Irradiation method and system

Abstract

The present invention provides an irradiation method and system for irradiating a target volume. [Solution] This method includes providing a thermal neutron-absorbing nuclide (for example, in the form of an agent with a large neutron cross-section) to a target volume, and irradiating nuclei in or near the target volume with a beam of particles consisting of one or more protons, deuterons, triuterons, and heavy ions to generate neutrons, thereby promoting neutron generation via inelastic collisions between atoms (including the target) and particles in the beam path. The neutron-absorbing nuclide absorbs neutrons generated by the inelastic collisions, thereby generating capture products or fragments that are irradiated to the target volume.

Description

[Technical Field]

[0001] Related applications This application is a reciprocal application to Australian Patent Application No. 2017903739, filed on September 14, 2017. The application (the contents of which are incorporated herein by reference in their entirety) I assert the interests of the day and the priority date.

[0002] The present invention relates to irradiation methods and systems for specific applications in the irradiation of biological materials. It is not exclusive in any way. [Background technology]

[0003] The primary goal of all forms of radiotherapy is to achieve maximum healing without damaging surrounding healthy tissue. The goal is to deliver the therapeutic dose of radiation to the target. One of the biggest challenges in radiation therapy is the 5% delivery of the treatment. Minimizing the latent effect, including the risk of secondary cancers that may occur sometime between a few years and several decades later. The goal is to keep the dose within a certain range [1-4]. By maximizing the probability of normal tissue complications (NT), including the probability of developing treatment-induced cancer, the probability of treatment-induced cancer is increased. The goal is to minimize CP) [4, 5]. Radiotherapy (e.g., intensity-modulated radiation) Thanks to advances in the technology of radiotherapy (including image-guided radiotherapy and particle beam therapy), radiosensitizers By using it, the local biological efficacy of the therapeutic dose is increased compared to healthy tissue, while also being more precise and It has become possible to selectively target tumors [6, 7].

[0004] Particle beam (or "hadron beam") therapy uses high energy to deliver the therapeutic radiation dose to the treatment area. It is a form of radiotherapy that uses a beam of energy consisting of protons or heavy ions. A single-energy beam of ions has a very clearly defined energy-dependent maximum dose depth. Because it exhibits a defined Bragg peak, it enables high conformal dose delivery. Thanks to its selectivity, treating deep tissues avoids delivering harmful doses to healthy tissue at other depths. Because it can be performed without any additional procedures, proton / heavy ion beam therapy is a superior treatment option compared to photon and electron beams. These are multiple-choice options [6, 8, 9].

[0005] During particle beam therapy, most of the primary particles in the beam interact with each other through numerous electromagnetic interactions. They deposit kinetic energy. However, some of these particles are inelastic with respect to the target nucleus. It will be hit by a collision. As a result, short distances will be emitted more or less isotropically from the point of impact. A series of nuclear fragments, such as high-LET charged particles and neutrons, are generated at the target site, and the incident particles The energy is deposited in the region surrounding the on-beam path [10, 11]. However, these fragments deposit some of the beam's kinetic energy outside the target volume. Such interactions involve indiscriminate irradiation of both target and non-target tissues. [9, 12] This is one of the main advantages of particle beam therapy, namely, large peak vs. plateau beams. Because it disrupts the dose-to-body ratio, it is typically considered a nuisance, especially when it occurs outside the therapeutic area. ru.

[0006] Light water (the main component of human tissue) has a moderate thermal neutron cross-section (0.335 burn). However, it has a very high neutron cross-section (3838 and 254000 burnes, respectively). 10 B or 157 To significantly increase the amount by administering an agent containing isotopes such as Gd. is possible. The inelastic thermal neutron interaction with water mainly results in neutron hydrogen capture and high-energy emission of γ photons, 10 but the inelastic thermal neutron interaction with B or 157 Gd results in generation of energetic charged particles with high relative biological effectiveness (RBE), which is the basic operating principle of neutron capture therapy (NCT).

[0007] In NCT, the biological dose based on the presence of the capture agent depends on the physical dose together with the relative biological effectiveness (RBE) of the secondary particles determined by a specific NCA (and thus depends on the concentration of the neutron capture agent). The RBE coefficient varies significantly between different cell types and situations (i.e., in vitro versus in vivo) and is also specific to each particular neutron capture agent. In the BNCT literature, this compound-specific RBE coefficient is usually referred to as the "compound biological effectiveness "(CBE), but most researchers studying with gadolinium simply call it RBE.

[0008] 10 In the case of B, the capture mechanism results in the production of several high-LET products as follows

[15] : 10 B + n th → 11 B] * → α + 7 Li + γ(2.31 MeV).

[0009] Both α particles and lithium ions are high-LET particles that produce ionization in the immediate vicinity of the reaction within a range of about 5 - 9 μm (the diameter of the target cell) [16, 17].

[0010] The most widely used 10 B-based neutron capture agent ( 10B-4-Borono-L-phenyl Lanin 10 In B-BPA, the effects on brain tumor cells and normal tissue are 3.6-3, respectively. CBE values ​​of 0.8 and 0.9-1.3 have been reported, and the tumor tissue to healthy tissue concentration ratio is 5: The ratio is 1-8:1 [14, 16, 17]. The alternative trapping agent is borocapte sodium (BSH). ) has shown potential for NCT applications, and the reported range of CBEs in brain tumors is 1. The uptake concentration ratio is 2-2.3 and 0.37-0.5 in normal tissue, but the uptake concentration ratio is higher than that of BPA. The levels tend to be quite low (1.2–3.5 in the brain)

[28] . Specific values ​​for other target tissues Unlike the other, the CBE values ​​reported for liver tumors with both agents are higher (BPA and B). SH values ​​were 9.94 / 4.25 and 4.22 / 0.94, respectively, which are comparable to tumor / liver CBE values. (Concentration ratio of 2.8 / 0.3) [26, 27, 39].

[0011] 157 The Gd neutron capture reaction follows a somewhat different pathway, and is excited as follows: 158 Gd This results in the generation of nuclei and high-energy gamma rays: 157 Gd+n th →[ 158 Gd] * → 158 Gd+γ+7.94MeV.

[0012] During the relaxation of the excited state, internal conversion (IC) and low-energy Auger electrons are produced, the latter being It is responsible for the majority of the therapeutic effect. Auger electrons, which are classified as high-LET radiation, are very short distances. After moving only a short distance (a few nanometers within the tissue), it deposits its kinetic energy, so The source is concentrated in the immediate vicinity of DNA molecules or essential organelles (such as mitochondria). If present, it becomes very effective. In thermal neutron capture reactions, 5 Auger electrons, 1.8 γ photons, The generation of 0.69 IC electrons and 1.0 recoil nuclei is also estimated.

[0013] 157 Gd has an extremely large thermal neutron cross-section, making it the most stable isotope among all stable isotopes. Because it is also large, it is attracting considerable interest in neutron capture therapy. 3+ Aeon, It is highly toxic to organisms both in vitro and in vivo, but Gd 3+ The compound is physiologically stable and therefore safe to use

[0045] . Very high intracellular concentrations of gadolinium are in v without significant cytotoxicity. This is achievable with itro (around several thousand ppm). Examples include Gd-DOTA and Gd-DTPA. Gadolinium contrast agents are approved for use in diagnosis in humans, It does not accumulate in significant concentrations in the cell nucleus.

[40] Of the experimental gadolinium compounds, Moteki Safin-gadolinium (MGd) has been proposed as a potential candidate for GdNCT.

[45] It is a tumor-specific radiosensitizer, and its use in combination with whole-brain radiotherapy is the first It has reached Phase III clinical trials.

[53] Tumor tissue to healthy tissue uptake ratio of 70:1, in Long-term retention of gadolinium in vitro (2 months), and 90% of glioblastoma cell nuclei Because it has % uptake, it is a promising candidate for use in NCT[54~56]. Recent efforts toward the development of gadolinium-based drugs targeting DNA and mitochondria This led to the development of several promising agents. Morrison et al. found that at concentrations of 3000 ppm... A tumor cell-selective mitochondrial agent designed for NCT applications with intracellular concentrations at [specific location] Development has been reported.

[45]

[0014] Using a neutron beam from a nuclear reactor 10 Radiotherapy based on B neutron capture has already proven effective. It is an established radiotherapy modality, used in Russia, Argentina, Italy, and the United Kingdom. Several accelerator-based epithermal neutron facilities are under consideration [18, 19]. 10 B sending Lp-Boronophenylalanine (L- 10 BPA and sodium mercaptone Decahydro-closo-dodecaborate(Na2) 10 B 12 H 11 SH, Na 2 10 BSH) is used clinically to treat patients with glioblastoma multiforme and malignant melanoma. It has been used in Argentina, Finland, Sweden, Japan, Taiwan, and In the United States, a Phase I clinical trial is underway for the treatment of head and neck tumors and liver metastases [20, 2 1] However, the surface neutron fluence required to achieve a therapeutic effect at the target is not Because the cost is always high, this technology is not feasible for treating tissue deeper than approximately 3 cm (human). (Result of the neutron moderation effect of water in tissues)

[22]

[0015] Japanese Patent Publication No. 2016 / 088895 describes a substance administered before irradiation of a tumor with carbon ion beams. Boron compound-bound fluorinated porphyrinoids were used as sensitizers for heavy ion radiotherapy. or a sensitizer for heavy ion radiotherapy and heavy ion radiotherapy using a metal complex-containing substance thereof This has been disclosed.

[0016] Japanese Patent Publication No. 2014 / 177421 describes a sensitizer for proton beam therapy and proton beam therapy The law is disclosed. Boron compound-bonded fluorinated porphyrinoids or their metal complexes are positive It is used as a sensitizer for sub-beam therapy, and after administering this radiosensitizer to mammals, cumulative effects occur. A proton beam therapy method is disclosed in which a proton beam is irradiated onto a tumor that has been treated with a radiosensitizer. Yes, they are.

[0017] Korean Patent No. 1568938B1 describes irradiating boron captured in a tumor with protons. Radiotherapy using a proton-boron nuclear reaction that generates three alpha particles to be irradiated to the tumor area. Diagnostic devices are also disclosed.

[0018] International Publication No. 2017 / 048944A1 pamphlet contains information on deaggregation agents and In radiotherapy, by administering high-Z particles together, target cells are made more sensitive to ionization rays. A method for using high-Z nanoparticles is disclosed. The particles are taken up intracellularly by target cells. It may contain targeting molecules that enable this.

[0019] Japanese Patent Publication No. 2017 / 096672 describes a beam for use in particle beam therapy systems. A radiation dose measuring device is disclosed, which provides a correction value for correcting the positional information of the fluorescent substance. It is equipped with a dose-location analyzer for determining the location. [Overview of the project] [Means for solving the problem]

[0020] According to a first broad aspect of the present invention, an irradiation method for irradiating a target volume is provided. This method is Thermal neutron-absorbing nuclides (for example, those with a large neutron cross-section) are located within or near the target volume. A stimulant, for example, 10 B and / or 157 To provide Gd) and Protons, deuterons, triuterons, and heavy ions (for example, ionized 4 He (that is) These are generally considered to be heavy ions (alpha particles), C, O, and Si, and specifically, 9 C, 10 C, 11 C, 12 C, 15 O, 16 Although they are O and high-n Si isotopes, they are not mutually exclusive. A beam of particles consisting of one or more of the following (not necessarily) ("primary beam") is used as a nucleus ( For example, present within the target volume, adjacent to the target volume, and / or distributed throughout the entire target volume. By irradiating (a substance) to generate neutrons, inelastic collisions between the nucleus and the particle can occur. To promote the generation of neutrons, Includes, Neutron-absorbing nuclides are those that absorb neutrons produced in inelastic collisions (i.e., the neutrons produced in the neutron sacs). (and those having suitable energies for interacting with neutron-absorbing nuclides) (into neutron capture reactions) By absorption (whether by neutron nuclear reactions or otherwise), the target volume is irradiated. It generates capture products or fragments.

