JP7126733B2 - Neutron source for neutron capture therapy - Google Patents

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 61/571,406, filed June 27, 2011, filed June 25, 2012, now abandoned. U.S. Application No. 14/190, filed February 26, 2014, issued May 2, 2017 as U.S. Patent No. 9,636,524, claiming priority to U.S. Application No. 13/532,447, No. 15/488,983, filed Apr. 17, 2017, which claims priority to '389. This application also claims priority to U.S. Patent Application Serial No. 62/749,875, filed October 24, 2018.

The present invention is in the technical field of devices and methods for boron neutron capture therapy for cancer.

Boron Neutron Capture Therapy (BNCT) is not new in the art as thermal neutrons are used in cancer therapy for the destruction of cancer tumors. These neutrons interact with boron-10 located at the cancer site. Neutrons interact with boron to create fission events that create alpha particles and lithium nuclei. These large amounts of ionized particles are then released, disrupting the chemical bonds of nearby cancer tumor cells. Currently, neutrons produced in nuclear reactors or accelerators pass through moderators that shape the neutron energy spectrum suitable for BNCT treatment. During their passage through the moderator and then the patient's tissue, the neutrons are slowed down by collisions and become low-energy thermal neutrons. Thermal neutrons react with boron-10 nuclei at cancer sites to form composite nuclei (excited boron-11), which then rapidly decay into lithium-7 and alpha particles. Both alpha particles and lithium ions provide dense ionization in the immediate vicinity of the reaction, in the range of approximately 5-9 micrometers, or roughly one cell diameter thick. This release of energy destroys surrounding cancer cells. This technique is advantageous because the radiation damage occurs over a short area, thus sparing normal tissue.

Gadolinium may also be considered as a trapping agent in neutron capture therapy (NCT) because of its very high neutron trapping cross section. Several gadolinium compounds are frequently used as contrast agents for imaging brain tumors. Tumors take up most of the gadolinium, making it an excellent sequestering agent for NCT. Accordingly, GNTC may also be considered as a variant in embodiments of the present invention.

The following definitions of the neutron energy range E are those often used by those skilled in the art of producing and using neutrons for medical, commercial, and scientific applications: fast neutrons (E>1 MeV), thermal exo-neutrons (0.5 eV<E<1 Mev), and thermal neutrons (E<0.5 eV).

BNCT has the potential to treat previously untreatable cancers such as glioblastoma multiforme (GBM). Brain tumors are the second leading cause of cancer-related death in men under the age of 29 and women under the age of 20 in the United States. GBM is almost always fatal and to date there is no known effective treatment. Approximately 13,000 people die annually due to primary brain tumors.

When conventional drugs are used where glioblasts are excited, new tumors almost universally recur, often distant from the primary tumor site. Therefore, effective radiation therapy must encompass a large volume and the radiation must be evenly distributed. Conventional radiotherapy is usually too harmful to help GBM.

For distributed tumors, effective radiotherapy must encompass a large volume and the radiation must be evenly distributed. This is also the case for liver cancer. The liver is the most common target of metastases from many primary tumors. Primary and metastatic liver cancers are usually fatal, especially after resection of large numbers of individual tumors. Response rates for unresectable hepatocellular carcinoma to conventional radiotherapy or chemotherapy are also very poor. However, recent results indicate that thermal neutron irradiation of the whole liver with ¹⁰ B compounds, which become bombarded with low-energy neutrons, may be one way to destroy all liver metastases.

Recent studies in BNCT show that neutron capture therapy can be used to treat many different cancers. BNCT has been shown to be effective and safe in the treatment of inoperable, locally advanced head and neck cancers that recur in sites previously irradiated with conventional gamma radiation. Therefore, BNCT can be considered for a wide range of cancers. BNCT is so promising because the dose to the cancer site can be greatly enhanced over that produced by γ-radiation sources. This is a result of the fact that neutron-boron reactions produce short-range (5-9 um distance) radiation emissions, and as a result normal tissue can be spared. In addition, boron can achieve tumor-to-brain enrichment ratios as high as 10 or more, thereby preferentially destroying abnormal tissue.

BNCTs have been tested using either nuclear reactors or accelerators to produce neutrons, which are not practical or available in most clinical settings. Nuclear reactors also do not produce ideal neutron spectra and are contaminated with gamma radiation.

Fusion generators produce fast neutrons from deuterium-deuterium (DD) or deuterium-tritium (DT) reactions and are generally smaller and cheaper than accelerators and nuclear reactors. The fast neutrons thus produced must be moderated or slowed down to thermal or epithermal neutron energy using, for example, water or other hydrogen bearing materials.

A fusion neutron generator has an acceleration structure with three basic components: an ion source, an electron shield, and a target. Ions are accelerated from the ion source, typically to a titanium target, using high potential differences of 40 kV to 200 kV, which can be easily delivered by modern high voltage power supplies. An electronic shield is typically disposed between the ion source and the titanium target. This shield is voltage biased to recoil electrons being generated when positive D+ ions strike the titanium target. This prevents these electrons from striking the ion source and damaging it due to electron heating.

The target uses a deuterium D ⁺ or tritium T ⁺ absorber such as titanium, which readily absorbs D ⁺ or T ⁺ ions to form titanium hydride. Subsequent D ⁺ or T ⁺ ions strike and fuse with these embedded ions, resulting in DD, DT, or TT reactions, emitting fast neutrons.

The prior art attempts to propose fusion generators that require the use of radioactive tritium and the DT reaction with the need for high acceleration forces. A high yield of fast neutrons/sec was required to achieve sufficient thermal neutrons for therapy within a reasonable time of therapy treatment. These prior art schemes for achieving epithermal neutron flux are continuous or planar in design: a single fast neutron generator followed by a moderator followed by a patient. Unfortunately, neutrons enter from one side of the head, so planar neutron irradiation systems result in high surface or skin doses and diminishing neutron doses deeper into the brain. The brain is not uniformly irradiated, and cancer sites have lower thermal neutron absorption the farther they are from the planar port.

A conventional planar neutron irradiation system 14 and its operation is shown in FIG. 1, labeled Prior Art. Conversion of fast neutrons 22 to thermal neutrons 30 occurs in a series of steps. First, fast neutrons 22 are produced by the cylindrical fast neutron generator 20 and then enter the moderating means 18 where they undergo elastic scattering (collisions with the nuclei of the atoms of the moderating material). This lowers fast neutrons to epithermal 24 energies. A mixture of thermal 24 and thermal neutrons 30 is emitted from the planar port 16 and then enters the patient's head 26 . The epithermal neutrons 24 are still further moderated in the patient's brain, further moderated to thermal neutrons, and eventually captured by boron at the tumor site. A nuclear fission reaction occurs, releasing alpha rays and Li-7 ions, which destroy the tumor cells.

Epithermal and thermal neutrons reach the patient's head through a planar port 16 formed from a neutron absorbing material forming collimating means 28 . Thermal and epithermal neutrons hit the patient's head on one side and many neutrons escape and are not used. One escaping neutron 38 is shown representatively. This is an inefficient process requiring a large amount of fast neutrons to be produced to produce enough thermal neutrons for a reasonable therapy or treatment time (eg, 30 minutes).

In order to achieve a high yield of fast neutrons, the planar neutron irradiation system 14 can be used for DD fusion reactions with very high acceleration power (e.g., 0.5 to 1.5 megawatts), or neutron It requires using any of the DT reactions with approximately a 100-fold increase in yield.

The use of tritium has many safety and maintenance issues. Tritium gas is radioactive and extremely difficult to remove once it touches a surface. In the art of producing fast neutrons, this requires that the generator be hermetically sealed and have means for achieving a vacuum that is completely hermetically sealed. The generator head cannot be easily maintained and its life is usually limited to less than 2000 hours. This reduces the possible use of this generator for clinical operation, as fewer patients can be treated before the generator head requires replacement.

On the other hand, the use of the DD fusion reaction allows one skilled in the art to use actively pumping vacuum means with roughing and turbopumps. The generator can then be opened for repair, extending its life. This makes the DD fusion reaction neutron generator optimal for clinical use. A drawback of the DD fusion reaction is that high acceleration forces are required to achieve the desired neutron yields required by prior art methods. Improving the efficiency of creating an adequate thermal neutron flux at the cancer site is essential to achieving BNCT in clinical and hospital settings.

Current Status of Neutron Capture Therapy (2001) IAEA-TECDOC-1223 Ｙａｍａｍｏｔｏ，Ｏ；Ｔａｋｕｍａ，Ｔ；Ｆｕｋｕｄａ，Ｍ；Ｎａｇａｔａ，Ｓ；Ｓｏｎｏｄａ，Ｔ“Ｉｍｐｒｏｖｉｎｇ ｗｉｔｈｓｔａｎｄ ｖｏｌｔａｇｅ ｂｙ ｒｏｕｇｈｅｎｉｎｇ ｔｈｅ ｓｕｒｆａｃｅ ｏｆ ａｎ ｉｎｓｕｌａｔｉｎｇ ｓｐａｃｅｒ ｕｓｅｄ ｉｎ ｖａｃｕｕｍ，”ＩＥＥＥ ＴＲＡＮＳＡＣＴＩＯＮＳ ＯＮ ＤＩＥＬＥＣＴＲＩＣＳ ＡＮＤ ＥＬＥＣＴＲＩＣＡＬ ＩＮＳＵＬＡＴＩＯＮ（２００３）、１０（４ ): 550-556

In an embodiment of the invention, a neutron generator comprising: a top surface, a bottom surface, first and second ends, first and second sides, a first length, a first length substantially less than the first length. A pre-moderator block of moderator material having a width of 1 and a first thickness and one side to the top surface of the pre-moderator block adjacent the first end of the pre-moderator block with a vertical axis perpendicular to the top surface. a cylindrical acceleration chamber having a first diameter substantially the first width of the pre-moderator block, the acceleration chamber being closed at an end of the pre-moderator block at a second end remote from the pre-moderator block A cylindrical acceleration chamber having a height and a top cover, a vacuum pump engaging the acceleration chamber to bring the acceleration chamber to a medium high vacuum, and a top cover of the acceleration chamber on the vertical axis of the acceleration chamber. a plasma ion chamber opening into the acceleration chamber through an ion extraction iris passing through; a gas source providing deuterium gas to the plasma ion chamber; a microwave energy source ionizing the gas in the plasma ion chamber; A cylindrical primary separation well centered on the axis and extending a substantial distance from the top surface into the pre-moderator block and within a first diameter of the acceleration chamber to a depth somewhat less than the substantial distance of the primary separation well. , a secondary separation well in the shape of a substantially hollow cylinder surrounding the primary separation well, and a water-cooled titanium target disk having a target surface perpendicular to the axis of the acceleration chamber, the target disk being larger than the diameter of the separation well. also has a substantially smaller diameter and is positioned at the lower end of the isolation well and biased to a substantially negative DC voltage, covering all exposed surfaces of the water-cooled titanium target disk and the pre-moderator block. A neutron generator is provided comprising an electrically grounded metal cladding. ions extracted through the ion extraction iris are accelerated to bombard a titanium target at the lower end of the primary separation well, producing energetic neutrons that pass through and are moderated by the pre-moderator block; Any path along the surface from the titanium target to the electrically grounded element is necessarily maximized by primary and secondary isolation wells.

