technology, UCN fluxes will increase by at least two to three orders of magnitude, up to the level of 10 ⁶ -10 ⁷ n / (cm ² · s) [II Gurevich, VP Protasov . Neutron physics. - M .: Energoatomizdat, 1997, p. 316]. Such values of the flux density allow us to consider the possibility of practical use of UCN in various fields of science and technology, including for the needs of nuclear medicine.

It is believed that the clinical application of the NRT method requires thermal neutron fluxes with a density of ~ 10 n / (cm ² · s), and the admixture of fast neutrons should not exceed 1%. The degree of damage to tumor cells during neutron therapy N _t can be assessed using a simple expression [K.N. Zaitsev, A.A. Portnov, V.A. Sazykin and others. Neutron capture thermal heat neutron therapy at the Moscow Institute of Physics and Technology MEPhI // Atomic energy, t. 91, issue 4, October 2001, pp. 307-314]:

where ρ _in-10 is the concentration of ¹⁰ V in the tumor;

φ is the thermal neutron flux density at the location of the tumor;

t is the duration of exposure

σ is the capture cross section of thermal neutrons by a ¹⁰ V nucleus.

At a concentration of ¹⁰ V in a tumor of 30 μg / g and a capture cross section of 3.84-10 ³ barn [Radiation capture of neutrons. Directory. M .: Energoatomizdat, 1986] for 1 hour of irradiation in every milliliter of its volume in a neutron flux of 10 ⁹ n / (cm ² · s) more than 2-10 ¹⁰ α-particles and ⁷ Li recoil nuclei are ^born . Since 1 ml of melanoma contains about 10 ⁹ cancer cells [K.N. Zaitsev, A.A. Portnov, V.A. Savkin et al. Neutron capture thermal heat neutron therapy at the IRT MEPhI reactor // Atomic Energy, vol. 91, vol. .4, October 2001], then for each melanoma cell there are about 20 pairs of α-particles and ⁷ Li nuclei. To destroy a cancer cell, only a few α particles are sufficient. [PMMacklis, YJLin, B. Beresford et al. Cellular kinetics, dosimetry and radiobiology of alpha-particle immunotherapy: induction ofapoptosis. Radiat. Res. 1992. V.130. p.220-226].

As follows from expression (1), the degree of damage to tumor cells depends not only on the magnitude of the neutron flux, but on the neutron capture cross section, which is much higher for UCNs than for thermal neutrons.

The ultracold neutron capture cross section for a 1 / v absorber, σ _a ^, can be obtained using the cross section for neutrons of arbitrary velocity σ _a (E ₀ = kT) using the following expression [II Gurevich, VP Protasov. Neutron physics. - M .: Energoatomizdat, 1997, p. 341]:

σ _a ^vn = σ _a (E ₀ = kT) / (v _kT / v _vn )

where v _kT is the neutron velocity at temperature T;

v _uhn is the velocity of an ultracold neutron.

In the case of the so-called Westcott approximation, the capture cross section σ _a (E ₀ = kT) is used for T = 293.6 ° K, which corresponds to the neutron velocity v ₀ = 2200 m / s. Then the UCN capture rate for 1 / v - absorber will be equal to:

N = φ _vn · [σ _a (v ₀ ) (v ₀ / v _vn )]

Since the velocity of UCN is ~ 8 m / s [I.I. Gurevich, V.P. Protasov. Neutron physics. - M .: Energoatomizdat, 1997, p. 316], then the value of N _t for UCN increases by 275 times in comparison with thermal energy neutrons.

The penetration depth of α particles in biological tissue varies from 30 to 80 microns, which corresponds to several cell diameters. The ionization density reaches -100 keV / μm, so that the distance between two consecutive acts of interaction is comparable to the distance between two strands of a DNA helix. Therefore, the probability of double helix breaking with a single α particle is high enough, which automatically means high therapeutic efficacy.

The therapeutic effect of UCN capture can also be estimated based on the absorbed dose rate in the tumor [RF Patent 2212260 Planning method for neutron capture therapy. Authors S.E. Ulyanenko, S.N. Koryakin, V.A.Yadrovskaya, etc.]:

P = F · (C _tumor. N _A / M) · σ _a ^sc E · K, [cGy / s]

where f is the flux density of UCN, n / (cm ² · s);

With _swelling. - concentration of ¹⁰ V in the tumor, g / g of tissue;

N _A is the Avagadro number;

M is the molecular mass of a chemical element with a high thermal neutron capture cross section;

σ _a ^ear - the capture cross section of ultracold neutron, cm ² ;

E is the energy from the reaction products, MeV;

K = 1.6 · 10 ^-8 cGy · g / MeV is the coefficient of coordination of dimensions.