[0021] This method may include composing a particle beam so as to irradiate a target volume. In some embodiments, sufficient thermal neutron fluence is generated during particle beam therapy, etc. Therefore, it is preferentially absorbed by the tumor at a higher concentration compared to the surrounding normal tissue. 10 B or 157 Gd Its fluence can be utilized for therapeutic purposes through the administration of a suitable non-toxic neutron capture agent containing [the specified substance]. This example includes combination therapy modalities, such as "neutron capture-enhanced particle beam therapy." It can be called NCEPT.

[0022] Generally, the term "in close proximity" is used in its broadest and most common sense, so "next to" This includes both "in or adjacent to" and "nearby," but also includes the irradiated nucleus and the beam particles. Neutrons produced in the inelastic collision between the two are absorbed by a neutron-absorbing nuclide, and accordingly, the target body It is limited by the requirement that it generates capture products or fragments that are irradiated to the product. It should be recognized that the terms "nuclide" and "nucleus" refer to the reactions in question. This is used in this specification because it occurs in species. In other words, related species interact with the beam of particles. It is either a substance that absorbs neutrons ("nucleus") or a substance provided for thermal neutron absorption ("nuclide"). Regardless of the specifics, it will be understood that they generally exist in atomic form.

[0023] Therefore, it is possible to generate a neutron region that can be wider than the (primary) beam of particles, In some cases, the area becomes 3 to 5 times larger. Therefore, the target of the primary particle beam is This makes it possible to target a region outside the volume into which it enters ("target volume"). Therefore, the nuclei irradiated by the primary particle beam may be located outside the target volume (if appropriate, target The target volume includes areas outside the subject where it is located internally, or neutron regions within the deep target volume inside the subject. (To create a region). This allows solid tumors and their surrounding satellite lesions, as well as diffuse carcinomas. or cancers that are detected in an inherently late stage and have a nearby organ of invasiveness (e.g., pancreatic cancer, gastric cancer, A mechanism is provided for irradiating liver cancer, lung cancer, or, in practice, parasites. In some cases, the target volume is contained within essentially the same boundaries as the subject or living organism. In some cases, it may be desirable to irradiate the entire subject (for example, the patient's entire body) with neutrons.

[0024] It is desirable to create a broad neutron region for purposes such as irradiating a target volume containing diffuse tumors. In the case of a nucleus located within the subject (where the target volume is located internally), the subject's life The primary particle beam is configured to deliver maximum energy outside the body (i.e., the subject's It may be advantageous to place the Bragg peak outside the body. This technique could be used, for example, to... It may be suitable for treating living organisms.

[0025] The beam is assumed to contain stable isotopes and / or radioactive isotopes.

[0026] In one embodiment, the beam includes high-energy protons and / or heavy ions.

[0027] Depending on the application, especially in applications where damage must be prioritized over profit, It will become clear that some primary particles will be preferable to others. For example, several In irradiation of several biological samples, ions heavier than oxygen reach their peak radiation biological levels. The effectiveness may occur before the peak of the physical dose accumulation, which may make it undesirable. Most useful primary beam particles, especially in biological applications, are (ionized). ) 1 H, 2 H, 3 H, 4 H, 5 H, 6 H, 3 He, 4 He, 5 He, 6 He, 7 He, 8 He, 9 He, 10 He, 18 He, 19 He, 9 C, 10 C, 11 C, 12C, 13 C , 14 C, 15 C, 16 C, 17 C, 18 C, 19 C, 20 C, 21 C, 12 O, 13 O , 14 O, 15 O, 16 O, 17 O, 18 O, 19 O, 20 O, 21 O, 22 O, 23 O , 24 O, 25 O, 26 O, and 28 It is expected to be O.

[0028] In other embodiments, this method is 10 B and / or 157 In the form of a composition containing Gd The invention provides a thermal neutron-absorbing nuclide. The composition is preferentially absorbed by malignant target tissues. It is possible.

[0029] In one embodiment, the capture product or fragment includes an energetically charged particle. The substance or fragment may contain energy-charged particles with high relative biological efficacy.

[0030] In further embodiments, the beam is a spot scanning method, a uniform scanning method. Scanning method, high-speed scanning method, raster scanning method, and / or passive scattering method The beam is then irradiated onto the material along its path (which may include the target volume). Appropriate energy can be obtained by an or synchrotron. As a result of irradiation, thermal neutron absorption occurs. Thermal neutrons are generated for subsequent capture by the nuclide.

[0031] According to a second broad aspect of the present invention, a beam of protons, deuterons, triuterons, or heavy ions Using this, biological tissue (for example, tumors, invasive satellite lesions, and / or intracranial metastatic lesions, etc.) For example, a method is provided for irradiating the brain. This method is provided for a biological assembly according to the method of the first embodiment. This includes irradiating a target volume, including the fabric.

[0032] In one embodiment, the target volume is within the subject, and the beam is stacked to its maximum energy. The point of accumulation (or "stopping") is outside the subject.

[0033] This embodiment also provides a method for treating a patient by irradiating living tissue.

[0034] In one embodiment, the target volume is within the patient, and the beam's maximum energy is directed towards the patient. To accumulate outside (or "to stop").

[0035] According to this embodiment, the method is used in combination with or in parallel with irradiation of living tissue as immunotherapy. This may further include applying such a treatment as for cancer and / or autoimmune diseases. Therefore, it is hypothesized that this could provide a mechanism for suppressing / activating immunoregulatory responses.

[0036] According to a third broad aspect of the present invention, tumors, satellite lesions (for example, one or more invasive satellite diseases) Inhibits the growth of one or more of the following: mutations, and / or metastatic lesions (e.g., intracranial lesions). A method is provided. This method is A composition containing thermal neutron-absorbing radionuclides (for example, in the form of an active agent with a large neutron cross-section). Administering substances to tumors, satellite lesions, and / or metastatic lesions (including two or more of these) , Protons, deuterons, trideuterons, and heavy ions (e.g., ionized He, C, O, and Si) are used to irradiate nuclei within and / or 4 proximate to tumors, satellite lesions, and / or metastatic lesions with a beam of particles consisting of any one or more thereof (a "primary beam") to generate neutrons via inelastic collisions between the nuclei and the particles within and / or proximate to tumors, satellite lesions, and / or intracranial metastatic lesions; and neutron absorbing nuclides included therein absorb neutrons generated by the inelastic collisions

[0037] to generate capture products or fragments that irradiate tumors, satellite lesions, and / or intracranial metastatic lesions. Thus, in some embodiments, tumors (and, if possible, other malignant tissues) take up neutron capture agents.

[0038] Upon irradiation of the tumor with the primary beam, a broad neutron region is formed via fragmentation, and the neutrons in that neutron region are then captured by the tissue that has taken up the neutron capture agent, resulting in the release of high-LET by-products at the cellular level. In certain other embodiments, tumors, parasites, and / or immunoregulators may take up neutron capture agents. The

[0039] Inhibiting the growth of satellite lesions and / or metastatic lesions inhibits the growth of multiple satellite lesions or metastatic lesions. It may take a harmful form, or cause the development of one or more additional invasive satellite lesions or invasive metastatic lesions. It can take a suppressive form.

[0040] For example, if sufficient thermal neutron fluence is generated during heavy ion beam therapy, the surrounding normal group Compared to tissue, it is preferentially absorbed by tumors, satellite lesions, and / or intracranial metastatic lesions at higher concentrations. A suitable (generally non-toxic) composition (for example, 157 Gd and / or 10 Carry B It can be used (for example, in treatment) through the administration of the composition.

[0041] In one embodiment, the beam includes high-energy protons and / or heavy ions.

[0042] In other embodiments, this method 157 Gd and / or 10 Heat The invention provides a neutron-absorbing nuclide. The composition is preferentially absorbed by malignant target tissues. Shut up.

[0043] In further embodiments, the capture product or fragment includes energy-charged particles. The captured products or fragments may contain energy-charged particles with high relative biological efficacy. .

[0044] The present invention also provides an irradiation system to carry out any of the methods of the present invention. The present invention provides a method for controlling an irradiation system, including control of the irradiation system.

[0045] According to a fourth broad aspect of the present invention, a computer determines the parameters of particle beam therapy. A method for implementing the ter is provided. This method is A set of default or selected parameters (which may include neutron fluence determined either theoretically or empirically), based on which, a) irradiating a target volume or nuclei adjacent thereto with a beam of primary particles consisting of any one or more of (e.g., 4 He, C, O, and Si), b) generating neutrons via inelastic collisions between nuclei within or adjacent to the target volume and the primary particles, c) generating capture products or fragments released as a result of neutron capture reactions and neutron nuclear reactions between at least one agent with a large neutron cross - section (e.g., B and / or (e.g., 10 B and / or 15 7 Gd) and thermal neutrons generated from inelastic collisions between atoms within the target volume and the primary particles, and modeling or simulating (e.g., by Monte Carlo simulation) the generation (e.g., expressed in the form of total biologically effective dose), determining the difference between the generation of capture products or fragments using either (i) a predetermined template of capture products or fragments for desired generation, or (ii) empirical verification data, and generating a set of modified parameters (i.e., typically by modifying one or more of the parameters) based on the difference, including. In certain embodiments, the modeling further includes modeling the irradiation of capture products or fragments to tissue within the target volume. The tissue may be a tumor or a part thereof, one or more and so on. and so on. and so on. and so on.

[0046] In certain embodiments, the modeling further comprises modeling the irradiation of capture products or fragments to tissue within the target volume. The tissue may be a tumor or a part thereof, one or more tissues, etc., This may include (e.g., invasive) satellite lesions and / or one or more metastatic lesions.

[0047] In other embodiments, modeling involves placing a composition containing a thermal neutron-absorbing nuclide within a target volume. This further includes doing the following.

[0048] The parameters may include one or more of the following: i) Duration of irradiation, ii) Beam composition, iii) Energy of the beam particles, iv) Peak radiobiological effectiveness of beam particles, v) Physical dose deposition of beam particles, vi) composition; vii) Concentration of the composition (e.g., parts per million or ppm), viii) Spatial distribution of the composition, ix) The fluence of the generated neutrons, x) Position of the target volume relative to the beam, and xi) Ion-specific biological efficacy.

[0049] In further embodiments, this method may be used with PMMA (poly(methyl methacrylate)) and other materials. This includes modeling or simulating the target volume as a tissue equivalent. In the limbs, tissue equivalent material is, for example, a phantom that simulates bone and then muscle. Morphologically, this includes a skull phantom.

[0050] In one embodiment, empirical reaction verification data includes neutron fluence data.

[0051] This method involves selecting one or more sets of parameters from a particle beam therapy parameter library. This may include making a decision.

[0052] According to this embodiment, when executed by one or more processors, the particle beam of this embodiment Computer software configured to implement a method for determining therapeutic parameters. Software is also provided. This embodiment also includes such computer software. Provides a computer-readable medium (which may be non-temporary).

[0053] According to a fifth broad aspect of the present invention, We supply primary particles containing one or more of the following: protons, deuterons, triuterons, and heavy ions. Particle source and An accelerator that provides a particle beam by accelerating particles, An extraction beamline for extracting particle beams from the accelerator, One or more beam steering units configured to direct a particle beam, A control system that controls the irradiation system, An irradiation system including the following is provided: The control system uses irradiation programs to achieve predetermined irradiation of the target volume. Gram (typically including a set of particle beam therapy parameters) or includes or acts upon it The system is configured to perform predetermined irradiations, By irradiating a nucleus within or near the target volume with a particle beam, within or near the target volume It facilitates the production of neutrons through inelastic collisions between nuclei and particles provided in close proximity, and Furthermore, thermal neutron-absorbing nuclides provided to the target volume before irradiation (for example, large neutron cross-sections) The active agent (in the form of a neutron) absorbs neutrons produced by inelastic collisions, reaching the target volume (possibly If available, for biological purposes, it is used to capture satellite lesions, parasites, and / or metastatic lesions. To generate a product or fragment, Includes.