In one embodiment, the material of the pre-moderator block is ultra high molecular weight polyethylene (UHMWPE or UHMW), or high density polyethylene (HDPE), or polytetrafluoroethene (PTFE). Also, in one embodiment, the surfaces of the primary and secondary separation wells are formed with continuous curves and are roughened to enhance resistance to high voltage flashover. In one embodiment, the generator further comprises water feed and return water channels longitudinally through the pre-moderator block from the second end of the pre-moderator block to the titanium target to provide cooling water for cooling the target. .

In one embodiment, the neutron generator is coupled to a high voltage busbar realized longitudinally through the premoderator block to the target to bias the target to a substantially negative DC voltage. Further comprising a female socket for a high voltage male connector at the second end of the block of material. Also, in one embodiment, both the first and second sides of the pre-moderator block are angled inwardly by 30 degrees from vertical for at least a portion of the height such that the six neutron generators are: Allowing the angled sides to lie perfectly adjacent, forming a closed ring around the center point. Also, in one embodiment, both the first and second sides of the pre-moderator block are angled inwardly by 45 degrees from vertical for at least a portion of the height such that the eight neutron generators are: Allowing the angled sides to lie perfectly adjacent, forming a closed ring around the center point.

In another aspect of the invention, a boron neutron cancer therapy system comprising a secondary moderator having a central treatment chamber for a subject and six substantially identical neutron generators, wherein six substantially substantially identical neutron generators each having a top surface, a bottom surface, first and second ends, opposite sides angled inwardly by 30 degrees along at least a portion of a height, a first length; a pre-moderator block of moderator material having a first width substantially less than the first length and a first thickness; and at a first end of the pre-moderator block with a vertical axis perpendicular to the top surface A cylindrical acceleration chamber having a first diameter substantially the first width of the pre-moderator block, sealed at one end to the upper surface of an adjacent pre-moderator block, the acceleration chamber A cylindrical acceleration chamber having a height and a top cover at a second end remote from the moderator block, and a vacuum pump engaging the acceleration chamber perpendicular to the vertical axis to bring the acceleration chamber to a medium high vacuum. a plasma ion chamber opening into the acceleration chamber through an ion extraction iris through the top cover of the acceleration chamber on a vertical axis of the acceleration chamber; a gas source providing deuterium gas to the plasma ion chamber; a cylindrical primary isolation well extending a substantial distance from the top surface into the pre-moderator block centered on the vertical axis of the acceleration chamber; a secondary separation well in the shape of a substantially hollow cylinder surrounding the primary separation well, to a depth somewhat less than the substantial distance of the primary separation well, and a water-cooled titanium with a target surface perpendicular to the axis of the acceleration chamber. A water-cooled titanium target, wherein the target disk has a diameter substantially smaller than the diameter of the isolation well, is positioned at the lower end of the isolation well, and is biased to a substantially negative DC voltage. A boron neutron cancer therapy system is provided comprising a disk and an electrically grounded metal cladding covering all exposed surfaces of the premoderator block. The six neutron generators are positioned around the secondary moderator with the axis of each acceleration chamber passing through the center of the treatment chamber and the angled sides of the neutron generators being fully adjacent.

In one embodiment, the system further comprises six generally rectangular spacing blocks of moderating material, one spacing block having a side of the spacing block aligned with an angled side of the neutron generator. and between each adjacent neutron generator. Also, in one embodiment, the secondary moderator is shaped to fill the entire volume between the neutron generator and the central treatment chamber. In one embodiment, the secondary moderator is a block or blocks of solid moderator material. In one embodiment, the secondary moderator is a vessel filled with heavy water. Also, in one embodiment, the secondary moderator is a container filled with granular moderator material.

In yet another aspect of the invention, a boron neutron cancer treatment system comprising a secondary moderator having a central treatment chamber for a subject, eight substantially identical neutron generators, and eight substantially identical neutron generators each having a top surface, a bottom surface, first and second ends, opposite sides angled inwardly by 45 degrees along at least a portion of the height, a first length; , a pre-moderator block of moderator material having a first width substantially less than the first length, and a first thickness; and a first end of the pre-moderator block with a vertical axis perpendicular to the top surface. a cylindrical acceleration chamber having a first diameter substantially the first width of the pre-moderator block, sealed at one end to the top surface of the pre-moderator block adjacent to the pre-moderator block, the acceleration chamber comprising: A cylindrical acceleration chamber having a height and a top cover at a second end remote from the premoderator block and a vacuum engaging the acceleration chamber perpendicular to the vertical axis to bring the acceleration chamber to a moderately high vacuum. a pump, a plasma ion chamber that opens into the acceleration chamber through an ion extraction iris through the top cover of the acceleration chamber on a vertical axis of the acceleration chamber, a gas source that provides deuterium gas to the plasma ion chamber, and a plasma ion chamber. a cylindrical primary isolation well extending a substantial distance from the top surface into the premoderator block centered on the vertical axis of the acceleration chamber; a secondary separation well in the shape of a substantially hollow cylinder surrounding the primary separation well to a depth somewhat smaller in diameter than the substantial distance of the primary separation well, and water cooled with a target surface perpendicular to the axis of the acceleration chamber. A water-cooled titanium target disk, the target disk having a diameter substantially smaller than the diameter of the isolation well, positioned at the lower end of the isolation well and biased to a substantially negative DC voltage. A boron neutron cancer therapy system is provided that includes a target disk and an electrically grounded metal cladding that covers all exposed surfaces of the premoderator block. Eight neutron generators are positioned around the secondary moderator with the axis of each acceleration chamber passing through the center of the treatment chamber and the angled sides of the neutron generators being fully adjacent.

In one embodiment, the system further comprises eight generally rectangular spacing blocks of moderating material, one spacing block having a side of the spacing block with an angled side of the neutron generator. Fully contiguous and positioned between each adjacent neutron generator. In one embodiment, the secondary moderator is shaped to fill the entire volume between the neutron generator and the central treatment chamber. In one embodiment, the secondary moderator is a block or blocks of solid moderator material. In one embodiment, the secondary moderator is a vessel filled with heavy water. Also, in one embodiment, the secondary moderator is a container filled with granular moderator material.

In yet another aspect of the invention, a treatment system for evaluating a boron source for boron neutron cancer therapy (BNCT), comprising a substantially square secondary moderator having a central treatment chamber for a subject and , four substantially identical neutron generators, each of the four substantially identical neutron generators having a top surface, a bottom surface, first and second ends, opposing parallel sides, a first length a pre-moderator block of moderator material having a length, a first width substantially less than the first length, and a first thickness; A cylindrical acceleration chamber having a first diameter substantially the first width of the pre-moderator block, sealed at one end to the top surface of the pre-moderator block adjacent the end, the acceleration chamber comprising , a cylindrical acceleration chamber having a height and a top cover at a second end remote from the premoderator block, and engaging the acceleration chamber at right angles to the vertical axis to bring the acceleration chamber to a medium high vacuum. a vacuum pump; a plasma ion chamber that opens into the acceleration chamber through an ion extraction iris through the top cover of the acceleration chamber on a vertical axis of the acceleration chamber; a gas source that provides deuterium gas to the plasma ion chamber; a microwave energy source for ionizing gases in the chamber; a cylindrical primary separation well centered on the vertical axis of the acceleration chamber and extending a substantial distance into the premoderator block from the top surface; a secondary separation well in the shape of a substantially hollow cylinder surrounding the primary separation well, to a depth somewhat less than the substantial distance of the primary separation well, within a diameter of the A water-cooled titanium target disk, wherein the target disk has a diameter substantially smaller than the diameter of the isolation well, is positioned at the lower end of the isolation well, and is biased to a substantially negative DC voltage. Treatment system for evaluating a boron source for boron neutron cancer therapy (BNCT) comprising a titanium target disk and an electrically grounded metal cladding covering all exposed surfaces of a premoderator block is provided. The four neutron generators are positioned around a generally square secondary moderator with the axis of each acceleration chamber passing through the center of the treatment chamber.

In one embodiment of this system, the secondary moderator is a block or blocks of solid moderator material. In one embodiment, the secondary moderator is a vessel filled with heavy water. Also, in one embodiment, the secondary moderator is a container filled with granular moderator material.

In yet another aspect of the present invention, a boron neutron cancer treatment system, the moderator chambers having parallel upper and lower surfaces filled with a liquid or particulate moderator material except for a central treatment chamber; a neutron generator and a mechanically adjustable carrier for the neutron generator, each of the plurality of neutron generators having a top surface, a bottom surface, first and second ends, opposite sides, a first length; a pre-moderator block of moderator material having a length, a first width substantially less than the first length, and a first thickness; A cylindrical acceleration chamber having a first diameter substantially the first width of the pre-moderator block, sealed at one end to the top surface of the pre-moderator block adjacent the end, the acceleration chamber comprising , a cylindrical acceleration chamber having a height and a top cover at a second end remote from the premoderator block; a vacuum pump engaging the acceleration chamber to bring the acceleration chamber to a medium high vacuum; a plasma ion chamber opening into the acceleration chamber through an ion extraction iris through a top cover of the acceleration chamber on a vertical axis of the chamber; a gas source for providing deuterium gas to the plasma ion chamber; a source of ionizing microwave energy, a cylindrical primary separation well centered on the vertical axis of the acceleration chamber and extending a substantial distance from the top surface into the pre-moderator block; within a first diameter of the acceleration chamber; With a secondary separation well in the shape of a substantially hollow cylinder surrounding the primary separation well to a depth somewhat less than the substantial distance of the primary separation well, and a water-cooled titanium target disk having a target surface perpendicular to the axis of the acceleration chamber. a water-cooled titanium target disk, wherein the target disk has a diameter substantially smaller than the diameter of the isolation well, is positioned at the lower end of the isolation well and is biased to a substantially negative DC voltage; Electrically grounded metal cladding covering all exposed surfaces of the premoderator block and mechanically adjustable carriers for the neutron generators, each carrier carrying one neutron generator. supporting and translating the neutron generator toward and away from the central treatment chamber and rotating the neutron generator in a plane parallel to the planes of the parallel upper and lower surfaces of the moderator chamber; thing A boron neutron cancer treatment system is provided that enables The modular generator and mechanically adjustable carrier are fully immersed in the liquid or particulate moderator material of the moderator chamber.