≈2·10¹⁸ ядер¹⁰В/г, сечении захвата ≈10⁶ барн(10^-18 см²) и плотности потока УХН ≈10⁶ н/(см²·с), мощность поглощенной в опухоли дозы излучения Р составит 4,2·10^-2 Гр/мин. При 2-часовой экспозиции поглощенная доза превысит 5 Гр.At a concentration of ¹⁰ V in the tumor, 30 μg / g, which is equivalent

≈2 · 10 ¹⁸ cores of ¹⁰ V / g, capture cross section ≈10 ⁶ barn (10 ^-18 cm ² ) and UCN flux density ≈10 ⁶ n / (cm ² · s), the radiation dose rate P absorbed in the tumor will be 4, 2 · 10 ^-2 Gy / min. At 2 hours of exposure, the absorbed dose will exceed 5 Gy.

The dose required to kill cancer cells depends on the number of viable or clonogenic cells. So, for 10 ¹² cells a dose of 60 Gy is needed, for 10 ⁸ cells - 40 Gy, for 10 ⁴ cells - 20 Gy and for 100 cells - a dose of 10 Gy [Gerd-Jurgen Beyer Alpha-emitting radionuclides - production and use. // Isotopes. Properties Receiving. Application. t.2, M .: Fizmatlit, 2005]. However, it should be borne in mind that the allowable dose for bone marrow is 1-5 Gy, for the gastrointestinal tract - 1-5 Gy, for the vascular system - 10-20 Gy and for the whole body as a whole - 2 Gy. The lethal dose for subclinical tumor formations of 10 ⁴ cells is 20 Gy. To limit the systemic dose to the body to 2 Gy, it is necessary to ensure a tumor / tissue dose distribution ratio of at least 10: 1. For 100 cancer cells circulating in the blood, 10 Gy is needed and, therefore, a 5: 1 ratio is needed. It is believed that a dose of 5 Gy approaches the optimal level of radiation exposure to a malignant tumor.

Thus, the use of ultracold neutron beams with a flux density of 10 ⁶ n / (cm ² · s) and an exposure of not more than 2 hours provides the necessary therapeutic effect in the treatment of cancer.

The implementation of the invention

As a neutron source, a nuclear reactor with a neutron flux in the core of ~ 10 ¹⁴ n / (cm ² · s) can be used.

Neutrons from the reactor core are transported to a low-temperature converter, which is a cryogenic cryostat filled with superfluid liquid helium. The wall of the converter is made of material that provides full reflection of UCN at the border.

After deceleration in a low-temperature converter, ultracold neutrons are fed through a thin transparent window with b <0 into a vacuum neutron guide, through which they are transported to the experimental room, where experiments or medical procedures using NRT are performed. A vacuum in a neutron guide is maintained to reduce neutron losses during their diffusion. As the wall material, copper, nickel or stainless steel are usually used.

, где D - коэффициент диффузии, определяемый степенью зеркальности поверхности; Т - время жизни нейтрона в нейтроноводе по отношению ко всем процессам: поглощению нейтронов стенками и их нагреванию при столкновении со стенками. Некоторая часть УХН теряется как в соударениях с ядрами атомов остаточного газа, так и в соударениях со стенками нейтроновода. Интенсивность УХН в зависимости от расстояния (1) до конвертора дается известным экспоненциальным законом: exp(-1/L_c). Для электрополированных нейтроноводов диаметром ~10 см экспериментальные значения L_c достигают ≈10 м.UCN propagation through a neutron guide is similar to the flow of a rarefied gas through pipes and is characterized by the diffusion length

where D is the diffusion coefficient determined by the degree of specularity of the surface; T is the neutron lifetime in the neutron guide with respect to all processes: the absorption of neutrons by the walls and their heating in a collision with the walls. Some UCNs are lost both in collisions with the nuclei of residual gas atoms and in collisions with the walls of the neutron guide. The UCN intensity depending on the distance (1) to the converter is given by the known exponential law: exp (-1 / L _c ). For electropolished neutron guides with a diameter of ~ 10 cm, the experimental values of L _c reach ≈10 m.