[0054] In this embodiment (and each of the other embodiments), the particle beam typically interacts with other matter along its path. This would facilitate the production of neutrons through such additional inelastic collisions. You can see that these neutrons, too, can, as a result, make a useful contribution to the generation of the neutron region. At the same time, it then interacts with thermal neutron-absorbing nuclides.

[0055] In one embodiment, the irradiation program or the set of parameters used therein is particularly It is adapted or individualized to a fixed target volume or subject.

[0056] In another embodiment, the irradiation system includes a beam cleaning and / or scanning element. It includes children (for example, a proportional counter and a filter).

[0057] In another embodiment, the particle source is hydrogen, helium, carbon dioxide, oxygen, or other supply gas Includes an ionizer that ionizes (and optionally decomposes) ions. However, it is clear that other suitable technologies exist and can be used effectively. It is possible. For example, an oxygen beam at a beryllium target 18 Obtained by fragmentation of O It can be separated using a fragment separator (FRS).

[0058] In one embodiment, the accelerator includes a cyclotron or a synchrotron. Accelerators provide initial acceleration to particles for use in cyclotrons or synchrotrons. It may further include a linear accelerator to supply power.

[0059] In one embodiment, the target volume includes a tumor or a portion thereof or one or more micrometastases.

[0060] According to a sixth broad aspect of the present invention, a control system for controlling an irradiation system is provided. The control system is A particle supply controller configured to control the particle source of an irradiation system, The particle source supplying the primary particles is one or more of the following: protons, deuterons, triuterons, and heavy ions. Including the above, the particle supply controller, Accelerator controller configured to control the accelerator of the irradiation system A roller that provides a particle beam by accelerating particles with an accelerator. , accelerator controller and Controlling one or more beam steering units configured to direct the particle beam The controllable beam steerer, An extraction controller that controls the extraction of accelerated particles from the accelerator, Includes, The control system uses irradiation programs to achieve predetermined irradiation of the target volume. Gram (typically including a set of particle beam therapy parameters) or includes or acts upon it The system is configured to perform predetermined irradiations, By irradiating a nucleus within or near the target volume with a particle beam, the nucleus within or near the target volume is subjected to a particle beam. This promotes the generation of neutrons through inelastic collisions between nearby nuclei and particles, thereby irradiating Previously, target volume (if possible, for biological applications, satellite lesions, parasites, and / or metastatic diseases) The thermal neutron-absorbing nuclide provided to the target absorbs neutrons produced in the inelastic collision, and the target To generate capture products or fragments that are irradiated onto the product, Includes.

[0061] The system uses a standard set of accelerator parameters and subject data (for example). A therapeutic device configured to determine the irradiation program based on the subject's medical images, etc. It may include a picture system (TPS).

[0062] The system positions the target volume relative to the particle beam provided by the irradiation system. The position and / or orientation of the subject's couch are changed once or twice to deliver the predetermined irradiation. It may further include a couch controller for overhead control.

[0063] In another embodiment, the present invention implements one of the methods of the first, second, and third embodiments. The present invention provides a method for controlling an irradiation system, which includes controlling the irradiation system in order to achieve this.

[0064] This specification includes various individual features and claims of each of the above embodiments of the present invention. The various individual features of the embodiments described can be suitably combined as desired. It should be noted that, in addition, the multiple components disclosed in the embodiments of this disclosure can be appropriately combined. By combining these, various embodiments can be provided. For example, from the disclosed embodiments... Several components can be removed. Furthermore, components from different embodiments can be appropriately combined.

[0065] Next, to better confirm the present invention, an embodiment is shown with reference to the attached drawings as an example. Explain the state. [Brief explanation of the drawing]

[0066] [Figure 1A] This is a schematic diagram of an irradiation system according to one embodiment of the present invention. [Figure 1B] Figure 1A is a schematic diagram of a patient lying on a couch in the irradiation system, where a beam of particles generated by the irradiation system is irradiated onto the tumor. [Figure 2] Figure 1A is a schematic diagram of the control system for the irradiation system. [Figure 3]This is a schematic diagram of the simulation configuration used to estimate the thermal neutron fluence and spectrum in Example 1. [Figures 4A-4F] This plot shows the thermal neutron fluence (expressed as neutrons / unit area / primary particle and / gray delivery dose) as a function of depth, obtained by irradiating a PMMA phantom with beams of single-energy protons, 12C, and 16O. [Figures 5A-5C] This is a three-dimensional visualization of the thermal neutron distribution obtained by irradiating a PMMA phantom with single-energy proton beams of 132 MeV / μ, 153 MeV / μ, and 182 MeV / μ, normalized by primary particles. [Figures 6A-6F] This is a two-dimensional thermal neutron fluence map shown on the XY and XZ planes where the incident beam and the point of maximum fluence intersect, corresponding to the three-dimensional visualizations in Figures 5A-5C. [Figure 7A-7C] This is a three-dimensional visualization of the thermal neutron distribution obtained by irradiating a PMMA phantom with single-energy 12C beams of 250 MeV / μ, 290 MeV / μ, and 350 MeV / μ, normalized by primary particles. [Figures 8A-8F] This is a two-dimensional thermal neutron fluence map shown on the XY and XZ planes where the incident beam and the point of maximum fluence intersect, corresponding to the three-dimensional visualizations in Figures 7A-7C. [Figures 9A-9F] This plot shows the thermal neutron fluence (expressed as neutrons / unit area / primary particle and / gray delivery dose) as a function of depth, obtained by irradiating a skull phantom with beams of single-energy protons, ¹²C, and ¹⁶O. [Figure 10] This is a diagram of the simulation configuration used to estimate the pencil beam thermal neutron fluence in Example 2. [Figure 11A-11D]This is a plot of the dose distribution obtained from 1 GyE carbon ion beam therapy in a volume of 50 mm × 50 mm × 50 mm (discrete beam energy in the range of 240-300 MeV / u with a depth of 100-150 mm and a step of 6 MeV / u). Figure 11A is the SOBP fit (along the YZ plane), Figure 11B is the total volume rendering of the dose distribution, Figure 11C is the center slice (XY plane), and Figure 11D is the center slice (YZ plane). [Figures 12A-12F] This is a plot of normalized neutron fluence obtained from irradiation of a target volume of 100-150 mm, where the contour lines represent fluence as a percentage of the maximum value in the slice (shading in the 3D figure indicates absolute fluence). Figure 12A is a plot in the XY plane (protons), Figure 12B is a plot in the XY plane (carbon), Figure 12C is a plot in the YZ plane (protons), Figure 12D is a plot in the YZ plane (carbon), Figure 12E is a 3D plot (protons), and Figure 12F is a 3D plot (carbon). [Figure 13] This is a diagram of an experimental setup used to test a specific embodiment of the present invention. [Figure 14] This is a plot of T98G cell line (2 flasks) proliferation over one week after irradiation with 3 Gy of carbon ions. [Figure 15] This is a plot of T98G cell line proliferation over one week, incubated with 10B-BPA (black) and 157Gd-DOTA-TPP (gray) and irradiated with 3 Gy of carbon ions. [Figure 16] This is a plot of T98G cell line (2 flasks) proliferation over one week after irradiation with 3 Gy of helium ions. [Figure 17] This is a plot of T98G cell line proliferation over one week, incubated with 10B-BPA (black) and 157Gd-DOTA-TPP (gray) and irradiated with 3 Gy of helium ions. [Figures 18A-18D] This is a plot of T98G cell line proliferation versus time after irradiation (hr) for up to 7 days after irradiation of cells irradiated with a carbon beam at 9 dose values. [Figures 19A-19D] This is a plot of T98G cell line proliferation versus time after irradiation (hr) up to 7 days (168 hours) after irradiation of cells irradiated with a total of 9 helium beam dose values ​​(i.e., 0-5 Gy). [Figures 20A-20D] Each of these presents the same data as in Figures 19A to 19D, but applied to an exponential growth model. [Modes for carrying out the invention]

[0067] Figure 1A is a schematic diagram of an irradiation system 10 according to one embodiment of the present invention. 10, for example, supplies and ionizes hydrogen, helium, carbon dioxide, or oxygen (place (Including decomposition as required), these are protons, deuterons, triprotons, alpha particles, and carbon iodine, respectively. System 10 includes a gas supply unit 12 that generates a particle beam of ions and / or oxygen ions. It also includes a linear accelerator 14 that provides initial acceleration to the particles, and a linear accelerator A synchrotron that receives particles from Tar-14 and further accelerates particles to the desired energy level. Includes accelerator 16.

[0068] System 10 includes one or more treatment rooms 20 (each including a patient couch or gurney 22). The system includes an extraction beamline 18 that delivers an accelerating beam of desired primary particles. 0 includes a gantry 24 at the tip of the beamline 18. The gantry 24 is mechanically supported A support structure, a drive mechanism, magnets (i.e., dipoles and quadrupoles), a vacuum vessel, and The point where the flume emerges (consisting of the component between the final deflection magnet and the exit window to the patient) Includes a treatment nozzle 26.

[0069] The patient on the couch 22 is transported by the gantry 24 and exits the treatment nozzle 26 with a beam. The target tissue is positioned to receive the particles. Penetration depth of primary particles in the patient. This controls the beam energy and shape to bring the Bragg peak of the beam to the desired target as required. It is controlled to be positioned relative to (and within) a given volume.

[0070] The beam emitted from the treatment nozzle 26 is, for example, used in spot scanning, uniform Scanning method, high-speed scanning method, raster scanning method, and / or scattering Depending on the method, it may be possible to control the irradiation of the target volume in any desired pattern. In the embodiment described above, the beam is raster-scanned as a spot in a successive plane within the target volume. (The plane is perpendicular to the beam direction.)

[0071] System 10 also has a gas supply unit 12 (hydrogen supplied by the gas supply unit 12, helium (including ionizers that ionize gases such as ions or carbon dioxide), linear accelerator Including the meter 14, synchrotron accelerator 16, and extraction beamline 18 Furthermore, in order to control the aforementioned components of system 10, and also the position of couch 22 and includes a user-controllable control system 28 for controlling the orientation. A console (not shown) that can be used to operate the control system 28 is located in each treatment room. 20 and / or the control system 28 itself may be located there. The control system 28 is generally, Data stored in or accessible by the control system 28, and applicable to a specific patient. Possible parameters (for example, patient digitization X-ray computed tomography or (Proton tomography) and past treatments, experiments, and modeling / simulations One or more treatments established before the start of treatment based on parameters obtained from the data. The system 10 is controlled by referring to a program. Such parameters are typically, The form of the control parameters or setpoints used by the control system 28 throughout the entire firing time. That is the case.

[0072] The irradiation system 10 also includes multiple beam stations configured to direct the particle beam. Includes an a-ring unit (not shown).

[0073] The control system 28 is configured to control the particle source (i.e., the gas supply unit 12). Particle supply controller, linear accelerator 14 and synchrotron accelerator Configure to control motor 16 (including controlling the average energy of the particle beam) The accelerator controller and one or more beams that direct the particle beam Tearing unit (including magnets) and acceleration from synchrotron accelerator 16 Includes an extraction controller that controls the extraction of particles. Delivering a uniform therapeutic dose to a target volume. They are passively formed (i.e., by placing ridge filters in the beam path). Alternatively, you can "paint" the treatment volume using a single energy beam for each slice. It is provided by either dynamically delivered or expanded Bragg peaks. Depth is provided by By tuning the energy of the frame and the Bragg peak on the target slice, The beam is controlled by its positioning, while the beam uses the magnets of the beam steering unit. It is steered along the x and y axes.

[0074] Therefore, the control system 28 preferably (in this embodiment) uses spot scanning. Flat biological delivery to the target volume via raster scanning, raster scanning, or passive scattering. The control system 28 enables the delivery of the desired irradiation program to deliver the dose. Furthermore, it can be used, for example, to plan irradiation programs involving irradiation of a phantom. Furthermore, the irradiation program can also be created by simulating the desired irradiation.