1 is a cross-sectional view of a planar geometry for introducing thermal neutrons into a patient's brain (prior art); FIG. FIG. 3 is a cross-sectional view of an embodiment of how multiple fast neutron generators are arranged around a hemispherical moderator to introduce a uniform thermal neutron dose into a patient's head. 1 is a perspective view of how multiple fast neutron generators are used in an embodiment of the invention to develop a high neutron dose into a patient's head; FIG. 4 is a cross-sectional view of the arrangement of FIG. 3 with a patient's head inside the interior of the neutron irradiation system; FIG. FIG. 4 is a graph of dose rate (Gy equivalent/hr) as a function of distance from the surface of the head (skin) for planar and hemispherical moderator (radial source) geometries. FIG. 4 is a graph of the treatable ratio as a function of distance from the head (skin) surface for hemispherical (radial source) and planar moderator geometries in an embodiment of the present invention; FIG. FIG. 2 is a cross-sectional view of an embodiment of a cylindrical neutron irradiation system for the liver or other body organ; 1 is a perspective view of a cylindrical neutron irradiation system for the liver or other organs of the body; FIG. 1 is a cross-sectional view of one of the embodiments of a neutron irradiation system in which the neutron generators can be independently controlled to maximize thermal neutron flux in the liver or other organs of the body; FIG. 1 is a simplified diagram of a cross-section of an irradiation system using neutron generators that can be controlled independently of each other; FIG. FIG. 4 is a graph of the therapeutic ratio as a function of distance along the axis of the liver in cm. FIG. 2 is a graph of dose rate as a function of distance along the axis of the liver in cm. 1 is a perspective view of a modular neutron generator according to an embodiment of the invention; FIG. Figure 12B is a perspective cross-sectional view of the module of Figure 12A taken along the axis of the acceleration chamber, perpendicular to the axis of the turbo vacuum pump; Figure 12B is a perspective cross-sectional view of the module of Figure 12A taken along the axis of the turbo vacuum pump; FIG. 4 is a plan view of six modular generators arranged around a chamber for moderator and patient, in an embodiment of the present invention; 14 is a perspective view of the system of FIG. 13 using six modular neutron generators in an embodiment of the invention; FIG. A perspective view of a cylindrical neutron irradiation system using eight modular generators, one removed to show how the irradiation system is assembled in an embodiment of the invention. is. FIG. 2 is a plan view of a modular generator with a fluid moderator and positioned to maximize dose to cancer sites in the brain, in an embodiment of the present invention. 1 is a simplified, almost schematic illustration of a central tube with eight modular neutron generators and a human head (pseudo) inside a helmet moderator and neutron reflector, in an embodiment of the present invention; FIG. 14B is a simplified, substantially schematic cross-sectional view taken along the 14B-14B section line of FIG. 14A; FIG. Fig. 10 is a graph showing the predicted horizontal dose equivalent rate (Sv/hr) as a function of horizontal position across the pseudo (head) in an embodiment of the present invention; 1 is a perspective view of a module for a small animal neutron radiation system employing four modules; FIG. 16B is a simplified top plan view of the small animal neutron irradiation system of FIG. 16A; FIG. 16B is a simplified cross-sectional view of the small animal neutron irradiation system of FIG. 16A; FIG. 16B is an exploded plan view of the small animal neutron irradiation system of FIG. 16A. FIG.

In the following description, reference is made to the accompanying drawings, which form a part hereof, and which are illustrated by way of illustrative specific embodiments in which the invention may be practiced. It is to be understood that other embodiments may be utilized and structural changes may be made without departing from the scope of the present invention.

Uniform Delivery of Thermal Neutrons to Cancer Sites To achieve an extremely high thermal neutron flux uniformly distributed over the patient's head, for example, a hemispherical geometry is used in one embodiment of the invention. used. This unique geometry positions the fast neutron source in a circle around the moderator, and the radial thickness of the moderator is optimized to deliver maximum thermal neutron flux to the patient's brain. This embodiment produces a uniform thermal neutron dose within 1/20 times the required fast neutron yield and line voltage input power of conventional planar neutron irradiation systems. This configuration allows the use of relatively safe deuterium-deuterium (DD) fusion reactions (no radioactive tritium) and commercial high voltage power supplies operating at moderate power (50 to 100 kW). do.

FIG. 2 is a cross-sectional view of a hemispherical neutron irradiation system 36 according to one embodiment of the invention. A number of fast neutron generators 68 surround the hemispherical moderator 34 which in turn surrounds the patient's head 26 . The titanium targets 52 are distributed around the hemispherical moderator 34 . Surrounding moderator 34 and fast neutron generator 68 is fast neutron reflector 44 .

In moderator 34, a moderator material such as ^7LiF , high density polyethylene (HDPE), and heavy water is molded into a hemisphere that is molded around the patient's head. The optimum thickness of the hemispherical moderator for irradiation purposes depends on the nuclear structure and density of the material.

FIG. 3 shows a perspective view of patient 58 on table 54 with the patient's head inserted into hemispherical illumination system 36 . A patient 58 lies on the table 54 with its head inserted into the hemispherical moderator 34 . Surrounding the moderator is a neutron reflecting material 44 such as lead or bismuth.

Referring again to FIG. 2, fast neutrons 22 are produced by fast neutron generator 68 . Generator 68 consists of titanium target 52 and ion source 50 . An ion beam is produced by an ion source 50 and accelerated toward a titanium target 52 embedded in a hemispherical moderator 34 . A DD fusion reaction occurs at the target, creating 2.5 MeV fast neutrons 22 .

The fast neutrons 22 enter the moderator 34 where the fast neutrons 22 are elastically scattered by collisions with the nuclei of the moderator atoms. This slows them down to epithermal 24 energies after a few collisions. These epithermal neutrons 24 enter the patient's head 26 where the epithermal neutrons 24 are further moderated to thermal neutron 30 energy. These thermal neutrons 30 are then captured by boron-10 nuclei at the cancer site, resulting in fusion events and death of proximal cancer cells.

Fast neutrons 22 are emitted isotropically in all directions from the titanium target 52 . The outwardly traveling fast neutrons 42 are reflected back by the fast neutron reflector 44 (reflected neutrons 48), while the inwardly traveling fast neutrons 40 are decelerated into epithermal energy and the patient's head 26. , where further moderation of the neutrons to thermal energy occurs.

The shell of protective shield 56 is also shown in FIG. In some embodiments, this may be essential to shield both the patient and operator from overexposure due to neutrons, x-rays, and gamma radiation. The shield can be made of various materials depending on the radiation component that it is desired to suppress.

In some embodiments, fast neutron reflector 44 is made of lead or bismuth. The fast neutron reflector also acts as a shield to reduce emitted gamma rays and neutrons from hemispherical neutron irradiation system 36 . As those skilled in the art will appreciate, a gamma ray absorbing or other neutron reflector means is layered around the hemispherical neutron irradiation system 36 to reduce unwanted and dangerous radiation from reaching the patient 58 and operator. can be placed in

Hemispherical moderator 34, fast neutron reflector 44, and head 26 act together to focus thermal neutrons within the patient's head. The patient's head and moderator 34 work together as a single moderator. With careful selection of moderating materials and geometry, a uniform dose of thermal neutrons can be achieved across the patient's head, and a large uniform therapeutic ratio can be achieved when the boron drug is administered.

The present invention provides a uniform dose of thermal neutrons to the head while minimizing fast neutron and gamma ray contributions. The required amount of fast neutrons to deliver this performance is reduced compared to that of prior art planar neutron irradiation systems (see FIG. 1).

A cross-sectional perspective view of a hemispherical neutron irradiation system 36 in an embodiment of the invention is shown in FIG. This cross-sectional view is of a radial cut directly through the patient's head 26 and the hemispherical neutron irradiation system 36 . As shown in this embodiment, ten fast neutron generators 68 consisting of ion sources 50 with titanium targets 52 radially surround hemispherical moderator 34 and patient's head 26 . Titanium target 52 in this embodiment is a continuous belt of titanium that surrounds moderator 34 . Titanium targets can also be sectioned as shown in FIG. The ion source in this embodiment is embedded in a fast neutron reflector 44 .

There are several materials that can be selected for the moderator 34 to achieve maximum thermal neutron flux at the patient's head 26 . The performance of HDPE, heavy water (D2O), graphite, _7LiF , and ^AlF3 _were analyzed using Monte Carlo neutral particle (MCNP) simulations. In general, there is an optimum thickness for each moderator material that produces maximum heat flux in the patient's head (or other body part or organ). Thermal neutrons/(cm ² -s) were calculated for these materials as a function of moderator thickness d ₃ , where d ₄ =25 cm and fast neutron reflector 44 with d ₁ =50 cm thick and made of lead. The combined fast neutron yield striking this area from all fast neutron generators 68 is assumed to be 10 ¹¹ n/s at MCNP, as seen in all calculations of the present invention. Optimal thicknesses, thickness ranges, and maximum thermal neutron fluxes (E<0.5 eV) are given in Table 1 for various moderating materials. These are approximate values given to help determine the overall dimensions of the moderator.

Calculation of the therapeutic ratio is also important and depends on the organ in question (brain, liver) and the weight of the patient. HDPE gives the highest flux, but it gives a lower therapeutic ratio compared to ^7LiF . Designers are expected to perform similar calculations to determine the optimal geometry for their neutron irradiation system.

MCNP simulations were used to determine the delivered dose and therapeutic ratio for patient 58 and compare it to a planar neutron irradiation system. In one simulation, the moderator 34 consists of 7LiF with a thickness d ₃ =25 cm. The inner diameter of the moderator (hole for the head) is d ₄ =25 cm. The distance between the hemispherical fast neutron reflector 44 and the hemispherical moderator 34 is d ₂ =10 cm. The head is assumed to be 28cm x 34cm. The fast neutron reflector 44 is made of lead with d ₁ =20 cm thickness in one embodiment. _Thicker values of d1 increase the tumor dose rate. At 10 cm thickness, the tumor dose rate is about half of the value at 50 cm thickness. Fast neutron generator 68 is assumed to emit a total yield of 10 ¹¹ n/sec. The combined titanium target 52 gives a total neutron emission area of 1401 cm ² .

In MCNP simulations, BPA (boronophenylalanine) was used as the delivery agent. The concentration of boron in tumor was 68.3 μg/gm, while healthy tissue was 19 μg/gm. The calculated neutron dose rate in Gy equivalent/hr is plotted in FIG. 5 as a function of the distance from the skin to the center of the head. Calculated dose rates are comparable to those used for gamma radiotherapy, typically 1.8 to 2.0 Gy per session. For the same dose, at a rate of 3 Gy equivalent/hr, the session length would be 30 to 40 minutes. These session times are considered reasonable for the patient's experience.

For this simulation, the treatable ratio for the hemispherical neutron irradiation system is plotted in FIG. 6 as a function of the distance from the skin to the center of the skull. The therapeutic ratio is defined as the delivered tumor dose divided by the maximum dose to healthy tissue. A therapeutic ratio greater than 3 is considered suitable for cancer therapy.

Conventional planar neutron irradiation systems require higher fast neutron yields (10 ¹² to 10 ¹³ n/s) to achieve equivalent dose rates and treatable ratios. ^In FIG. 5, the planar neutron irradiation system 14 of FIG. 3 and 4). As can be seen from FIG. 5, the hemispherical neutron irradiation system (referred to as the radial source in FIG. 5) achieves a dose rate approximately twenty times that of the conventional planar neutron irradiation system 14. A planar geometry would require a fast neutron source of 2×10 ¹² n/s to achieve the same result. In fact, if a DD fusion generator is used, a planar source would require a 20-fold increase in wall-plug power, or a prohibitively large power requirement of 2.0 MW.

Additionally, as can be seen from FIG. 5, over a distance of ±5 cm across the center of the head, the hemispherical neutron irradiation system 36 has less than 10% variation in dose. A uniform dose rate is crucial for the treatment of GBM, where it is desired to maintain the maximum therapeutic ratio and where the tumor may be distributed throughout the brain.

The hemispherical neutron radiation system 36 in embodiments of the present invention also provides a more uniform therapeutic ratio (FIG. 6) across the brain. This ratio is more uniform for the radial source, requiring only 1/20 the fast neutron yield of the planar source (Fig. 1).

In alternate embodiments, other materials may be used for the hemispherical moderator 34 . High density polyethylene (HDPE), heavy water ( ^D2O ), graphite, and _7LiF can also be used, as those skilled in the art know. Additionally, combinations of materials (eg, 40% Al and 60% AlF ₃ ) can also be used. Moderators of different thickness d1 can be used to optimize the neutron flux to give the _highest treatable fraction.