Neutrons with energy E <E _gr during movement inside the neutron guide will be reflected many times from the walls, and the neutron path will follow the bends of the neutron guide. Even a 180 ° rotation does not increase the “resistance” of the neutron guide. Neutrons with an energy E> E _g will leave the neutron guide either immediately after the converter after the first collision with the wall (if the conditions of total external reflection are not satisfied), or at the point of bending of the neutron guide after several reflections in straight sections. The probability of specular reflection of UCN is about 0.8-0.9.

The end part of the neutron guide is made in the form of a flexible bellows-type catheter - a thin-walled metal corrugated tube. At the end of the catheter there is a thin transparent window with b <0, through which ultracold neutrons enter the malignant tumor.

An example of the method

A method for the implementation of neutron-capture therapy of cancer is implemented on the installation shown in the drawing. The setup consists of a reactor core 1, a neutron reflector 2, a horizontal channel 3, a cryogenic converter 4 — a UCN source, a vacuum neutron guide 5 for delivering ultracold neutrons to the site of medical procedures for neutron capture therapy, a flexible neutron guide catheter 6 for direct UCN supply to the affected organ or tissues of a person.

As the primary source of neutrons, the experimental research reactor IR-8 with a thermal power of 8 MeV was selected. The maximum neutron flux in the reactor core reaches 2 · 10 ¹⁴ n / (cm ² · s).

Neutrons from the reactor core 1 along a tangential horizontal channel 3 with a diameter of 100 mm made of aluminum are fed into a low-temperature converter 4 filled with superfluid liquid helium. The converter wall is made of the nickel isotope Ni-58, which provides full reflection of UCNs at the boundary. On the outside, the converter is surrounded by thermal and radiation protection.

As a result of scattering on superfluid helium nuclei, a neutron loses almost all its energy. Neutrons with an energy of ~ 10 ^-7 eV are fed through a thin transparent window with b <0 into a vacuum neutron guide 5, through which they are transported to the experimental room, where they conduct experiments or medical procedures using NRT. The residual pressure in the neutron guide is maintained at a level not higher than 1.3-10 ^-2 Pa. Nickel is used as the material of the neutron guide wall. The inner surface of the neutron guide is covered with anhydrous Fomblin oil (F ₃ CCF ₂ OCF ₂ CF ₅ ) _n to reduce UCN losses on the walls.

If necessary, the neutron beam can be blocked using neutron gates, which are an opaque screen for ultracold neutrons made of nickel.

The end part of the neutron guide is made in the form of a flexible neutron guide-catheter 6 of the bellows type - a thin-walled metal corrugated tube. Through a catheter with a diameter of 10-15 mm ultracold neutrons, the screen is delivered directly to the affected organ through the esophagus, oral cavity, bronchi, urinary tract, rectum or other way. The neutron flux at the outlet of the catheter reaches ~ 10 ⁶ n / (cm ² · s), which provides the necessary dose loads for neutron-capture therapy operations.

The proposed method for the implementation of invasive neutron-capture therapy of malignant tumors allows using minimized neutron beams to minimize damage to healthy patient tissues, transporting the neutron beam to deep-lying tumors, and effectively affect small tumors.

Claims (4)

1. A method for carrying out neutron-capture therapy of oncological diseases, comprising introducing into the affected organ or human tissue a medicine containing an isotope with a high neutron absorption cross section and subsequent irradiation of the affected organ or tissue with neutrons from a nuclear reactor, characterized in that the irradiation is carried out with ultracold neutrons with energy below 10 ^-7 eV, which are removed from the cryogenic neutron converter of a nuclear reactor and delivered to the affected organ or tissue via a vacuum neutron guide, to The back part of which is made in the form of a flexible catheter. 2. The method according to claim 1, characterized in that ultracold neutrons are delivered to the affected organ or tissue, for example, through the esophagus, oral cavity, bronchi, urinary tract, and rectum. 3. The method according to claim 1, characterized in that the flexible catheter is made, for example, of copper, or nickel, or stainless steel. 4. The method according to claim 1, characterized in that lithium - 6, or boron - 10, or gadolinium - 157 are used as an isotope with a high neutron absorption cross section.