[0075] Figure 1B shows a patient lying on a couch 22 with a beam 34 generated by system 10 directed at tumor 3. This is a schematic diagram of patient 30 being irradiated with 2.

[0076] When used, a certain dose of a thermal neutron-absorbing nuclide, such as tumor 32, is preferentially absorbed. 157 Gd and / or 10 A composition containing B is administered to the patient. Then the tumor 32 The target volume contains a desired scan pattern, depth, duration, beam energy, etc. A beam 34 of primary particles (i.e., protons, helium, carbon ions, etc.) is irradiated. (According to a previously established treatment program). This involves couch 2 between or during irradiation. 2. This may include moving the target volume. However, patient movement may involve a time delay. This could lead to the introduction of large target volume misalignment and positioning errors. Because it may cause problems, it is generally kept to a minimum, and in most cases, instead, The Stream 24 (or the particle transport line supported by it) is centered around an axis (or multiple axes). It is rotated.

[0077] During irradiation, some of the primary particles in the beam 34 undergo inelastic collisions with nuclei within the tumor 32. As a result, a series of nuclear flare-like particles and neutrons, including short-range, high-LET charged particles, are emitted from the collision point. A condensation is generated at the target site, and its energy is transferred to the region around the path of the incident primary beam 34. Energy is deposited [10, 11]. Neutrons are then used to absorb the thermal neutrons of the administered composition. It has the potential to generate energy-charged particles that are absorbed by radionuclides and possess high relative biological efficacy. It seems possible.

[0078] Figure 2 is a more detailed schematic diagram of the control system 28 of the irradiation system 10. M28 is typically an irradiation system 1 controlled by or from the control system 28. A computer (or other computing device) that communicates with component 0. This will be realized.

[0079] The control system 28 simulates the method implemented by the irradiation system 10 and This combines the generation and verification of irradiation parameters with the control of the irradiation system 10. It should be clear that these can be implemented individually. For example, the offline operation of this method Since it is desirable to implement simulations, similarly, the irradiation parameters are measured offline. The generator was generated and verified, and the obtained parameters were loaded into the control system 28. If Risa doesn't have it, we could make it accessible to her.

[0080] Referring to Figure 2, the control system 28 includes a processor 40 and a memory 42. The processor 40 includes a display controller 44, a treatment planning system 46, and Monte Carlo Simulator 48, Comparison Module 50, Parameter Determiner 52, Particle Supply controller 54, accelerator controller 56, beam steerer 58 It implements several components, including the extraction controller 60.

[0081] For clarity, other standard components (e.g., user interface, I / You can see that things like the O bus have been omitted.

[0082] The display controller 44 is the user interface of the control system 28. Controls the display of parameters, images, and control panels on a display (not shown). Control. The treatment planning system 46 uses standard irradiation parameters adapted to the irradiation system 10. - Desired biological effective dose distribution for tissue (e.g., tumor), empirical model (even (Phantom simulations and experiments), and subject data (specific subject or patient data). Specific to, and therefore typically CT / MR data or other medical imaging It is configured to receive data (including data) and generate a specific irradiation or treatment program. The Monte Carlo Simulator 48 includes simulating the associated Phantom. Furthermore, for the purpose of evaluating the proposed irradiation plan and creating a new irradiation plan, the irradiation system 10 It is adapted to simulate the irradiation provided by [the system / source].

[0083] The comparison module 50, in particular, compares the obtained total biological effective dose distribution. Using a specific irradiation or treatment program output by the treatment planning system 46, Monte It is configured to compare irradiation plans simulated by the Carlo Simulator 48. The Monte Carlo simulator 48 also uses relevant subject data. The results are para Provided to the meter determinationr 52, this is the simulation result and the desired irradiation and According to some difference between them, the parameters used by the Monte Carlo simulator 48 Modify or refine the data and generate new or modified parameters that are adapted so that the simulation better matches the desired irradiation (a procedure that can be performed incrementally / repeatedly).

[0084] The particle supply controller 54 is configured to control the source 45 of the irradiation system 10, the accelerator controller 56 is configured to control the accelerator 16 (including the linear accelerator 14) of the irradiation system 10, the beam steerer 58 is configured to control one or more beam steering units of the irradiation system 10, and the extraction controller 60 is configured to control the extraction of the accelerated particles from the accelerator 16.

[0085] The memory 42, in this example, includes neutron fluence data 66, an electromagnetic interaction model 68 used by the Monte Carlo simulator 48 when modeling electromagnetic interactions, and empirical reaction verification data in the form of a hadron physics model 70 used by the Monte Carlo simulator 48 when modeling radioactive decay, particle decay, hadron elastic collisions, ion inelastic collisions, neutron capture, neutron inelastic collisions, and proton inelastic collisions.

[0086] The memory 42 also, in this example, includes the duration of irradiation by the beam 34, the composition and energy of the beam 34, the peak radiobiological effectiveness of the particles of the beam 34, the physical dose deposition of the particles of the beam 34, the composition administered to the subject and its dose distribution, the fluence of neutrons generated in a specific irradiation configuration, the position of the target volume with respect to the beam 34, and the configuration of the beam 34. ​​​​​​​​​​​​​​​In the form of a particle beam therapy parameter library 72, which includes ion therapy parameters. , it stores the parameter set library.

[0087] Memory 42 also contains subject data 74 (typically) relating to one or more subjects or patients. (In medical applications, this includes image data of the subject) and in this example, one or more subjects A treatment program for a person or patient, in the form of 76, includes an irradiation program. [Examples]

[0088] Example 1 To demonstrate the feasibility of this approach, Monte Carlo techniques were used to study protons or heavy Neutron generation under ion irradiation and 10 The absorption of neutrons by a composition containing B This was muted. This is a neutrality that can be generated by typical forms of irradiation with protons or heavy ions. This was done to determine the applicable uses of neutron fluence and, consequently, its neutron fluence.

[0089] I. Materials and Methods All Monte Carlo simulations are performed using the Geant4 toolkit (version 10). The experiment was conducted using .2.p03) [23, 24]. Electromagnetic interaction was performed using standard Geant4 material Physics Option 3 Model (G4EmStandardPhysics option3) The model was created using [this method]. On the other hand, the hadron physics model used in the simulation was: They are listed in Table I.

[0090] [Table 1]

[0091] Section IB (below) describes single-energy protons with different energies.12 C, and 16 beams of O were irradiated onto a uniform poly(methyl methacrylate) phantom (PMMA) to obtain the three-dimensional distribution of the thermal neutron fluence (delivered to the Bragg peak / per primary particle and / Gy both), and in Section IC (below), how this fluence distribution can be used to calculate the increase in dose attributable to boron capture of the thermal neutrons generated will be explained.

[0092] A. Configuration of Simulation and Analysis The configuration of the Geant4 simulation and analysis is schematically outlined in 80 of Figure 3. Referring to Figure 3, protons, each having a rotationally symmetric 5 mm FWHM Gaussian beam profile, 12 C ions, and 16 single-energy beams 82 of O ions were directed perpendicular to the surface of a simulated uniform PMMA phantom 84 of 250 mm × 250 mm × 250 mm during simulation. 125 parallel neutron fluence quantization planes 86 (each 50 mm × 50 mm) were defined every 2 mm along the

[0093] path of the beam 34 within the PMMA phantom 84 perpendicular to the beam and centered on the beam axis (however, for clarity, only every 5th quantization plane is shown in Figure 3).

[0094] for the <00009x> 12 For the C beam, four reference primary beam energies were selected to obtain Bragg peak depths in PMMA ranging from 4 cm to 20 cm. Then, for the proton and 16 O beams, the beam energies were calculated so that their Bragg peaks were located at approximately the same depth. For each primary The complete set of particle-type beam energies and the corresponding Bragg peaks in each phantom. The locations are listed in Table II.

[0095] [Table 2]

[0096] The simulated phantom is made of PMMA (poly(methyl methacrylate)) and has a 250mm diameter. It is a 250mm x 250mm cube, and its physical properties are those of the National Institute of Standards and Technology (NAT). onal Institute of Standards and Technolo The data was taken from the gy)(NIST) database

[25] .

[0097] B. Estimation of thermal neutron fluence The conventional definition of neutron fluence is the number of neutrons (n / cm²) across a unit area. 2 ) However A more useful measure of fluence in this example is neutrons / unit area / primary particle or / gray. This is the delivery peak dose. This is because these do not depend on the intensity of the primary beam, This is because fluence is expressed using iontotherapy parameters. Importantly, this definition is Based on the estimated achievable tissue concentrations of boron and heavy ions, the therapeutic parameters are based on Therefore, the effect of the neutron region on the enhancement of the boron neutron capture dose can be appropriately predicted.

[0098] The thermal neutron fluence (as defined above) resulting from heavy ion irradiation of the phantom is averaged Each of the 86 surfaces was evaluated. Each of the 86 surfaces was scored with a spatial resolution of 1 mm × 1 mm. For all 86 planes, the central 5mm x 5mm area of ​​each plane and the entire 50mm x 5 The fluence was calculated across the 0mm plane.

[0099] In addition, the plane 86' closest to the Bragg peak, and the region of maximum neutron fluence, are also included. The fluence is also measured across the 5mm x 5mm region in the upper left corner of both extremes of the 86" plane passing through. The calculation was performed. The full measurements were taken at the upper left corner 88 and the center 90 of each of these planes 86', 86''. The ratio between ences was calculated to evaluate the uniformity of the neutron regions in the planes 86' and 86''.

[0100] To obtain an estimate of thermal neutron fluence / unit dose, the lines deposited on the Bragg peak are used. The quantity was also estimated. A 5mm x 5mm x 5mm sensitive volume centered on the Bragg peak was defined. The accumulated energy was scored and then converted into dose. The thermal neutron fluence / unit dose was calculated using this value.

[0101] The minimum number of primary particles to be used in the simulation was estimated using simple analysis of variance. M=50 Run(N(k)=2 k N0, N0 = 1 × 10 5 Using (as a primary particle), We conducted a series of test simulations. Each simulation within the test area, centered on the Bragg peak... The thermal neutron fluence was calculated using a simulation, and the average value and The standard deviation (SD) was calculated. Since N(k) tends to become infinite, the inter-run standard deviation was calculated. It should approach zero, and therefore the ratio of the run-to-run standard deviation to the mean is an arbitrary threshold of 5%. The experiment was repeated using gradually increasing k values ​​until the value fell below a certain threshold. The results of this analysis showed N=5×1 0 7 The incident proton and N=5×10 6 of 12 C and 16 If it is an ion of O, thermal neutron full It was suggested that this was sufficient to obtain a satisfactory estimate of fluence (99% of the estimated fluence). The probability is within ±5% of the true fluence.

[0102] C. Quantification of neutron capture dose enhancement Estimating the achievable overall boost in biological dose in the therapeutic area to enhance neutron capture. To evaluate the feasibility and potential benefits of particle beam therapy, a simple treatment plan was implemented and promoted. The defined thermal neutron fluence (n / cm²) 2 ( / Gy) total thermal neutrons generated within the treatment volume Number (N th ) converted. In realizing this software, multiple Pristine Blackp Simulate the expanded Bragg peak as a superposition of several single-energy beams. Using the results of the simulated neutron fluence score, we estimate the corresponding neutron fluence. It was decided.

[0103] Two cubes, 50m in diameter, centered at depths of 125mm and 175mm along the beam axis. A target volume of m × 50 mm × 50 mm was defined within the phantom. Each target volume was 5 mm thick. By dividing it into a series of 10 slices, and then further dividing it into a 10x10 grid, A total of 1000 5mm x 5mm x 5mm voxels were obtained. The therapeutic dose was delivered for each slice. Once the planned particle dose was achieved in each voxel, the beam was leveled to the next voxel. I moved the row.

[0104] After irradiation of each slice, the depth of the Bragg peak is reduced for treatment of the next slice. The beam energy was varied accordingly. The process was repeated until the entire target volume was treated. I repeated it. To simplify things, the plan is to show the build-up portion of the particle dose deposition profile. The dose obtained from this was not taken into consideration. This is essential for designing a true treatment plan, however For the purpose of determining the feasibility of the proposed scheme, all energy is directed towards Bragg. It is sufficient to assume that it will be delivered at the peak.