The term "neutron generator or source" is intended to cover a wide range of devices for the generation of neutrons. The cheapest and most compact generators produce neutrons by accelerating isotopes of hydrogen (e.g., tritium and deuterium) together using modest acceleration energies, thereby creating neutrons by fusing "fusion neutrons." generator”. These fusion neutron generators are compact and relatively inexpensive compared to linear accelerators that can produce directed neutron beams.

Other embodiments rely on the choice of plasma ion source used to generate neutrons at a cylindrical target. These are: (1) an RF-driven plasma ion source using a loop RF antenna; (2) a microwave-driven electron cyclotron resonance (ECR) plasma ion source; (3) an RF-driven helical antenna plasma ion source; ) a multiple cusp plasma ion source, and (5) a Penning diode plasma ion source. All plasma ion sources can be used to create deuterium or tritium ions for fast neutron generation.

Cylindrical Irradiation System for Liver and Other Cancer Sites FIGS. 7A and 7B show the present invention using a cylindrical geometry to irradiate other organs and parts of patient 58, such as liver 76. 2 shows another embodiment of FIG. 7A is a cross-sectional view of a cylindrical neutron irradiation system 62 and FIG. 7B is a perspective view of the same embodiment. In this embodiment, eight fast neutron generators 68 surround cylindrical moderator 46 . All these generators 68 emit their fast neutrons at the surface of the moderator. A cylindrical fast neutron reflector 44 surrounds a cylindrical moderator 46 .

As with hemispherical moderator 34, cylindrical moderator 62 may consist of well-known moderator materials such as ⁷ LiF, high density polyethylene (HDPE), and heavy water. These are shaped like a cylinder that surrounds the patient. The optimal thickness of cylindrical moderator for neutron capture purposes depends on the material core structure and density.

In this embodiment, a fusion neutron generator is used to provide fast neutrons. Fast neutron generator 68 consists of titanium target 52 and ion source 50 as before. The titanium target is continuous with a cylindrical moderator 46 . The ion beam 60 is accelerated using a DC high voltage (eg, 100 kV) to a titanium target 52 where fast neutrons are produced from the DD fusion reaction. Fast neutrons are emitted isotropically from the titanium target 52 on the moderator, some migrate outward to the fast neutron reflector 44, and others migrate inward to extrathermal or thermal energy. immediately decelerated. Those reflected return to the cylindrical moderator 46 where they are moderated into extrathermal and thermal energy and ultimately directed to the patient 58 .

Cylindrical neutron irradiation system 62 allows uniform illumination of an area of a patient's body (eg, liver) compared to conventional planar neutron irradiation systems. In the case of the brain, the body itself acts as part of the moderation process, thermally equilibrating incoming epithermal neutrons from the cylindrical moderator 46 .

As those skilled in the art will appreciate, other cancers such as throat and neck tumors can be effectively irradiated with a hemispherical neutron irradiation system such as system 36 . Moderator thickness and material content may be adjusted to maximize the desired energy of neutrons entering the patient. For example, for pharyngeal and neck tumors, moderators can be made of deuterated polyethylene or heavy water ₍ D2O) to maximize thermal neutron irradiation of tumors near the surface of the body. For deeper neutron penetration, the moderator may be made of _AlF3 to create epithermal neutrons. These are best suited to reach the liver and create a uniform illumination of that organ.

Segmented Moderators In yet another embodiment, fast neutron sources with segmented moderators can be moved individually to achieve uniform doses over liver or other cancer sites. This geometry produces a uniform thermal neutron dose at 1/10 to 1/20 times the required fast neutron yield and line voltage input power of previous linear designs. This also allows for relatively safe deuterium-deuterium (DD) fusion reactions (no radioactive tritium) and the use of commercially available high voltage power supplies operating at moderate power (≦100 kW).

A segmented neutron irradiation system 70 in an embodiment of the invention is shown in FIG. Surrounding the patient 58 are ten fast neutron generators 68 each having a wedge-shaped moderator 74 . The exact shape of each moderator may vary and may be of other geometries. Each generator and moderator pair can be moved independently of the others to achieve neutron flux uniformity across the liver, organ, or body part.

Additional moderator material ("filler moderator material" 72) is inserted between the wedge-shaped moderators 74 to form a single large moderator. The "filler" moderating material 72 can be heavy water or powered moderating material such as _AlF3 . Pie-shaped fillers of moderator material may also be fitted into the spaces between the wedge-shaped moderators 74 . Since neutrons scatter easily, there may be some space between the wedge-shaped moderator 74 and the pie-shaped filler without excessive loss of neutron moderation efficiency.

The neutron yield from each fast neutron generator 68 and the position of each fast neutron generator 68 can be adjusted to achieve uniformity across the liver or body part. The position and neutron yield of the generator can be varied to achieve a desired radiation dose at a particular location within the patient's body. Since cancer can be located anywhere in the body, this benefit can be particularly useful in optimizing dose at the cancer site.

Surrounding the entire fast neutron/moderator system is a cylindrical fast neutron reflector 44 . Fast neutrons are produced by fast neutron generator 68 and enter moderator 74, where they are elastically scattered by collisions with the nuclei of moderator atoms, which after several collisions expel them. Slow down into energy. As with other embodiments, these epithermal neutrons enter the patient 58 and liver 76 where they are further moderated to thermal neutron energy.

The present invention in various embodiments provides a uniform dose of thermal neutrons to the liver, organ, or body part while minimizing fast neutron and gamma ray contributions. The required number of fast neutrons (eg, 2×10 ¹¹ n/s) to hammer out this performance is again that required for prior art planar neutron irradiation systems (eg, 2× 10 ¹³ n/s).

Another embodiment of a segmented design is shown in FIG. The shape of the neutron irradiation system 78 is elliptical with six fast neutron sources shown as distributed targets embedded in an inner elliptical moderator 96 . Fast neutrons 22 are emitted isotropically in all directions. Those outwardly traveling fast neutrons 22 are reflected back by the fast neutron reflector 44 (see arrow 48), while inwardly traveling fast neutrons 22 are slowed down to epithermal energy, the liver 76 , where further moderation of the neutrons to thermal energy occurs. The inner elliptical moderator 96 , the outer elliptical moderator 98 , the reflector 44 , and the patient's body 58 act together to slow down and focus the thermal neutrons in the patient's liver 76 . Through careful positioning of moderators and fast neutron sources 90, 92, 94, a uniform dose can be achieved over the patient's liver, and boron agents administered to tumors can achieve excellent therapeutic ratios.

Elliptical neutron irradiation system 78 in FIG. 9 is a simplified cross-sectional view of patient 58 inside elliptical moderator 96 . This cross-section is of a radial cut directly through the patient's torso and moderator and fast neutron generator system. To maintain visual simplicity, only the titanium target is shown and not the ion source. The six fast neutron sources are therefore represented by three flat titanium targets 90,92,94. The remaining fast neutron generators are not shown. Other components (eg plasma ion source) are ignored in the analysis. The wedge-shaped moderator 74 (used in FIG. 8) is also not shown in FIG.

In a simple simulation of a neutron irradiation system, targets 90, 92, 94 are fast neutron sources and are placed within an elliptical material 96 (eg, _AlF3 , LiF). The effects of the moderating material 96, the fast neutron reflector 44, and the patient's body 58 used the Monte Carlo N-particle (MCNP5) transport code to determine how quickly neutrons were converted to thermal neutrons in a neutron irradiation system. calculated by

Dose calculations were performed along the central axis of the liver. The fast neutron sources (titanium targets) are 2 cm x 2 cm in area and each produce 10 ¹¹ /N n/s, where N is the number of sources. The human body 58 dimensions are 35.5 cm along the major axis and 22.9 cm along the minor axis. The inner elliptical moderator 96 is made of ⁷ LiF and is 10 cm thick, while the outer moderator 98 is made of AlF ₃ and is 40 cm thick. The fast neutron reflector 44 is made of 50 cm thick lead. Boron-10 concentration is 19.0 μg/g in healthy tissue and 68.3 μg/g in tumor. The six sources are in cm, (-15,18.06,0), (-15,-18.06,0), (-17,17,0), (-17,-17,0) , (0,15.85,0), (0,-15.85,0). These measurements are taken along the axis of liver 76 from points (-15,0,0) to (-5,0,0). In the x-direction, the first two sources 90 are centered on the left edge of the liver shown in FIG. 9, the two sources 92 are centered on the body edge, and the third two 94 are located above and below the origin. do. The origin is shown in FIG. 9 as a small cross + at the center of the body in the plane of the liver.

Figure 10 shows the therapeutic ratio for a large single dose and for multiple small doses (photon dose to healthy tissue is not included) plotted as a function of distance along the axis of the liver. not available). Photon dose can be ignored if there is some amount of time between exposures. Many of the body's healthy cells are able to self-repair and recover during exposure. The predicted therapeutic ratio is between these two curves when there is a split into multiple exposures. In this simulation, BPA was again used as the delivery agent with a boron concentration of 68.3 μg/gm in tumor and 19 μg/gm in healthy tissue.

FIG. 11 shows that the goal of having a very uniform dose to the tumor was achieved, with a variation of approximately ±6% along the x dimension. Calculated dose rates are those used for ^{gamma radiotherapy} , typically from 1.8 to Equivalent to 2.0 Gy equivalent. Therefore, it is possible to obtain a therapeutic ratio and a uniform dose to the tumor at approximately 2×10 ¹¹ to 3×10 ¹¹ n/s. Approximately 10 to 20 treatments of 30 to 40 minutes are required, with good treatability ratios, dose uniformity, and chances of healthy tissue repair between treatments.

Again, planar neutron irradiation systems require high fast neutron yields to drive them. In one prior art system known to the inventors, a fast neutron source of 3×10 ¹³ n/s is required to obtain a realistic treatment time of ˜1-2 hours. Acceptable treatment times were obtained using a DT neutron source with a yield of 10 ¹⁴ n/s (30 to 72 min for a single beam and 63 to 128 min for three beams in different directions). However, these are yields impossible to achieve with realistic wall plug power. Instead of 50 to 100 kW for hemispherical and cylindrical neutron irradiation systems, planar geometries with DT generators take a minimum of 0.5 MW to achieve adequate yields. These are high power for clinics and hospitals.

As those skilled in the art know, other cancers such as throat and neck tumors can be effectively irradiated with a neutron irradiation system. Moderator thickness and material content may be adjusted to maximize the desired energy of neutrons entering the patient. For example, in pharyngeal and neck tumors, moderators can be made of deuterated polyethylene or heavy water ₍ D2O) to maximize thermal neutron irradiation of tumors near the surface of the body. For deeper neutron penetration, the moderator is made of _AlF3 to create epithermal neutrons. These are best suited to reach the liver and create a uniform illumination of that organ.

Modular Generators Introduction As shown in Figures 8 and 9, a number of modular generators can be enclosed in moderating material and arranged to maximize the thermal neutron flux at the site of the cancer tumor. obtain. Fast 2.5 MeV neutrons must be slowed down (moderated) to an energy (usually exothermic) that penetrates into the cancer site without too many neutrons being lost to capture by healthy tissue during progression to cancer. must. These modular generators act as independent neutron sources and each can be optimized by adjusting the energy, direction and intensity of each individual beam. Modular generators can be configured to match a site to the location and structure of a particular subject's component. This also applies to the location of cancer tumors.

Neutron energies can also be adjusted by adding or subtracting moderating materials. This can be done more easily than with single beam LINACs or nuclear reactors, which usually have a fixed beam line integrated with the neutron source. In the prior art, some adjustments may be made, but the DD fusion generator in the much smaller embodiments of the present invention may have more degrees of freedom in direction, strength and deceleration. This has the added benefit of helping the physician tailor the neutron radiation to the patient's cancer.

Comparison to Linear Accelerators and Nuclear Reactors Modular generators in various embodiments of the present invention may also form the mechanical structure of, and be part of, a cancer irradiation system. This has the added benefit of moving the neutron source as close as possible to cancer sites and diseased body parts, resulting in efficient use of the neutron source. Since the neutrons are emitted in a 4π solid angle from the modular generator, a higher flux of fast neutrons closer to the cancer site is utilized. Linear accelerators (LINAC) are somewhat collimated, but are far from the cancer site and cannot provide this advantage.

Compared to linear accelerators, which can be several meters long or longer and can include large microwave power sources, the DD fusion source in embodiments of the present invention is less than one meter long and can be a solid-state microwave source or a small inexpensive unit. Equipped with a miniature microwave source, which may be any one of the microwave oven magnetrons. The accelerator structure in embodiments of the present invention is compact and uses 5-10 cm of high density polyethylene (HDPE) or 15-20 cm of polytetrafluoroethene (PTFE) to create the first stage of neutron beam conditioning. ) includes a premoderator 118 that is added only from Teflon. The pre-moderator in these embodiments is an integral part of each modular generator, as taught below with reference to several figures. In alternate embodiments, other pre-moderation materials such as _AlF3 , _MgF2 , ^7LiF , and Fluental(TM) may be used.

Smaller, non-toxic, less complex target for neutron production Modular DD fusion generator 118 in embodiments of the present invention is supported by a small titanium target (e.g., water-cooled copper fins) to produce neutrons. A 5 cm diameter titanium disc) is used. The target is supported directly on the pre-moderator, which is an integral part of the apparatus in this application, called the modular generator. Linac and other methods in the prior art use larger or toxic targets that require complex cooling and rotation. For example, the neutron source used by Neutron Therapeutics has a 2.6 MeV electrostatic proton accelerator and a rotating solid state lithium target for generating neutrons. In that prior art process, lithium becomes radioactive and toxic and when exposed to air it decays. This prior art source has a large target chamber containing a large Li disk that is rotated within an intense 2.8 MeV proton beam produced by a large accelerator. The lithium wheel is approximately two meters in diameter and is divided into pie-shaped sections that are removed by mechanical robotic means. In embodiments of the present invention, the Ti target is relatively small diameter (~5 cm) and is typically attached to the premoderator block by 6-8 screws and sealed to the block by a Viton "O" ring. be done. The Ti target in embodiments of the invention can be easily manually removed and replaced. They also have a long lifespan and have been tested for over 4000 hours without failure.

Nuclear reactors are large structures with a significant amount of shielding (water and concrete) and cooling systems to maintain a hot core. The reactor first provides thermal neutrons whose energy must be stepped up using an energy amplifier, then the neutron beam must be stepped up to IAEA standards to produce epithermal neutrons with minimal gamma radiation. must.

Optimizing Neutron Energy for Penetration and Minimal Damage to Healthy Tissue For tumors at depths in subjects greater than 3 cm, moderator targets should be at least a few centimeters into the human target. To provide sufficient energy to penetrate while avoiding higher energies that are more damaging to human tissue, the goal is to provide a neutron beam that clusters the energy at about 10 keV in the skin. High conversion to epithermal energy occurs in HDPE at a thickness of approximately 5 cm, but it also produces a high yield of thermal neutrons and 2.2 MeV gamma rays that can damage healthy tissue at the skin. .

Modular Generator In embodiments of the present invention, the modular generator is a very important component. Modular generators combine a number of functions that were separate functions in the prior art. These integrated functions include both neutron production and beam conditioning. FIG. 12A is a perspective view of an individual modular generator 118 in an embodiment of the invention.

FIG. 12B shows the module of FIG. 12A taken along the axis of the acceleration chamber 100 for ion beam generation and storage and perpendicular to the axis of the turbo vacuum pump 124, which is part of the modular generator 118. 3 is a cross-section of the equation generator 118. FIG. 12C is a cross-section of the modular generator 118 of FIG. 12A taken along the axis of the acceleration chamber 100 and along the axis of the turbo vacuum pump 124, perpendicular to the cross-section of FIG. 12B. Each modular generator 118 can operate independently of the other modular generators, each possessing all the necessary components to generate neutrons. In addition, various modular generators are pre-moderators shaped to engage other building blocks of the project, such as adjacent generators or spacing moderators as described in possible detail below. can have

As seen in FIGS. 12A, 12B, and 12C, each modular generator 118 includes a premoderator 108 made of materials known to moderate the energy of energetic neutrons. In most embodiments, the pre-moderator is a solid block of material with a rather complex shape for a specific purpose. Modular generator 118 comprises three key elements: (1) deuterium ion source 102, (2) acceleration chamber 100 through which deuterium ions can be accelerated, and (3) It has a titanium target 106 (shown in FIGS. 12B and 12C) which is bombarded by deuterium ions to produce high energy neutrons. The deuterium ion source 102 has an attached microwave source 160 and a microwave slug tuner 172 connected by a cable 178 . The deuterium gas slowly leaks into the plasma ion chamber 174 at the top of the acceleration chamber, where microwave energy ionizes the gas to create deuterium D+ ions.

The gas is ionized by microwave energy to create deuterium (D+) ions, which are accelerated out through ion extraction iris 138 into acceleration chamber 100 and through electron suppression shroud 180, which 180 prevents backflow electrons from being accelerated back into the plasma source and thereby potentially damaging the device. Electrons are created by collisions of D+ ions in the deuterium gas created in the acceleration chamber.

Deuterium ions are positively charged, target 106 is negatively charged to levels of 120 kV to 220 kV, and D+ ions are strongly attracted to negatively biased target 106 . Acceleration chamber 100 is connected to a turbo vacuum pump 124 that provides a moderate vacuum in one embodiment of about 10 ⁻⁶ Torr to scatter D ^{1 +} ions as they travel from extraction iris 138 to target 106 . Minimize. Titanium target 106 is positioned in a primary electrically insulating well 181 at the bottom of the chamber of premoderator 108 embedded in the premoderator material, which can be UHMW, HDPE, or Teflon. There is also a secondary electrical isolation well 182 surrounding the primary electrical isolation well. The surface of the moderating material in the primary and secondary electrical isolation wells can be viewed as a corrugated insulator that allows any surface charge to follow a curved path in any direction. The purpose is to provide a very long surface path to prevent electrons from traveling from the target to the acceleration chamber 100 wall or any grounded elements and to avoid surface electrical breakdown or flashover within that surface path. That is. As those skilled in the art know, wells form electrically insulating pathways. Additional corrugations or wells can be added to lengthen the path.

The pre-moderator 108 has high voltage busbars 122 and fluid cooling channels 120 to and from the target. High voltage is introduced through a high voltage receptacle 130 connected to the high voltage busbar. Premoderator 108 acts as a HV insulator and as a mechanical support for target 106 at high negative bias. The premoderator 108 has a metal cladding 140 at ground potential to minimize high voltage breakdown through the premoderator plastic. During operation, D ⁺ ions in the ion beam are attracted to the titanium target 106, where fast (2.5 MeV) neutrons are created in the resulting DD fusion reaction.

FIG. 13A illustrates an assembly of six modular generators 118, with pre-moderators 108 spaced apart by spacers 128, also made of moderator material. FIG. 13B shows the configuration of FIG. 13A in perspective view. Figure 13C shows the configuration of Figure 13B with one modular generator 118 removed from the assembly. FIG. 13D is a more schematic illustration showing a configuration in which the modular generator can be mounted on a translation and rotation mechanism so that it is positioned for maximum irradiation of the cancer site. As shown in FIGS. 13A-13D, modular generators in embodiments of the invention can be configured in an array to form a complete mobile system of irradiation neutron sources with premoderators. For example, as shown in Figures 13A-13C, in the simplest configuration of the array, the modular generators may form a circle around the human torso or body part. Modular generators are arranged in a three-dimensional array around the subject to maximize neutron flux to a cancer site 148 that may not be centered on a body part 146 illustrated as the human brain in FIG. 13D. can be moved in. Therefore, depending on body contour, shape, and size, and cancer location and distribution, modular generators maximize dose to cancer and minimize dose to other body parts For this reason, it can be moved to match the shape and tumor location. Referring to FIG. 13D , rotation 150 and translation 151 of modular generator 118 may be accomplished by electric motors attached to modular generator 118 .

Seven Functions of Premoderator Because the titanium target is on the premoderator (first stage of moderation), fast neutrons coming from the target enter the premoderator immediately and are quickly moderated to thermal or exothermic energy. be done. The premoderator also provides mechanical support, high voltage supply, and cooling fluid transport to the titanium target. Exemplary pre-moderation materials that can accomplish this are Teflon and HDPE. Both Teflon and HDPE are excellent high voltage dielectrics that can also support the HV busbars 122 and water channels 120 to be used to transport the HV and cooling fluids to the Ti target, as shown in Figure 12C. is. As shown in FIGS. 12A, 12B, and 12C, a single generator 118 consists of an acceleration chamber 100, an ion source 102 that emits deuterium ions, a titanium target 106, and a premoderator 108. FIG. The premoderator 108 is also a high voltage insulator for a high voltage busbar 122 that delivers high voltage (e.g., 80 kV to 300 kV) to the titanium target 106, and water channels 120 that deliver cooling fluid to the titanium target 106. provide the function of being High voltage is delivered from a high voltage power supply through a standard HV receptacle 130 to busbar 122 and then to titanium target 106 , all of which are mounted on premoderator 108 .

In various embodiments of the present invention, the premoderator 108 performs seven functions: (1) moderation, (2) mechanical support of the titanium target, (3) cooling fluid transport to the target, (4) High voltage transport, (5) minimal surface flashover, (6) and a portion of the high vacuum vessel (wall) is performed without outgassing (7). These seven attributes allow for a significant reduction in the distance and amount of material between the fast neutron source and the patient, helping to maintain the maximum neutron flux delivered to the patient.

Modular Generator Around Subject FIGS. 13A-13D show how a generator can be configured. In FIG. 13A, the six modular generators 118 form a ring around the secondary moderator 112 and are part of the structure formed by the secondary moderator 112, spacers 128, and premoderator 108. . Pre-moderator 108 and secondary moderator 112 provide a moderating function by slowing neutrons to extrathermal energy (Function #1). These elements also provide mechanical support for the entire generator and moderator system (function #2).

The secondary moderators 112 can also be separate sections directly attached to the modular generator directly after the premoderator, each separate from the others instead of being a ring 112 as in FIG. 13A. is.

As shown in FIGS. 12B-12C, fluid transport (function #3) is provided through channels 120 that deliver cooling fluid to target 106 to maintain the target at an acceptable operating temperature. Each generator has separate cooling fluid inputs and outputs, with cooling fluid provided through connector 132 shown in FIGS. 12A-12C. Thus, the premoderator provides fluid transport (function #4). High voltage is delivered via high voltage bus 122 through premoderator 108 (function 4, high voltage transport). HDPE, UHMW, and Teflon are excellent insulators and withstand high voltage flashover (feature #6). All three can be used in a vacuum system without excessive outgassing and can help maintain the vacuum of the system (function #7). Achieving these seven functions provides a very compact and flexible neutron source.