[0105] With the planned treatment dose, the beam covers the entire planned location within the target volume. Since it is stepped, the planned physical dose at each position is multiplied to obtain the fluence / gray. n / cm 2 By taking the sum of ( / Gy), the total number of thermal neutrons in each voxel within the target volume can be calculated. I evaluated it.

number

[0106] Next, by taking the sum of all thermal neutrons traversing all voxels in the target volume... , the total number of thermal neutrons (Nth) generated within the total target volume obtained from the delivery of the entire planned therapeutic dose We calculated it as follows:

number

[0107] The total absorbed dose of each voxel in the therapeutic volume is delivered by a primary beam of protons or heavy ions. Physical dose D p And the boron neutron capture reaction that occurs within the target volume ( 10 B(n,α) 7 Li Boron neutron capture dose D resulting from ) B It is the sum of and . This latter reaction is when high concentration of is Thermal neutrons are an advantageous means of depositing energy onto ion-supported tissues.[26, 27] Next, the total weighted biological dose (D w ) is the RBE of each component and the biological efficacy of the composition ( It is estimated via the incorporation of CBE and expressed as photon equivalent dose (Gy-Eq)

[28] . D w =RBE P ×D P +CBE×D B In the formula, RBE P This is the relative biological effectiveness of particle P, and D P and D B These are, These are the physical dose components (gray) of primary particles and boron neutron capture. RBE is Blackpie In the case of protons, the ratio is 1.1 (RBE). H =1.1), 3.04 (RBE) for carbon and oxygen. ion,BP ), in the expanded Bragg peak with a width of 5 cm, carbon and oxygen showed 2. 5(RBE ion ) is considered to be

[28] . CBE is 3.8 in tumor tissue. It is considered to be [22, 28].

[0108] Next, the boron physical dose was estimated using the estimated number of thermal neutrons. D B =N th ×C a ×N B In the formula, C a = 6.933 × 10 -14 teeth, 10 Neutron fluence dose conversion for reaction B Coefficient (Gy / cm 2 / ppm) and NB is 10 This is the concentration of B in parts per million.

[29]

[0109] A series of boron concentrations have already been reported in the literature. The concentration is the ratio of tumor to healthy tissue concentration. Both are listed in section III.

[0110] Boron neutron capture doses are calculated using four different concentrations. 10 Using B, protons, 12 C, and 1 6 For a photon equivalent dose of 100 Gy-Eq delivered to both target volumes by the O beam: It is calculated as follows.

[0111] [Table 3]

[0112] 4 He is a suitable heavy ion, as are the radioactive isotopes of other heavy ions considered herein. It is expected that deuterium and tritium are also suitable for several applications. Ions heavier than oxygen reach their maximum RBE before their maximum dose deposition point (BP). Since it has been shown that 16O and lighter ions are not suitable for use in therapy, stomach.

[0113] II. Results A. Neutron flux Figures 4A-4F show single-energy protons. 12 C, and 16 Each Io against the beam of O Simulated using different types of beams at each of the four beam energies on PMMA Phantom 84. The thermal neutron fluence is plotted as a function of depth. In Figures 4A to 4F, the fluence is shown. The unit is expressed as neutrons / square centimeter / primary particle and / gray ion dose. The flux is a 5mm x 5mm square perpendicular to the beam and centered on the beam axis. 50 x 50 mm 2 It is averaged over the area, across the entire 50mm x 50mm plane and each plane The results, averaged only over a 5mm x 5mm area at the center of the surface, are shown as solid and dashed lines, respectively. This is expressed. For clarity, the 95% confidence interval (±2σ) is shown only at 20mm intervals. The interrun fluence variability at any given depth is distributed almost normally. The position is represented as a solid vertical marker attached to the horizontal axis, and its width corresponds to the width of the corresponding f It coincides with the Luens-depth curve.

[0114] Figures 5A-5C show 132 MeV / u (i.e., MeV / nucleon), 153 MeV / u, and P The three-dimensional distribution of thermal neutrons generated within MMA Phantom 84 is shown, normalized by primary particles. In Figures 5A-5C, the incident beam is shown as a white cylindrical region and terminates at the Bragg peak. End. (Note: The beam profile is actually a Gaussian type with a 5mm FWHM.) .)

[0115] Figures 6A-6F show the XY and XZ planes intersecting the incident beam and the point of maximum fluence. The corresponding two-dimensional fluence contour plots estimated across parallel slices are shown.

[0116] Figures 7A-7C show single samples of 250 MeV / u, 290 MeV / u, and 350 MeV / u. For carbon with energy beam energy, equivalent three within PMMA phantom 84 The dimensional thermal neutron distribution is shown normalized by the primary particle. In this case as well, the incident beam is represented by the white cylindrical region. It is shown as a region and terminates at the Bragg peak. (Note: The beam profile is actually 5 It is a Gaussian type with an FWHM of mm. )Figures 8A-8F show the incident beam and The corresponding two-dimensional fluence shown in the XY and XZ planes intersecting the point of maximum fluence. Show the map.

[0117] Figures 9A-9F show single-energy protons. 12 C, and 16 Each Io against the beam of O Thermal neutrons simulated in a skull phantom at each of the four beam energies using different types of thermal neutrons. The fluence is plotted as a function of depth.

[0118] The skull phantom measures 250 x 250 x 10 mm. 3 The bone and 250 x 250 x 240 mm 3 The material composition was simulated as including muscle. The material composition was determined by the National Institute of Standards and Technology (Na tional Institute of Standards and Techno Based on organizational models adopted from the (NIST) database.

[0119] Similar to Figures 4A-4F, in Figures 9A-9F, the fluence is neutrons / cm². Expressed in units of meter / primary particle and / gray ion dose. The flux is applied to the beam. Vertical, square 5mm x 5mm and 50mm x 50mm centered on the beam axis 2 In the area It is averaged across the entire 50mm x 50mm plane and in the central 5mm x 5mm area of ​​each plane. The averaged results across the specified range are shown as solid and dashed lines, respectively. For clarity: The 95% confidence interval (±2σ) is shown only at 20mm intervals, and for any given run of depth Inter-frequency fluence fluctuations are also distributed almost normally. The position of each Bragg peak is indicated on the horizontal axis. It is represented as a solid vertical marker, and its width matches the corresponding fluence-depth curve. do.

[0120] B. Quantification of neutron capture dose enhancement Using the estimated thermal neutron fluence value / gray, the experimental results obtained from boron neutron capture The additional biologically effective dose deposited in the target volume was evaluated. (e.g., 100 Gy-Eq photons) The physical dose required to achieve the valence dose is 90.91 Gy for protons and 90.91 Gy for carbon and oxygen. Both values ​​are 40 Gy. The conversion coefficient C is listed in Table III along with the tumor boron concentration. a = 6.933 × 10 -14 And, specific physical doses and estimated thermal neutron fluence / Gray By combining (i) and (ii), the dose boost was estimated, and all ion species and the evaluated boron concentration were... The values ​​for each degree are listed in Table VIII (below).

[0121] III. Discussion For each of the simulated energies of all three ion species, the estimated thermal neutron full Ens has defined two 50mm x 50mm x 50mm targets within the PMMA phantom. An axis passing through both the Bragg peak (Table IV) and the point of maximum neutron fluence (Table V) within the volume. The cross-section differs by less than 11% from the center to the corner.

[0122] [Table 4]

[0123] [Table 5]

[0124] Similarly, for each of the simulated energies of all three ion species, the estimated thermal The stron fluence is defined within the cranial phantom by two 50mm x 50mm x 50mm Both the Bragg peak (Table VI) and the point of maximum neutron fluence (Table VII) within the target volume In this case as well, the difference from the center to the corner of the axial cross-section passing through it is less than 11%.

[0125] [Table 6]

[0126] [Table 7]

[0127] The gradient of thermal neutron fluence with respect to depth along the beam axis is the beam energy It depends on the energy of the primary particle and increases near the Bragg peak as the primary particle energy increases. Furthermore, the distance between the plane of maximum thermal neutron fluence and the Bragg peak is the distance of the primary particle. It increases with increasing energy. Therefore, a series of beam energies (and consequently the Z direction) In a typical treatment plan, which would include the depth of movement and horizontal and vertical steps (in the XY plane), The total thermal neutron fluence integrates to create a virtually uniform neutron region within the therapeutic volume. It will generate.

[0128] The neutron fluence / unit absorbed physical dose is based on the tissue boron concentration already reported in the literature. In this case, by executing a typical treatment plan, the proton beam reaches 20-40 degrees within the target volume. An increase in total biologically effective dose of approximately % and 6-12% for carbon and oxygen ion beams. It is the quantity that makes strength possible.

[0129] [Table 8]

[0130] For each of the reported boron concentrations, assuming a CBE coefficient of 1.3 for normal brain tissue: It is possible to estimate the additional dose in adjacent normal tissue using the tumor-to-normal tissue ratio. [33, 34]. Highest concentration of boron (174 ppm) and lowest intratumor: boron in healthy tissue. In terms of concentration ratio, the dose of a 100 Gy-Eq proton beam delivered to the treatment volume depends on the presence of boron. This will likely induce a maximum additional dose of 4.8 Gy-Eq in the surrounding tissue (to the therapeutic volume). (For a dose boost of 42.48 Gy-Eq). 12 C and 16 The corresponding value of O is, For dose boosts of 11.79 Gy-Eq and 9.72 Gy-Eq, respectively, the difference is 1.3 The values ​​are Gy-Eq and 1.1 Gy-Eq. For comparison, BNCT for glioblastoma multiforme. The treatment plan typically involves delivering 8-14 Gy-Eq of pulsed radiotherapy to normal brain tissue over 2-3 fractions. Deliver a dose.

[33]

[0131] Recent literature suggests that heavy ion radiotherapy should be performed using fractional irradiation (only 1-2 fraction irradiation). It is recommended that [6, 35-37] be done once or twice. Since it may or may not be necessary, add the step of injecting boron-carrying agent to the treatment process. This minimizes the burden on the patient.

[0132] The main obstacle to the widespread adoption of boron neutron capture therapy has always been Therefore, the availability of a suitable epithermal neutron source is more important than the availability of a suitable pharmaceutical agent for boron delivery. It has recently been observed that it is a proton or deuterated a

[38] . Embodiments of the present invention involve any proton or deuterated a On-site treatment facilities can also provide novel thermal neutron sources located at the treatment site within the patient's own body as needed. Possesses potential. Development of new drugs and delivery methods supported by boron and gadolinium. With further progress in mind, if tumor specificity and potentially achievable tissue concentrations are increased... It is anticipated that even greater dose increases will be achievable in the future.

[0133] Example 2 In further embodiments, a similar set of simulations was performed. Significance was demonstrated by neutron capture. The photon equivalent dose within tumors obtained from a non-toxic bolus administration of the targeting agent increases by an average of 10%. This can be arbitrarily defined as (however, regardless of which desired dose increase factor is used, this implementation (It is assumed that the method of form can be used). To do so, a simple simulation is In the proton / heavy ion therapy plan, it is necessary to provide a 10% increase in the effective photon equivalent dose. The concentration of the neutron-capturing agent is determined and compared with the concentration reported in the literature.

[0134] The first step involves obtaining the neutron fluence from irradiating a point within the target volume with a pencil beam. The objective is to evaluate the protons and 12 Both beams of C In contrast, a set of such pencil beam simulations was performed on a uniform PMMA target. The dose and neutron fluence distributions were recorded in each simulation, and these energies By interpolating between the distributions obtained, the corresponding energy distributions between them can also be estimated. Then, a series of pencil beams of different energies traverse an array of points within the treatment volume. A simple treatment plan was implemented, involving cutting and stepping. Then, the defined treatment volume was used... To ensure that a nearly flat biological effective dose (BED) is delivered by the ion beam, each E The primary particle fluence is weighted by energy, with one centered at a depth of 125 mm and two The eyes are centered at a depth of 165mm and consist of two 50mm 3 The volume was evaluated. Next, the primary particles Based on fluence weighting, the neutron fluence distribution is estimated and crosses the total treatment volume in each case. The sum was taken. Based on the neutron fluence estimate obtained through this process, the dose To determine the concentration required for a 10% increase, additional neutron capture dose / unit primary Proton / heavy ion dose / unit 10 The B-BPA concentration was estimated.