Secondary Moderator The secondary moderator 112 (FIGS. 13A-13C) is any one of a number of moderator materials that optimize both maximum flux and neutron energy for maximum dose to the cancer site. one, or a combination thereof. The selection (material, size, and shape) can vary depending on the depth of cancer in the subject and the desired dose at the cancer site. The secondary moderator can be, for example, D2O (heavy water) for delivery of thermal neutrons to pharyngeal and neck cancers _, or a combination of _AlF3 and Teflon for delivery of epithermal neutrons to brain tumors. . Recommended levels of fast thermal and gamma radiation by the IAEA are given in Table 1.

These IAEA recommendations rely on conventional drugs such as p-boronophenylalanine (BPA) that have been approved for human use by the Food and Drug Administration (FDA) for other medical uses. Delivery of higher boron concentrations to cancer sites may depend in part on new drugs to be developed, allowing lower power, less efficient neutron beams to be used. Treatment times can also be faster, so the neutron beam quality does not need to be as high. DD fusion generators in embodiments of the present invention have relatively low beam flux, thus enabling them to be used for cancer therapy.

In some embodiments, multiple modular generators can be distributed around a secondary moderator surrounding a central chamber that holds a subject for treatment, providing an alternative to a fully integrated multi-ion beam system. provide, and may have particular benefits in some circumstances. The benefits are (1) the ability to quickly replace single generators that have failed and need repair, and (2) change the alignment of the generators relative to each other, to the moderator, and to the subject. can include the ability to Alignment of the generator with respect to the subject can optimize neutron dose distribution and density at the cancer site while minimizing spurious radiation, such as gamma rays, that can be emitted outside the device or into healthy tissue of the subject. .

In the prior art, when nuclear reactors and accelerator neutron sources are used, to meet the IAEA criteria for BNCT developed in 2001 for the International Atomic Energy Agency (IAEA), for achieving high quality neutron beams (Current Status of Neutron Capture Therapy (2001) IAEA-TECDOC-1223. In embodiments of the present invention, when multiple modular DD fusion generators are used, these criteria are The IAEA specification assumes that there is a single neutron beam used for all cancers and body locations, which is divided into three neutron energies (thermal, epithermal, and fast neutrons). The moderator and neutron spectrum shifter are then designed to achieve these values for a particular fast neutron source as input specifications, which is the available fast neutron source. Neutrons cannot be used economically, resulting in designs in the prior art that may waste some of them to achieve IAEA universal specifications.DD in embodiments of the present invention For generators such as fusion sources, early calculations indicate that a single DD fusion generator has difficulty achieving the required fast neutron input to the moderation process. In the embodiment of , the use of multiple generators increases the total available fast neutron yield, instead of allowing the beam to enter a single location on the body, so that the decelerated dose is distributed over a wider area of the body. For example, neutrons n are entering the head from many directions, as shown in Figure 13D. Allows reduction of the thermal neutron flux at any one point on the skin of the head while still achieving In early prior art reactor BNCT experiments, the thermal neutron flux burns the subject's skin let me

When considering neutrons to be used for specific cancers, it is desirable to direct the maximum flux to the cancer site, and therefore the specific cancer to be treated must be considered. This includes the location and depth of the human body. Because of their relatively small size and large neutron yield, the modular generators in embodiments of the present invention do this by being positioned to maximize their flux at cancer sites, among others. can be achieved.

In embodiments of the present invention, the generator is placed as close as possible to the patient's body to maximize flux at the cancer site, so a more holistic problem exists. There are a number of parameters for each modular generator: (eg neutron flux, neutron energy, position relative to the body). Out of a single neutron beam pipe (1998 IAEA standards, Table 1) is not the only one to consider. Body parts can now be irradiated in all directions in the novel embodiment of the present invention and neutron intensities are better flux and even more optimal neutron Energy can be adjusted at each modular generator to achieve. The direction of each neutron beam can be adjusted by rotating and displacing each modular generator 118 . The yield of each modular generator can be electronically adjusted by varying the accelerator voltage and ion beam current. Because the moderator size is relatively small and compact compared to the prior art, the neutron spectrum of each modular generator 118 can be tuned by selection of different moderator materials and thicknesses.

Reducing the Required Beam Quality In embodiments of the present invention, the subject's body is bombarded with neutrons from multiple directions. Neutrons can come from all sides of the body part, which minimizes the amount of distance each beam must traverse. Unwanted neutrons striking the skin are now distributed over a larger area, reducing the skin dose of harmful components (eg, gamma rays, and thermal and fast neutrons) per unit area. These ingredients are simply delivered over a larger area of skin. This allows for dose modulation at the cancer site, which is higher than that achieved with a single beam, but with reduced harmful components on a larger area of skin.

It could be argued that the patient could be rotated between exposures in the single beam case of the prior art, but due to possible patient motion, the neutrons are not as accurate as the multibeam embodiment of the present invention. not placed in For each placement, the patient must be carefully reoriented with respect to the single neutron beam, which requires careful placement of the patient.

In embodiments of the present invention, the multiple beam directions and the ability to adjust the neutron flux of each modular generator allows for optimal delivery to cancer sites while reducing harmful components. For example, if the cancer is located in the left lobe of the brain, the neutron flux to the tumor can be adjusted to deliver epithermal neutrons in the direction of that tumor. Since each modular generator neutron flux can be rapidly adjusted by varying the accelerator high voltage or ion beam current, as well as by translation and rotation, this is easily done with delivery determined by a computer program. can break In the present invention, the control computer monitors ion beam current, accelerating voltage, and output neutron yield, which can be adjusted automatically.

Small modular generators in embodiments of the present invention can utilize novel boron drug delivery methods for higher concentrations of boron to cancer sites. Higher concentrations of boron lower the required neutron dose and require shorter delivery times. A higher boron concentration to the cancer site allows the use of neutron generators with lower neutron yields, such as the modular DD fusion generators in embodiments of the present invention.

Each modular generator 118 is an independent device capable of producing neutrons independently of other generators. This allows all available power P to be distributed over the N generators and the heat load to be applied without damaging e.g. a titanium target (single target device using lithium and (unlike) results in a safe distribution. Since the number of neutrons per unit area is fixed by the ion beam power per unit target area, in one example there are six modular generators to distribute the total heat load per titanium target.

A large amount of neutrons is required to adequately treat a tumor in a subject. For thermal management and stability reasons, DD fusion generators are currently limited to fast neutron yields of less than 4×10 ¹⁰ n/s. To increase the neutron yield, the number of neutron generators can be increased in embodiments of the invention. The pre-moderator 108 can be shaped so that more modular generators can be fitted around the subject to be treated. In the example illustrated by FIG. 13A , there are six generators equally spaced around a common secondary moderator 112 , subject cavity 116 , and subject 134 . A spacing block 128 of moderating material (e.g., Teflon or polyethylene), which may be the same as that of pre-moderator 108, is placed between each pre-moderator to provide adequate spacing to fit subject cavity 118. be placed. The wedge angle α as shown in FIG. 12A for the pre-moderator in FIG. 13A is determined by the number of modules 118 with pre-moderator 108 that can fit in a circle around the patient, and how close the surface can be to the patient. determine whether For example, the wedge angle α=30° for 6 generators and α=22.5° for 8 generators.

Movable Source with Fluid Moderator One embodiment of a modular generator system is shown in FIGS. 13A and 13B. In FIG. 13A, a plan view of six modular neutron generators 118 that fit within a cylinder (or ring) is shown. In FIG. 13B, a perspective view is shown. Modular generators can also be configured in other patterns to maximize dose and deliver cancer therapy to selected body organs at specific locations within the subject's body. In some embodiments of the present invention, the modular generator is moved by electric motors and mechanical means to optimized locations for boron biodistribution test biopsy and pathology analysis, positron emission computed tomography. It can provide maximum dose to the cancer site and tumor profile as determined by CT (PET-CT), computed tomography (CT), or magnetic resonance imaging (MRI).

A moderating material can be utilized between the moveable modular generators. For clinical systems, there must be a moderating material between the modular generators. Ideally, the material can be quickly positioned to a new location in the modular generator and be a moderating material. As shown in FIG. 13D, a liquid moderator 156 may be used to surround the modular generator 118 and act as a secondary moderator. The moderating material is shown between moveable modular generators. Liquids are contained in suitable liquid containers. A liquid that also has good deceleration properties can be used and is easily displaced by the modular generator as it moves. For example, different grades of 3M(TM) Fluorinert(TM) e-liquids (eg, FC-40), which are non-conductive, thermally and chemically stable fluids, can be inserted between the generators. Like Teflon, it contains mostly fluorine atoms and no hydrogen, which makes it an excellent moderator.

Moderation Phase The use of multiple modular generators in embodiments of the present invention allows for efficient use of moderator material, reduced size of moderator and shield material, and thus reduced overall system size. . It also reduces the required flux density of fast neutrons by bringing the neutron source closer to the patient and directing the limited number of neutrons to the cancer site in a more efficient manner. The subject's body also becomes part of the equation for the deceleration process. Having neutrons coming from multiple directions reduces the local skin dose and the localized body dose to healthy tissue. Rather than coming into the body at one location, neutrons come from approximately 360 degrees around the body.

Moderation of fast neutrons in embodiments of the present invention is a three-step process. In the first step (1), the pre-moderator 108 acts to reduce the energy of fast neutrons over as short a distance as possible with a minimal amount of gamma radiation being produced in the process. The premoderator also serves as a medium for transporting (2) high voltage and (3) cooling fluid to the fast neutron producing titanium target 106 . Combining these three functions ((1) moderation, (2) fluid transport, and (3) high voltage transport) reduces the distance and amount of material between the fast neutron source and the patient, ultimately helps maintain the maximum neutron flux delivered to the patient at The partially slowed neutrons can then transfer to the secondary moderator 112, which continues the slowing process without excessive generation of gamma rays from, for example, hydrogen. . For small animal models, the moderator of choice may be heavy water ₍ D2O). Neutron energy reduction is continued by D ₂ O without the generation of ˜2.2 MeV gamma rays, which occurs when materials consisting of hydrogen are used.

When irradiating tumors greater than 3 cm deep in the human body, the neutrons need to be moderated to epithermal neutron energies. The human body also acts as a partial final moderator. Thus, epithermal energy neutrons are further slowed down as they travel through the body and are eventually slowed to thermal energy at the tumor site. Those skilled in the art will understand that moderation is a statistically random process of reducing neutron energy accompanied by fluctuations or spread of neutron energy. This process can also result in undesirable gamma ray components (eg, 2.2 MeV gamma rays from hydrogen capture of neutrons) that damage healthy cells. In embodiments of the present invention, the selection of moderating materials can reduce (1) the excess thermal energy component in the skin, (2) the cost and availability of moderating materials, and (3) reduce the harmful gamma ray component while reducing the cancer site. It depends at least in part on the desired energy of the neutrons in the skin of the body to achieve maximum penetration. The energy, yield, direction, and deceleration of each generator can be determined from the moderator material, generator voltage, and accelerating current. Unlike the prior art, moderator dimensions and content can be changed on the fly. In some embodiments of the invention, a liquid moderator (eg, Fluorinert FC40) or granular (eg, AlF ₃ ) moderator may be used. The modular generators are positioned within liquid or particulate moderating materials, where they can be moved quickly and freely between different cancer sites by mechanical means. In the prior art, moderators and shields are large, massive, and usually fixed for single beam reactors or linear accelerators. The patient is typically moved relative to a fixed neutron source.

Using liquid or granular moderating materials allows more efficient reduction of fast neutrons to extrathermal energy while minimizing heat and fast neutrons. Selection of pre-moderation material is important for optimal neutron beam quality. Generally speaking, beam quality is not only concerned with minimizing the harmful component of radiation with thermal neutron production at the cancer site, but also minimizing fast and thermal neutrons at the skin surface. In this process, gamma rays are produced and, depending on the cancer site, fast neutrons are brought to the correct energy so that they penetrate the body and deliver thermal neutrons to the tumor site with minimal irradiation of healthy tissue. must be converted.

Moderating neutrons to thermal energy can result in skin damage. In fact, the thermal neutron dose to the skin can be greater than the dose to the tumor. As neutrons pass through the body, the body itself slows and absorbs the neutrons. The choice of moderating material requires a material that does not moderate fast neutrons to thermal energy too quickly. Thermal neutrons can damage the skin, and if hydrogen atoms are present in the slowing process, damaging gamma rays are also produced. Like moderators, the human body also slows down and absorbs neutrons. The desired and required penetration depth depends on the location of the tumor within the body. Simulations show that thermal neutron penetration starting in the skin results in penetration depths of 3 to 5 cm before most of the neutrons are absorbed.

Teflon Moderator for Clinical Machines When used as a pre-moderator, Teflon (PTFE) can fulfill six of the seven functions listed above. In fact, Teflon excels in some of its attributes. For example, Teflon has no atomic hydrogen, thus avoiding gamma ray production, whereas the use of HDPE does have hydrogen, so the 2.2 MeV gamma ray component is added and with them comes thermal neutron moderation. maximize The choice of HDPE as the pre-moderating material results in the production of thermal neutrons at short distances from the Ti target, while the use of Teflon reduces the production of epithermal neutrons for deeper penetration into the body and2. Resulting in a slower rate of neutron energy reduction from 2.5 MeV, allowing no 2 MeV gamma rays.

Teflon can have a minimum high voltage where a surface arc (flashover or surface discharge) will momentarily short the high voltage, causing damage to the Teflon surface and possibly damage to the high voltage power supply. This is primarily a material issue, not a structural issue (accelerator shape and Teflon shape and structure). Surface discharge along solid insulators in vacuum in high voltage devices determines the maximum voltage between the anode and cathode. The voltage holdoff capability of a solid insulator in vacuum is typically less than that of a similarly sized vacuum gap. O. Ｙａｍａｍｏｔｏら（Ｙａｍａｍｏｔｏ，Ｏ；Ｔａｋｕｍａ，Ｔ；Ｆｕｋｕｄａ，Ｍ；Ｎａｇａｔａ，Ｓ；Ｓｏｎｏｄａ，Ｔ“Ｉｍｐｒｏｖｉｎｇ ｗｉｔｈｓｔａｎｄ ｖｏｌｔａｇｅ ｂｙ ｒｏｕｇｈｅｎｉｎｇ ｔｈｅ ｓｕｒｆａｃｅ ｏｆ ａｎ ｉｎｓｕｌａｔｉｎｇ ｓｐａｃｅｒ ｕｓｅｄ ｉｎ ｖａｃｕｕｍ，”ＩＥＥＥ ＴＲＡＮＳＡＣＴＩＯＮＳ ＯＮ ＤＩＥＬＥＣＴＲＩＣＳ ＡＮＤ ＥＬＥＣＴＲＩＣＡＬ ＩＮＳＵＬＡＴＩＯＮ（２００３）、 10(4):550-556) studied a simple and reliable method to improve the surface dielectric strength of dielectrics such as Teflon, PMMA, and _SiO2 by roughening the surface of the dielectric. did. Some experimental results revealed that in vacuum, charging along the surface of the insulating spacer precedes flashover. Charging occurs through a process in which electrons are emitted from the triple junction where the cathode, insulator, and vacuum meet, propagate toward the anode, and cause a secondary electron emission avalanche (SEEA) along the insulator surface. A dielectric (eg, Teflon or HDPE) can hold a charge and then release it along a surface like a battery or capacitor. This limits the use of plastics such as Teflon and HDPE as insulators and moderators inside the vacuum chamber of the acceleration chamber 100 of the neutron generator.

For a short distance (10 mm) across Teflon, Yamamoto notes that roughening the surface (e.g., by sandpaper or sandblasting) affects the charging of various plastics (such as Teflon and HDPE), which is We found that it decreased as it increased. Yamamoto used a maximum roughness of 37.8 μm, but used a lower voltage gradient and a smaller dielectric thickness (10 mm). Studies in embodiments of the present invention show that larger surfaces of Teflon (e.g., 8 inch distances) can be roughened with a roughness value of 5 microns or greater and 150-2 cm for distances greater than ~2 cm without flashover. We have found that voltages as high as 220 kV can be achieved.

More importantly, the roughening method provides higher dielectric strength without the time-consuming conditioning previously used. This provides a significant advantage and allows the generator in embodiments of the present invention to be operational more quickly.

Depending on the maximum field strength required, the adjustment by the roughening process can take minutes or days. Below 1 MV m ^-1 , the tuning process is relatively fast. Between 1 and 10 MVm ⁻¹ the tuning process takes longer. The best way to monitor how the conditioning is progressing is to record the number of transient discharges (or sparks) per hour. At very high electric fields the arc rate may not get better than a few arcs per hour. The allowable arc rate is application dependent. If the high voltage breakdown (arcing) cannot be tolerated, the system must first be adjusted to a higher electric field and then when the voltage is reduced to operating levels the arc rate will drop to near zero. For very high electric field strengths above 10 MVm ⁻¹ it is very difficult to tune the electrodes to give a zero arc rate. Electrode geometry and material composition become very important at these electric field levels.

Importance of the human body in the moderation process The human body acts as a moderator to reduce epithermal neutrons to thermal energy at cancer sites. The amount of neutron energy reduction by the human body depends, at least in part, on the depth of the tumor within the body. This determines the maximum neutron flux for delivery to the patient. The desired reduction in neutron energy depends on the depth of the tumor within the human body. For example, in pharyngeal and neck cancers, a reduction of neutron energy to thermal energy is desirable for maximum dose to the cancer site. Thermal energy is also desirable for small animal models.

The dimensions within the body from the skin (epidermis) to the cancer site can vary, requiring neutron energy to be sufficiently great for penetration into the cancer, while still being primarily in thermal energy, and boron to capture and destroy cancer cells. In the case of skin cancer in small animal models or humans, neutrons can be in thermal energy. For cancers at greater depths within the body, epithermal neutrons (0.025 to 0.4 eV) may be used.

For tumors deep within the torso, for example pancreatic tumors, epithermal neutrons are required. Pancreatic tumors lie deep within the torso and require epithermal neutrons at the entrance to the body to penetrate to the tumor. Moderation of epithermal neutrons occurs as they pass through the body. Simulations in various embodiments are correct, such as Teflon, ⁷ LiF, and AlF ₃ , which produce epithermal neutrons that penetrate the body and thermalize by the time they reach the depth of the tumor at maximum neutron flux. Indicates the presence of a thickness of material. In embodiments of the present invention, this occurs while minimizing the production of thermal neutrons in the skin.

Clinical Machine Shape to Match the Human Body The shape of the patient chamber within the machine can be contoured to match the human body part to maximize radiation to the cancer site. The shape depends on the body part to be irradiated and the location of the tumor. As shown in FIG. 13D, in the case of glioblastoma 148 (brain cancer), the modular generator 118 is configured in a closed ring around the head 146, which is the cancer site 148 in the brain. can maximize the neutron flux to The intensity of each generator can be varied to achieve maximum thermal neutron delivery to the tumor while minimizing dose to healthy tissue. As discussed above, application in embodiments of the present invention allows control of the distance of each generator from the cancer site. Cancer sites can be mapped using radiological means (CT scan) and/or MRI. A treatment planning protocol can then be determined for optimal use of the clinical neutron source. So the intensity of the neutrons coming from each neutron generator can vary and the location of each individual generator can be optimized.

As shown in FIG. 13D, an improved moderator surrounding the modular generator is a liquid 156 that does not contain hydrogen (a gamma ray generator) but has medium atomic number atoms such as fluorine, carbon, or nitrogen. is to hang or enclose a modular generator. Various types of Fluorinert™, FC-70 or FC-40, or FC3839 can be used. A fluid may be placed between the modular generators, and by mechanical means each modular generator may be moved to some degree independently of the other generators. This fluid can also absorb some heat from the modular generator.

As shown in FIG. 13D, an improved moderator surrounding the modular generator is a liquid 156 that does not contain hydrogen (a gamma ray generator) but has medium atomic number atoms such as fluorine, carbon, or nitrogen. is to hang or enclose a modular generator. Various types of Fluorinert™, FC-70 or FC-40, or FC3839 can be used. A fluid may be placed between the modular generators, and by mechanical means each modular generator may be moved to some degree independently of the other generators. This fluid can also absorb some heat from the modular generator.

Generator Alignment In embodiments of the invention, as seen in FIG. 13D, each stand-alone generator can be positioned and aligned to give maximum flux and neutron distribution at the cancer site, for example. Each generator is of sufficient size and weight that it can be mechanically moved and positioned such that optimal neutron flux at the cancer site is achieved, depending on the location and distribution of the cancer. is small. The generator may be constructed around a moderator whose radial thickness is optimized to deliver maximum thermal neutron flux to the cancer site. Depending on the body part being irradiated, the geometry can be circular or elliptical. By selecting the moderating material and radial thickness, thermal neutrons can be delivered to the cancer site.

FIG. 14A shows an on-axis view of an exemplary clinical neutron source using multiple modular generators 118 for BNCT of the human head. This example uses eight modular generators 118 and various moderating materials combined with reflective and shielding materials (eg, graphite 144). Secondary moderators (166 and 170) may consist of one or more materials. In one embodiment, there is a moderator spacing block 128 made of the same material as the secondary moderator, high density polyethylene (HDPE), ultra high molecular weight polyethylene (UHMW), or (PTFE (Teflon)). These blocks of material fit between the modular generators and adjoin the pre-moderator of each generator. They act as mechanical spacers as well as moderator components. The outside of this area, between and behind the modular generators 118, is filled with either graphite or lead 144 to act as a neutron reflector and shield.

Figure 14B also shows a cross-sectional view of the device of Figure 14A taken along a line through the upper and lower generators. Additional moderator material extends slightly above the premoderator and exists before and after the modular generator. In the present example, the cylindrical space 164 available for the patient's head is 52 cm deep and 30 cm in diameter. This space may be lined with 1-mm cadmium 162 to block too large a thermal neutron dose to the patient's skin. A shield 162 is also shown in FIG. 14A. In other embodiments, this space may be lined with ⁶ LiF.

An exemplary configuration, as illustrated in FIGS. 14A and 14B, consists of multiple layers of 40% Al and 60% AlF ₃ (166) and an additional deceleration cylinder 170 of either ⁷ LiF or D ₂ O. has a secondary moderator of These materials are shown as concentric rings in FIG. 14A. Since ^7LiF or D2O can be expensive, the thickness was varied to obtain the desired neutron beam quality without _overusing either _7LIF or ^D2O . In the example shown in FIGS. 14A and 14B, the thickness ratio between the two regions is changed, the total moderator thickness is 34 cm, and the source is R=52.5 cm from the origin (center of the brain). The effect of changing these materials in this way is plotted graphically in FIG.