[0135] A. Pencil beam simulation Figure 10 shows the simulation used in this example to estimate the thermal neutron fluence of the pencil beam. This is a diagram of the configuration. In this case as well, the same number of incident protons and 12 Using C ions, on the other hand, in this place The hadron physics models used in the simulations are listed in Table I, and also include protons and 12 The entire set of C ion beam energies and the Bragg peak within each phantom The corresponding positions are listed in Table II.

[0136] Pencil beam physical dose and neutron fluence for each beam type and energy The fabric was obtained (see Table II) and normalized with primary particles. The beam energy was not simulated. To estimate the distribution of energy dose and neutron fluence (at all intermediate energies) Since performing the simulation would incur actual computational costs, an interpolation procedure was implemented. First, the position measured from the dose distribution obtained for each of the four simulated energies. The predicted position of the Bragg peak for each intermediate energy is estimated through quadratic polynomial interpolation between the intermediate energies. It was determined. Next, the Bragg peak was aligned to the highest energy simulation. To enable this, all dose and neutron simulations other than the highest energy simulations are performed. The distribution of fluence is shifted, and the distribution of intermediate energy dose and neutron fluence is also shifted. 3D spatial interpolation was performed. Finally, the 3D interpolated dose and neutron fluence distributions were obtained. The Bragg peaks for each energy were shifted back to their previously estimated positions. The results showed that for protons, the voltage was 73-182 MeV / u and 12 In C, the range is 150-350 MeV / u. Protons and energy steps of 1 MeV / u within the range 12 Estimated from the C beam The library consisted of the radioactive dose distribution and the thermal neutron fluence distribution / primary particle. This method is a recent development. Although it is only a similarity, simulations can be performed with additional energy within the target range upon request. By implementing this, the accuracy can be improved.

[0137] Next, the library of physical dose distributions deposited by the pencil beam is used for biological doses. It was converted to this. For protons, the relative biological effectiveness coefficient was assumed to be 1.1, while, 12For C, the Bragg peak is 3.0, and the inlet plateau and build-up region (most 1.5 in the region having a deposition dose of less than 60% of the maximum value, and in the intermediate region (defined as the region with a deposition dose of less than 60% of the maximum value), and 1.5 in the intermediate region. These values ​​were then considered as linearly interpolated values. Next, the biological dose distribution was used for each beam. We developed a simple treatment plan with two target volumes for the type. k-th energy (k∈ The three-dimensional dose distribution for the central pencil beam [1...K]) is shown in BED ct r,k It is represented as follows: The corresponding neutron flux is Φ ctr,k It is represented as follows.

[0138] B. Estimation of neutron capture dose enhancement This embodiment relates to determining the feasibility of this embodiment, rather than evaluating a specific treatment plan. Therefore, it is thought that this would be necessary to achieve a 10% increase in photon equivalent biological dose. To estimate the order of magnitude of the neutron capture agent concentration, a simple generic method was used with a PMMA target. A set of treatment plans was developed. For each energy level, BED and neutron fluencer were used. The top (calculated by the interpolation method already introduced) is R for each k energy. The lateral (xy) plane of the treatment volume corresponding to the Bragg peak depth for each energy up to position ×C. It steps across the surface.

number

number

number

[0139] The enhancement of biological dose obtained from the presence of neutron capture agents is described in BNCT literature as boron dose. This is the usual expression, and the following relationship: D B =Φσ NCA N NCA ×CBE It is estimated using the formula. In the formula, σNCA is the fluence kerma transformation coefficient ( 10 In B, approximately 8: 66×10 -14 and 157 In Gd, 9:27 x 10 -15 ) and NNCA is million This is the concentration of the neutron capture agent in fractional units, and the compound biological effectiveness CBE = 3.8( 10 (In the case of B-BPA) and ≈40 (DOTA157-gadolinium triphenylphosphoniul (In the case of a mu salt complex) (using the same active agent and correcting the expected Auger electron generation) (Based on research results in the field of photon activation therapy.)

[0140] In this embodiment, the target dose is set to D=1GyE, R=C=11, and the intervals between rows and columns are set to 11. Each step is 50mm with energy. 2 5 mm relative to the treatment plane (i.e., the beam) (Same as FWHM) was set. In the first treatment volume, the depth range was 100 mm to 150 mm and The second one expands to an enlarged Bragg peak (SOBP) at a depth of 140mm to 190mm. A series of energies were selected to achieve tension. The energy was in steps of 1 MeV / u. It was incremented. Therefore, each treatment volume is 50 mm 3 This is the volume of a line of 1 GyE. The quantity is delivered by an ion beam.

[0141] C. Reported neutron capture agent concentrations The selection of reported clinical and / or preclinical tissue concentrations of boron and gadolinium is as follows: These are listed in Tables III and IX, along with the concentration ratios of tumor to healthy tissue.

[0142] [Table 9]

[0143] D. Results Treatment plan and neutron fluence distribution Treatment plans were prepared for each target volume of both proton and carbon ion beams. Each energy required to achieve an average biological dose of 1 GyE across a volume The total number of primary particles was calculated, and the 3D dose distribution was also calculated. A shallower treatment volume (100 mm) was also considered. Figures 11A to 11D show the case of carbon ion irradiation (to a depth of ~150 mm).

[0144] The neutron distribution per primary particle corresponding to each energy of the treatment plan is determined for each plan. It is scaled by the number of primary particles and summed over all energies. An example of the obtained neutron fluence distribution (shown as a percentage of the maximum value) is shown in Figure 1. This is shown in sections 12A to 12F.

[0145] Maximum neutron fluence, mean neutron fluence, and minimum neutron fluence obtained within the treatment volume List the fluences in Table X.

[0146] [Table 10]

[0147] [Table 11]

[0148] [Table 12]

[0149] The results in Tables XI and XII are superior to those in Example 1 (see Table VIII), and Please note that this will replace the previous one. The ad hoc treatment plan implemented in Example 2 is each The incident dose is appropriately corrected when calculating the weighting factor of the discrete beam energy. Subsequent estimation of neutron fluence as a result of thermal neutron fragmentation and internal generation is This is a more accurate representation of what is seen in the clinical treatment plan compared to Example 1.

[0150] Required NCA concentration The amount needed to achieve a 10% increase in the biologically effective dose 10 B and 157 Gd intratumoral concentration The degrees are listed in Tables XI and XII, respectively. The CBEs of each agent are listed separately. Based on estimated values ​​from supporting publications. These estimated intratumor concentrations, reported tumors: Based on the normal tissue concentration ratio and normal tissue CBE, the maximum percentage of the normal tissue biologically effective dose The increases in points are listed in Table XIII.

[0151] [Table 13]

[0152] BPA and tumors related to BPA in the brain: healthy individuals 10 The B concentration ratios are, respectively, Bar Values ​​reported in th et al.

[14] and Koganei et al.

[32] Based on this, the value for BSH is reported in Suzuki et al.

[26] Tumor: Healthy 157 The Gd concentration ratio is considered to be 70:1, but even higher values ​​have been reported in the literature. It has been reported that normal tissue CBEs are 157 Gd system agonists are still not well known. However, we will assume here that it has the same value as in the case of a tumor (worst-case assumption).

[0153] E. Discussion By examining the intratumoral concentrations of each NCA listed in Tables XI and XII, how many This conclusion can be drawn. First, both BPA and BSH have biological efficacy in the liver. The NCA concentration required to achieve a 10% increase in volume is substantial compared to what the brain needs. Low BPA, combined with high CBE and good tumor / normal tissue contrast, is Su It appears particularly promising, as it has been reported by zuki et al.

[26] . On the other hand, 1 BSH concentrations that are expected to achieve a dose boost close to 0% have been reported in the literature. For example, Suzuki et al.

[39] found that in the liver, it accounts for approximately 6.4-7.5%. BSH + two different embolic agents are thought to provide a dose boost of 200 And levels up to 234 ppm have been reported.

[0154] The situation is somewhat worse in the brain, and a 10% increase in the biologically effective dose during proton therapy in the brain is required. What is needed to achieve 10 The B-BPA concentration is approximately 3 times the maximum concentration reported in previous literature. It seems that twice the amount would be needed, but the concentration required for carbon ion therapy was even higher.

[0155] Conversely, if we use the highest BPA concentration reported in the literature, 125 ppm, the dose The increase is approximately 3.2-3.6% in proton therapy, which is about half that of carbon. The results indicate that using a boron neutron capture agent to treat the brain according to this embodiment is possible. While not ruling it out, this demonstrates the need for further development of boron-based NCAs.

[0156] Interestingly, the pancreas, an organ notoriously difficult to treat for cancer, shows strong uptake of BPA. There are studies that report on this. Research on BNCT, which is particularly applicable to the pancreas (especially tumor-resistant (Regarding the normal NCA concentration ratio and CBE) it is thought to be very small, but in this embodiment This appears to be a good candidate.

[0157] Several promising new 10 The B-series NCA is still under development.

[30] BSH The main reason is that it cannot directly penetrate the cell membrane, which is why it is somewhat expected to be the NCA of BNCT. This is incorrect. However, we will try to combine up to 8 BSH compounds with peptide chains. Several BSH-derived compounds have been proposed, and these can permeate the membrane and introduce high concentrations of boron into the cell. It is possible to deliver boron. Boron concentrations exceeding 5000 ppm have been reported with these compounds.

[51] Other promising recent studies have shown that boron nitride nanotubes can be used as NCAs in BNCT. The use of a bu has also been investigated, and this too is very high. 10 Potentially affecting B concentration in tumors It can be delivered to

[52] .

[0158] 157 The situation is more complex in Gd. The values ​​are: 157 How to distribute Gd atoms It is highly dependent on either electrostatically binding to DNA or concentrating it in the cell nucleus. In that case, the required concentration is well within the range reported in the literature, and gadolinium is in the cytoplasm. Or this is maintained even when outside the cell membrane. Gadoliniumization is currently under development. Some of the compounds exhibit highly selective tumor uptake, particularly high uptake into the nucleus and mitochondria. Since uptake is observed, it is thought to possess many very promising properties and is most suitable for neutron capture therapy. It is also effective. Importantly, many of the gadolinium compounds developed recently are very This is thought to provide a high tumor-to-normal tissue concentration ratio.

[0159] The required intratumoral concentrations and boron (up to 231 ppm in the liver

[26] ) obtained in this study were also found. Both gadolinium (up to 3000 ppm in vitro

[45] ) have been used to date. By comparing with the published values, it can be concluded that for some agonists and some target tissues , achieving an increase of at least 10% in the biologically effective dose (or synonymously, external radiation dose) It has been shown that efforts should be made to reduce the amount of disease and, consequently, the probability of complications in normal tissues. To be tempted.

[0160] In addition, there is also the possibility of further increasing the neutron yield of heavy ion beam therapy. Neutron generation within a product is typically considered a nuance rather than a central issue. Research aimed at identifying specific primary species that produce high thermal neutron generation rates in human tissue targets is They are almost nonexistent. We have relatively neutron-rich elements such as deuterium and helium. The primary ion species increase the thermal neutron yield, and consequently, either protons or carbon ions are used. We hypothesize that thermal neutron capture provides a greater dose boost than is possible otherwise. This is currently the subject of further research, and the results will be reported in future studies. It will become.

[0161] Regarding the additional dose introduced into healthy tissue obtained from the realization of this embodiment, most In the proposed NCA, the dose increase is extremely relative to the dose boost delivered to the tumor. Table XIII shows that it is small (in the liver, the tumor:normal tissue contrast ratio is (Since the value is relatively low at 0.3, the worst-case scenario is BSH). Primary tumor If the on-dose is 70 GyE (typically delivered over several fractions), BPA If the concentration is sufficient to provide an additional 7 Gy tumor dose via NCEPT, The additional normal tissue dose (at the periphery of the treatment volume) was 0.47 GyE in the brain and 1.1 G in the liver. It is likely to be yE (1.8 GyE and 5.2 GyE in the brain and liver, respectively, using BSH). (E is obtained). In comparison, the BNCT treatment plan for glioblastoma multiforme is typically The treatment delivers a peak dose of 8–14 GyE to normal brain tissue over two or three fractions.

[33] .

[0162] One of the limitations that may arise in this embodiment is the need to divide the delivery of the therapeutic dose, This requires the use of NCA with a long residence time or repeated injection of NCA. It will result in either this or that. However, recent literature suggests that fractional irradiation (1 Heavy ion radiotherapy using (only 2-fraction irradiation) is recommended [6, 35-37]. From a practical standpoint, this may only need to be done once or twice. Therefore, by adding a boron-carrying agent injection step to the treatment process, the burden on the patient is minimized. It can be kept down to that.

[0163] As a final finding regarding the practicality of this embodiment, the main reason for widely adopting neutron capture therapy is The obstacle is not the availability of suitable NCAs, but the limited supply of suitable epithermal neutron sources. It is possible to treat patients in any proton or heavy ion therapy facility.

[38] It has the potential to appropriately provide a new thermal neutron source located at the treatment site within the user's own body. In anticipation of further advancements in the development of new NCAs, tumor specificity and potentially achievable tumors If the internal concentration is increased, and if combined with ultrasound or other methods of enhancing uptake, It is anticipated that even greater dose increases will be achievable in the future.

[0164] F. Conclusion In this example, thermal neutron fluence obtained from proton therapy and carbon ion therapy The fabric mainly originates near the Bragg peak (i.e., from a point within the treatment volume), and all The neutron fluence decreases as the distance from the Bragg peak increases in that direction. To demonstrate, the fluence distribution obtained from realistic treatment plans is larger than those already reported in the literature. This is sufficient to allow for a significant increase of about 10% in realistic NCA concentration. The dose increase obtained in the tissue is extremely modest and does not pose a potential risk of causing additional harm to the patient. It is considered to be low.

[0165] Example 3 The approach of the above-described embodiment was experimentally tested. To quantify the effective increase in physical dose, a series of proof-of-concept experiments were conducted at the HIMAC facility in Japan. The procedure was carried out. Cultured T98-G cancer cells were attached to the inner surface of a T25 cell culture flask, and neutral Carbon and helium ion beams were irradiated in the presence or absence of realistic concentrations of the bait trap. .

[0166] Three freeze vials of T98G (JCRB9041, human glioblastoma multiforme) cell lineage The National Institute of Biomedical Innovation, Health and Nutrition al Innovation,Health and Nutrition)JCRB details We purchased the cells from a cell bank and used them throughout the entire experiment.

[0167] Before starting the experiment, the cells were revived, passed through twice, and then placed in 5 mL of complete growth medium (DMEM). Seeds were sown in 160 T25 flasks containing (+10% FBS) under a 5±1% CO2 atmosphere. The flask was incubated at 37±1℃ using gas.

[0168] In the experiment, the 60mm magnified Bragg peak (SOBP60) spectrum and 1 Gy / mi were obtained. n has an approximate dose rate 12 C and 4 He beam was used. Cell viability was among the two types. Sperm-capturing agents, that is, 10 B. Enriched 4-Borono-L-phenylalanine ( 10 B- BPA) and 2,2',2''-(10-(4-(((triphenylphosphonio)methyl )benzyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl) Triacetatogadolinium(III) trifluoroacetate (157Gd-DOTA- T98-G human glioblastoma cells cultured in the presence or absence of TPP salt complexes It was measured as a function of beam dose.

[0169] Combined with a PMMA container to hold two flasks, it measures 300 x 300 x 10 m. m 3 A set of PMMA slabs was used. This arrangement is schematically shown in Figure 13. A 300x cube in a plane perpendicular to the incident beam at a depth corresponding to the midpoint of SOBP60. 300 x 300 mm 3 A flask containing cell cultures is placed inside the PMMA phantom. It was placed. For illustrative purposes, the predictions made by Monte Carlo simulation in Example 2 were The neutron fluence is overlaid on this diagram. The ion beams are 29 each. Average energy of 0 MeV / u and 150 MeV / u (approximately 8-14 cm of SO in PMMA) 100 x 100 mm (corresponding to BP depth range) 2 (Width x Height) and SOBP60 Dimensions of the energy spectrum 12 C and 4 It was He's beam.

[0170] In vitro measurement We conducted a four-night irradiation campaign at the HIMAC Biological Beamline (with helium). Ion beam irradiation was performed on the second and fourth nights, and carbon ion beam irradiation was performed on the first and fourth nights. (Implemented over 3 nights). The concentration of insects each night was 80% to 90% (approximately 3.75 x 10⁻¹⁰).5 Cells / Flasks Forty flasks were irradiated with (corresponding to). 24 hours before each irradiation, 10 flasks were... 500 μM 10 Incubate with B-BPA, while in the second of 10 flasks Set to 500 μM 157 It was incubated with the Gd-DOTA-TPP salt complex. The remaining 20 flasks were used as controls.

[0171] During irradiation, the beam dose rate is calibrated, and the center of the Bragg peak (corresponding to the cell location) Dose depth deposition and dose rate were measured in an ionization chamber. Immediately before irradiation, the flask was completely filled. DMEM medium (approximately 30 mL / flask) was packed into the flasks. The flasks were irradiated in pairs, and neutron capture was performed. The flask containing the neutron capture agent is irradiated together, and then the corresponding control flask (neutron capture agent) is irradiated. The ion beam was irradiated with 10 different dose values, i.e., helium (which does not contain helium). Then 0, 0.9, 1.8, 2.3, 2.7, 3.2, 3.6, 4.1, 4.6, and 7. 3 Gy, and for carbon, 0, 0.6, 1.3, 1.6, 1.9, 2.2, 2.5, 2.8 3.1 and 5 Gy were used.

[0172] After irradiation, the culture medium was removed from the irradiation flask under sterile conditions. The cells were washed with 5 mL of DPBS. The DPBS was purified and removed and discarded. The cells were then trypsinized and removed from the flask. The cells were separated and resuspended in the final growth medium. Cell count and viability were recorded.

[0173] Each night, cells were populated into 16 96-well plates. Each well contained approximately 375 cells. Each set of 3 wells contains and corresponds to one flask. 8 sets of 96 wells One set of cells is a complete set of cells incubated and irradiated with a neutron capture compound. It contains (as shown in Table XIV), while the second set of 8-well plates contains The sample contained cells that had been irradiated without the use of any sperm-capturing agents (Table XV).

[0174] [Table 14]

[0175] [Table 15]

[0176] Reaction evaluation Carbon and helical were irradiated at the midpoint within SOBP60 at dose values ​​of 10 (i.e., 0-5 Gy). The dose response of cell cultures to the Um beam was initially around 18 hours after irradiation, and then 7 For 24 consecutive hours throughout the night, Lesazlin (alamarBlue), established high thru The viability of put cells was evaluated using a put cell viability assay. An automated plate reader was used to analyze each cell. By measuring the fluorescence signal from the well (proportional to the number of cells), the number of cells per well can be determined. The signal was quantified and normalized to the signal from a well containing blank medium.

[0177] Figure 14 shows T9 over one week (168 hours) after irradiation with a carbon ion beam at 3 Gy. This is a plot of 8G cell proliferation (2 flasks). Figure 15 shows 10B-BPA (black) and Carbon ion vi when incubated with 157Gd-DOTA-TPP (gray) T98G cell proliferation over one week (168 hours) after 3 Gy irradiation with a 2 flask (2 flasks) Figure 16 is a plot of the period (1 week after irradiation with a helium ion beam of 3 Gy). Figure 17 shows a plot of T98G cell proliferation (2 flasks) over 68 hours, while Figure 17 shows Incubate together with 10B-BPA (black) and 157Gd-DOTA-TPP (gray). During the week (168 hours) following 3 Gy irradiation with a carbon ion beam, the results were as follows: This is a plot of T98G cell proliferation.

[0178] Figures 18A to 18D show that a total of nine dose values ​​of carbon beam (i.e., 0 to 5 Gy) were applied. Cell proliferation (growth to a viable cell count) for up to 7 days (168 hours) after irradiation of the cells. This is a plot of the time (hr) after injection.

[0179] Figure 18A contains cells incubated with a 10B neutron capture compound before irradiation. Figure 18B shows the same dose in the absence of the neutron-capturing compound, corresponding to the flask, while Figure 18B shows the same dose in the absence of the neutron-capturing compound. This corresponds to the flask irradiated with a value (0-5 Gy). Figure 18C shows the flask at 157 Gd before irradiation. This corresponds to a flask containing cells incubated with a stron capture compound, while Figure 18D was irradiated with the same dose value (0-5 Gy) in the absence of its neutron-capturing compound. Corresponds to Lasco. Cell proliferation is incubated with neutron capture compounds before carbon beam irradiation. In a baked flask, this is substantially reduced.

[0180] Figures 19A to 19D show the irradiation of helium beams with a total of nine dose values ​​(i.e., 0 to 5 Gy). Cell proliferation (growth at a viable cell count) occurs for up to 7 days (168 hours) after irradiation of the treated cells. This is a plot of time (hr) after irradiation.

[0181] Figure 19A contains cells incubated with a 10B neutron capture compound before irradiation. Figure 19B shows the same dose in the absence of the neutron-capturing compound, corresponding to the flask, while Figure 19B shows the same dose in the absence of the neutron-capturing compound. This corresponds to the flask irradiated with a value (0-5 Gy). Figure 19C shows the flask at 157 Gd before irradiation. This corresponds to a flask containing cells incubated with a stron capture compound, while Figure 19D was irradiated with the same dose value (0-5 Gy) in the absence of its neutron-capturing compound. Corresponds to Lasco. Cell proliferation is induced with neutron capture compounds before helium beam irradiation. In a cubated flask, the effect is substantially reduced.

[0182] Figures 20A to 20D show cells irradiated with a helium beam, respectively. The same data as that of the corresponding figure is presented, but a growth model is applied. This involves cell proliferation (growth to a viable cell count) for 7 days (i.e., 168 hours) after irradiation. To give an example.

[0183] In summary, the analysis is about neutron capture agents ( 10 B-BPA and 157 Gd-DOTA-TP The introduction of the P salt complex (in the control cell culture) resulted in clear and substantial radiosensitization. The effects of all dose values ​​(in the absence of neutron capture agents) are minimized. However, 10 B and 157 Cells treated with compounds containing Gd showed a reduction of 1 / 4 to 1 / 5. This shows a reduction in the growth rate. Replicating these results in tumor-bearing animals and, consequently, in human patients, By reducing the dose delivered by the primary particle beam to a fraction of its original value, effective tumor control can be achieved. This is expected to result in complications in normal tissues and undesirable radiation exposure to decision-making organs. It is expected to result in a reduction of side effects.

[0184] These results demonstrate the effectiveness of NCPET, specifically in targeting lesions that are close to or near the target volume. This further supports additional hypotheses regarding its ability to target. In clinical particle beam therapy, the target volume Tissues in close proximity to and near the beam receive 40-60% of the dose (the latter being organs in the beam's path). (corresponding to) From the above results, when a neutron capture agent is added, a portion of the primary beam It has been demonstrated that it may affect cell viability. Highly selective neutral It is hypothesized that using a graft agent would allow for precise targeting of lethal doses at the cellular level to malignant lesions. That is the case.

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[0186] Those skilled in the art can easily modify the present invention within its scope. Therefore, the present invention is It should be understood that the embodiments described above are not the only ones that are applicable. That is the case.

[0187] The following claims and the above description of the invention contain explicit or implicit statements. Unless the context requires a different interpretation, "comprise (to include)" is used. The word "comprises" or "comprising" Derived words such as "ru" are used in a comprehensive sense. That is, they specifically refer to the existence of the specified characteristics. However, this does not preclude the existence or addition of further features in various embodiments of the present invention.

[0188] Furthermore, any reference to prior art in this specification is not necessarily related to any prior art. This is intended to suggest that it forms or has formed part of common general knowledge in the country. It is not something that can be done.

Claims

1. An irradiation method for irradiating a target volume, A thermal neutron-absorbing nuclide is placed within or near the target volume, for example, with a large neutron cross-section. To be provided in the form of an activating agent, A beam of particles consisting of one or more of the following: protons, deuterons, triprotons, and heavy ions, is used as a nucleus. To irradiate the particle and promote the generation of neutrons through inelastic collisions between the nucleus and the particle. This generates neutrons, Includes, The neutron-absorbing nuclide absorbs neutrons produced in the inelastic collision, A method for generating a capture product or fragment that is irradiated onto a target volume.

2. The claim 1 includes configuring the beam of particles to irradiate the target volume. Method of loading.

3. The beam comprises high-energy protons and / or heavy ions, as described in claim 1 or 2. method.

4. The aforementioned beam contains protons, ４ He, １０ C, １１ C, １２ C, １５ O, and / or １６ O The method according to any one of claims 1 to 3.

5. １０ B and / or １５７ The thermal neutron-absorbing nuclide is provided in the form of a composition containing Gd. The method according to any one of claims 1 to 4, including the action of

6. The composition is preferentially absorbed by malignant target tissue, according to any one of claims 1 to 5. Method of description.

7. Any of claims 1 to 6, wherein the capture product or fragment includes energy-charged particles. The method described in item 1.

8. The aforementioned capture products or fragments contain energy-charged particles with high relative biological efficacy. The method according to claim 7.

9. The beam is a spot scanning method, a uniform scanning method, a high-speed scanning method. Scanning method, raster scanning method, and / or passive scattering method along the path The method according to any one of claims 1 to 8, wherein a substance is irradiated.

10. The beam obtains the appropriate energy by a cyclotron or synchrotron. The method described in any one of the requests 1 to 9.

11. This method involves irradiating biological tissue with a beam of protons, deuterons, triuterons, or heavy ions. Therefore, the target volume including the biological tissue according to the method described in any one of claims 1 to 10. A method that includes irradiating.

12. The nucleus to which the beam of particles is irradiated is located within the subject whose target volume is located inside The claim is made that the point at which the beam accumulates its maximum energy is outside the subject. The method described in any one of items 1 to 11.

13. A method for treating a patient, wherein the patient is treated according to the method described in any one of claims 1 to 12. A method comprising irradiating a target volume of a person, wherein the target volume includes biological tissue.

14. The target volume is within the patient, and the beam reaches its maximum energy outside the patient. The method according to claim 13, wherein the material is deposited.

15. The said biological tissue is a tumor or a part thereof, one or more satellite lesions, and / or one or more The method according to any one of claims 11 to 14, including metastatic lesions.

16. The further includes applying immunotherapy in combination with or in parallel with irradiation to the aforementioned target volume. The method according to any one of claims 1 to 15.

17. A method of inhibiting the growth of one or more tumors, satellite lesions, and / or metastatic lesions. hand, A composition containing a thermal neutron-absorbing nuclide is administered to the tumor, satellite lesion, and / or metastatic lesion. That thing, Protons, deuterons in the nuclei within or adjacent to the tumor, satellite lesion, and / or intracranial lesion By irradiating with a beam of particles consisting of one or more of the following: triple protons and heavy ions and the nuclei within or adjacent to the tumor, satellite lesion, and / or metastatic lesion and the particles The generation of neutrons through inelastic collisions between them, Includes, The neutron-absorbing nuclide absorbs neutrons produced in the inelastic collision, Generates capture products or fragments that are irradiated onto the tumor, satellite lesions, and / or metastatic lesions. How to do it.

18. The method according to claim 17, wherein the beam comprises high-energy protons and / or heavy ions. Law.

19. The beam is a proton, ４ He, １０ C, １１ C, １２ C, １５ O, and / or １６ O The method according to claim 17 or 18.

20. １０ A claim comprising providing the thermal neutron-absorbing nuclide in the form of a composition containing B. The method described in any one of items 17 to 19.

21. １５７ The invention includes providing the thermal neutron-absorbing nuclide in the form of a composition containing Gd. The method described in any one of the requests 17 to 19.

22. The composition is preferentially absorbed by the tumor, satellite lesions, and / or intracranial metastatic lesions. The method according to claim 20 or 21.

23. Claims 17 to 22, wherein the capture product or fragment includes energy-charged particles. The method described in either of the above terms.

24. The aforementioned capture products or fragments contain energy-charged particles with high relative biological efficacy. The method according to claim 23.

25. The beam is a spot scanning method, a uniform scanning method, a high-speed scanning method. Scanning method, raster scanning method, and / or passive scattering method along the path A substance is irradiated, and the irradiation can subsequently be captured by the thermal neutron-absorbing nuclide. The method according to any one of claims 17 to 24, which results in the generation of offspring.

26. The target volume is within the subject, and the beam does not exceed its maximum energy outside the subject. The method according to any one of claims 17 to 25, wherein the material is deposited in a container.

27. The beam obtains the appropriate energy by a cyclotron or synchrotron. The method described in any one of the requests 17 to 26.

28. Combined with or in conjunction with irradiation of the aforementioned tumors, satellite lesions, and / or intracranial metastatic lesions. The method described in any one of claims 17 to 27 further includes applying immunotherapy. method.

29. A computer implementation method for determining the parameters of particle beam therapy, Based on the default or selected set of parameters, a) Protons, deuterons, triuterons, and heavy ions into nuclei within or near the target volume. Irradiation with a beam of primary particles consisting of one or more of the following: b) Inelastic collisions between the nucleus and the primary particle within or near the target volume Neutron generation via, and c) an agent with at least one large neutron cross-section, atoms in the target volume and the Thermal neutrons generated from inelastic collisions with primary particles, and neutron capture reactions between them and neutral The formation of capture products or fragments released as a result of the nuclear reaction, Modeling or simulating, (i) A predetermined template for the capture product or fragment (ii) Using either the desired generation or empirical verification data, the capture product or flare To determine the difference between the generation of the substance, Based on the aforementioned difference, a set of parameter modifications is generated, Methods that include...

30. The modeling involves capturing products or fragments into the tissue within the target volume. The method according to claim 29, further comprising modeling the irradiation of a light.

31. The aforementioned tissue is a tumor or a part thereof, one or more satellite lesions, and / or one or more metastases. The method according to claim 29 or 30, including transmissible lesions.

32. The aforementioned modeling involves distributing the composition containing the thermal neutron-absorbing nuclide within the target volume. The method according to any one of claims 29 to 31, further comprising placing.

33. The aforementioned parameter is, i) Duration of irradiation, ii) The composition of the beam, iii) Energy of the particles in the beam, iv) Peak radiobiological efficacy of the beam particles, v) Physical dose deposition of particles of the beam, vi) The composition, vii) The concentration of the composition, viiii) Spatial distribution of the composition, ix) The fluence of the neutrons generated, x) The position of the target volume relative to the beam, and xi) Ion-specific biological efficacy, The method according to any one of claims 29 to 32, comprising one or more of the following:

34. Claims include modeling or simulating the target volume as a tissue equivalent. The method described in any one of paragraphs 29 to 33.

35. Claim 34, wherein the tissue equivalent material includes PMMA (poly(methyl methacrylate)). Method of description.

36. If the aforementioned modeling or simulation includes Monte Carlo simulation, please The method described in any one of the requests 29 to 35.

37. The empirical reaction verification data includes neutron fluence data, according to any of claims 29 to 36. The method described in any one of the items.

38. Determine one or more sets of parameters for a particle beam therapy parameter library. The method according to any one of claims 29 to 37, including the act of

39. The nucleus to which the beam of particles is irradiated is located within the subject whose target volume is located inside The beam of such energy is positioned such that its point of maximum dose accumulation is within the target volume. Model or simulate a subject located inside a body, to be used outside of that body. The method according to any one of claims 29 to 38, including the act of

40. When executed by one or more processors, as described in any one of claims 29 to 39. A computer configured to implement a method for determining the parameters of particle beam therapy. software.

41. A computer-readable medium comprising the computer software described in claim 40.

42. We supply primary particles containing one or more of the following: protons, deuterons, triuterons, and heavy ions. Particle source and An accelerator that provides a particle beam by accelerating the aforementioned particles, An extraction beamline for extracting the particle beam from the accelerator, One or more beam steering units configured to direct the particle beam and, A control system for controlling the irradiation system, Includes, The control system, in order to achieve a predetermined irradiation of the target volume, The program is configured to include or access the program, and the predetermined The irradiation, The particle beam is irradiated onto a nucleus within or adjacent to the target volume, and within or This promotes the generation of neutrons through inelastic collisions between a nearby nucleus and the particle, and thereby Furthermore, the thermal neutron-absorbing nuclides provided to the target volume before irradiation are generated by the inelastic collision. By absorbing neutrons, the capture product or fragment is generated which is irradiated onto the target volume. and, An irradiation system, including...

43. The irradiation program or the set of parameters used therein may be used to target a specific target volume or The irradiation system according to claim 42, wherein the irradiation system is adapted or individualized to a subject.

44. The particle source ionizes hydrogen, helium, carbon dioxide, oxygen, or other supply gases. The irradiation system according to claim 42 or 43, comprising an ionizer.

45. Claims 42 to 44, wherein the accelerator includes a cyclotron or a synchrotron. An irradiation system as described in any one of the items.

46. The accelerator provides initial acceleration to the particles and the cyclotron or syn The irradiation system according to claim 45, further comprising a linear accelerator for supplying to the crotron. Stem.

47. Claims 42 to 42, wherein the target volume includes a tumor or a part thereof or one or more micrometastases. The irradiation system described in any one of item 46.

48. When the nucleus is located outside the subject in which the target volume is located, the system Any one of claims 42 to 47, which is controllable to irradiate the nucleus with a beam of the particles. The irradiation system described in item 1.

49. A control system for controlling an irradiation system, A particle supply controller configured to control the particle source of the irradiation system. The particle source that supplies the primary particles is a proton, deuteron, triuteron, or heavy ion. A particle supply controller including one or more of the following: An accelerator controller configured to control the accelerator of the irradiation system A control unit in which the accelerator accelerates the particles by making them bead The accelerator controller provides the function, One or more beam steering units configured to direct the particle beam A beam steerer that controls the beam steerer, An extraction controller that controls the extraction of accelerated particles from the accelerator, Includes, The control system, in order to achieve a predetermined irradiation of the target volume, The program is configured to include or access the program, and the predetermined The irradiation, The particle beam is irradiated onto nuclei within or adjacent to the target volume, within the target volume via inelastic collisions between a thermal neutron-absorbing nuclide provided in or near thereto and the particle This promotes the generation of neutrons, thereby providing thermal neutron absorption to the target volume before irradiation. The nuclide absorbs the neutrons produced in the inelastic collision, and the captured nuclide irradiates the target volume. To produce a product or fragment, A control system including...

50. A treatment planning system (TPS) configured to determine the aforementioned irradiation program is further configured The system according to claim 49, including.

51. The target volume is positioned relative to the particle beam provided by the irradiation system. The position and / or orientation of the subject's couch are changed once or twice to deliver the predetermined irradiation. The system according to claim 49 or 50, further comprising a couch controller for controlling the above.

52. When the nucleus is located outside the subject in which the target volume is located, the control system , controllable to achieve irradiation of the nucleus with a beam of particles, claims 49-5 A control system as described in any one of item 1.

53. Control the irradiation system to carry out the method according to any one of claims 1 to 39. A method for controlling an irradiation system, including the action of doing so.

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