The reflector material graphite 144 is 30 cm thick in this example, the thickness t of the Teflon 168 in front of the 2.5 MeV source can be varied, and the moderator portion 170 can be either ⁷ LiF or D ₂ O. is. As t varies, the thickness of the moderator Al/AlF ₃ 166 varies, while all other dimensions remain constant. Targets are embedded in Teflon 168, UHMW, or HDPE. The source is a titanium target 106 bombarded by a 5.0 cm diameter deuterium ion beam. Each target emits 4×10 ¹⁰ neutrons/sec. Eight modular generators 118 emit a total radiation dose of 3.2×10 ¹¹ n/s.

It has been found that there may be concentrations of ¹⁰ B in tumors and healthy tissues (eg skin). ¹⁰ B tumor concentration is assumed to be 50 ppm, while ¹⁰ B in healthy tissue is 15 ppm. The relative biological effectiveness ratio (RBE) for ¹⁰ B in tumors is 2.7 and 1.3 in healthy tissues. Tumor and healthy tissue doses are calculated using the NRC and ICRP models for neutron RBE. Material ⁷ LiF gave the best performance and D ₂ O was the second best.

An important primary objective in these examples is to provide a sufficient dose of neutrons to the cancer while minimizing the dose to and not damaging healthy tissue. FIG. 15 shows the performance for moderators with different values of t in cm and either ⁷ LiF or D ₂ O in the secondary moderator. The ordinate R is the ratio of the tumor dose at the origin to the healthy tissue skin dose, which is the tumor dose at the center of the brain, assuming that it is the site of cancer. As can be seen from Figure 15, ^7LiF outperforms _D2O . Best performance is with R=1.9 and tumor dose above 1.4 Sv/hr. The result of RBE is that a small fraction of fast neutrons is essential to obtain high values for R; and that a reasonable number of epithermal neutrons are required to penetrate the target. Therefore, the combination of ⁷ LiF and D ₂ O outperforms either material alone.

The need for a small animal neutron source Development of boron delivery agents for BNCT is an ongoing and difficult task of high priority. Several boron-10-containing delivery agents have been prepared for potential use in BNCT. With the development of new chemical synthetic techniques and increased knowledge of the biochemical requirements required for effective drugs and their methods of delivery, a wide variety of novel boron agents have emerged, among them Only two, oronophenylalanine (BPA) and borocaptate sodium (BSH), are in clinical use and have US FDA approval. Patient-derived xenografts (PDX) are created by transplanting primary tumors from patients into mouse or small animal models. Testing of drug delivery and efficacy to cancer sites can then be performed. In the prior art, only beams from nuclear reactors and linear accelerator structures can be used. Small laboratory neutron sources, such as those in embodiments of the present invention, are therefore beneficial in the development and testing of novel boron delivery agents and their efficacy in destroying cancer sites.

Fewer stand-alone generators, such as generator 118, are required for delivery systems for small animals, such as mice, as compared to clinical delivery systems. The modular generator used has a slab sidewall angle of α=0 (see α defined in FIG. 12A). The secondary moderator can be a separate container of heavy water ₍ D2O).

Because the small animal target is actually small, the secondary moderator volume can be reduced and the small modular generator can be moved closer to it, allowing the modular generator to be closer to the animal target. Therefore, the neutron flux at the cancer site is increased, and with proper selection of moderating materials and sizes, neutrons can still be moderated to IAEA standards. Additionally, by moving closer, the number of generators can be reduced while still maintaining a high thermal neutron flux at the cancer site.

In the present example of the new technology for small animal sources, four modular generators 118 can be used to emit sufficient thermal neutrons at the cancer site. We can use a 12A, B, C modular generator with a slab sidewall angle of α=0. This makes the premoderator 108 a rectangular cuboid (or "rectangular slab"). FIG. 16A is a perspective view of a modular generator with such a rectangular premoderator 108, suitable for the configuration of four generators in a rectangular array, as shown in FIG. 16B. In FIG. 16B, four modular generators are arranged around a secondary moderator 112, which in one embodiment can be a container of heavy water or granular moderator material. Figure 16C is a cross-sectional view of the configuration of Figure 16B taken along section line 416C-16C of Figure 16B. Elements previously annotated for the modular generator are reused in Figures 16A, 16B, and 16C.

FIG. 16D is an exploded view of four generators 118 returning from a small heavy water moderator 112. FIG. Each generator 118 has a premoderator 108 with a fast neutron generator with a titanium target 106 . A deuterium ion beam is generated by a plasma ion source 102 and accelerated in an acceleration chamber 100 to a titanium target 106 where a DD fusion reaction occurs and emits fast 2.5 MeV neutrons. This description is common to all descriptions or other embodiments within this specification. The generated neutrons pass through a premoderator 108 where they are partially moderated to thermal neutron energy. They then pass to moderator block 112 where they are further moderated, reducing the energy of fast neutrons to thermal neutron energy. Thermal neutrons then enter cylindrical mouth chamber 114 where they enter small animal 116 .

The premoderator is designed to slow down fast neutrons to thermal neutrons by scattering the fast neutrons via collisions with hydrogen in HDPE or UHMW plastics. The distance that a 2.5 MeV neutron must traverse is approximately 3 to 5 cm, and approximately 50% of the neutrons lose enough of their energy to be classified as thermal neutrons. These neutrons, containing both thermal and fast neutron components, then travel into moderator box 112 where they are further moderated by collisions with deuterium atoms. Broadly speaking, HDPE with hydrogen atoms slows down neutrons to thermal energy over short distances; Small animal models are used to test the delivery of boron to cancer sites.

For the premoderator, high density polyethylene (HDPE) is best suited to produce maximum flux of thermal neutrons. As in the clinical generator, it is desirable to create maximum heat flux at the cancer site. Mice are small objects and thermal neutron penetration into cancer sites can be easily achieved. Moderation of fast neutrons to thermal energy is desired with minimal production of gamma radiation that is harmful to healthy cells. As those skilled in the art will appreciate, hydrogen atoms are excellent at scattering fast neutrons, resulting in moderation of the neutrons to thermal energies within the shortest path length in the moderating material. In fact, the use of 5-6 cm high density polyethylene (HDPE) or UHMW plastic results in moderation of 2.5 MeV neutrons to about 50% thermal energy. Further moderation of neutrons due to longer distances in HDPE results in more fast neutrons being converted to thermal energy. However, this results in a reduction of the total available flux (n/cm ² ) since the neutrons are emitted at a 4π solid angle. Hydrogen capture of neutrons produces high-energy gamma radiation, which is destructive to both healthy and cancer cells. Adding another moderator to further thermalize the neutrons is accomplished through the use of heavy water ₍ D2O).

Those skilled in the art should understand that the embodiments described in this application are illustrative and not limiting. Many variations may well fall within the scope of the invention, which is limited only by the following claims.

Claims (24)

A neutron generator,
A moderator material having a top surface, a bottom surface, first and second ends, first and second sides, a first length, a first width substantially less than the first length, and a first thickness. a pre-moderator block of
The first diameter is substantially the first end of the pre-moderator block, sealed at one end to the top surface of the pre-moderator block adjacent the first end of the pre-moderator block, with the vertical axis perpendicular to the top surface. a cylindrical acceleration chamber having a width of 1, the acceleration chamber having a height and a top cover at a second end remote from the premoderator block;
a vacuum pump engaging the acceleration chamber to bring the acceleration chamber to a moderately high vacuum;
a plasma ion chamber that opens into the acceleration chamber through an ion extraction iris through the top cover of the acceleration chamber on the vertical axis of the acceleration chamber;
a gas source providing deuterium gas to the plasma ion chamber;
a microwave energy source for ionizing gas in the plasma ion chamber;
a cylindrical primary separation well centered on the vertical axis of the acceleration chamber and extending a substantial distance from the top surface into the pre-moderator block;
a secondary separation well substantially in the shape of a hollow cylinder surrounding the primary separation well within the first diameter of the acceleration chamber to a depth somewhat less than the substantial distance of the primary separation well;
A water-cooled titanium target disk having a target surface perpendicular to the axis of the acceleration chamber, the target disk having a diameter substantially smaller than the diameter of the separation well, positioned at the lower end of the separation well and substantially a water-cooled titanium target disk biased to a positive negative DC voltage;
an electrically grounded metal cladding covering all exposed surfaces of the premoderator block;
ions extracted through the ion extraction iris are accelerated to bombard a titanium target at the lower end of the primary separation well to produce energetic neutrons that pass through and are moderated by the pre-moderator block; A neutron generator in which any path along the surface from the titanium target to the electrically grounded element is necessarily maximized by primary and secondary separation wells. 2. A neutron generator as claimed in claim 1, wherein the material of the premoderator block is ultra high molecular weight polyethylene (UHMWPE or UHMW), or high density polyethylene (HDPE), or polytetrafluoroethene (PTFE). 3. The neutron generator of claim 2, wherein the surfaces of the primary and secondary separation wells are formed with continuous curves and are roughened to enhance resistance to high voltage flashover. 3. The neutron generator of claim 1, further comprising water feed and return water channels extending longitudinally through the pre-moderator block from the second end of the pre-moderator block to the titanium target for providing cooling water for cooling the target. A high voltage male at the second end of the pre-moderator block coupled to a high voltage busbar realized longitudinally through the pre-moderator block to the target to bias the target to a substantially negative DC voltage. 3. The neutron generator of Claim 1, further comprising a female socket for the connector. Both the first and second sides of the pre-moderator block are angled inwardly by 30 degrees from the vertical for at least a portion of the height such that the six neutron generators are fully aligned with the angled sides. 2. A neutron generator as claimed in claim 1, capable of being placed side by side and forming a closed ring around a central point. Both the first and second sides of the pre-moderator block are angled inwardly by 22.5 degrees from vertical for at least a portion of their height, and the eight neutron generators are arranged so that the angled sides are 2. A neutron generator as claimed in claim 1, allowing them to be placed completely adjacent and forming a closed ring around a central point. A boron neutron cancer therapy system, comprising:
a secondary moderator having a central treatment chamber for the subject;
six substantially identical neutron generators;
Each of six substantially identical neutron generators has a top surface, a bottom surface, first and second ends, opposite sides angled inwardly by 30 degrees along at least a portion of its height, a first a pre-moderator block of moderator material having a length, a first width substantially less than the first length, and a first thickness; a cylindrical acceleration chamber having a first diameter substantially the first width of the pre-moderator block, sealed at one end to the top surface of the pre-moderator block adjacent the end of the acceleration chamber, the acceleration chamber has a height and a top cover at a second end remote from the premoderator block, and engages the acceleration chamber at right angles to the vertical axis to bring the acceleration chamber to a moderately high vacuum. a plasma ion chamber opening into the acceleration chamber through an ion extraction iris through the top cover of the acceleration chamber on a vertical axis of the acceleration chamber; a gas source providing deuterium gas to the plasma ion chamber; a microwave energy source for ionizing gases in the ion chamber; a cylindrical primary separation well centered on the vertical axis of the acceleration chamber and extending a substantial distance from the top surface into the premoderator block; having a secondary separation well in the shape of a substantially hollow cylinder surrounding the primary separation well, within a diameter of 1, to a depth somewhat less than the substantial distance of the primary separation well, and a target plane perpendicular to the axis of the acceleration chamber. A water-cooled titanium target disk, wherein the target disk has a diameter substantially smaller than the diameter of the isolation well, is positioned at the lower end of the isolation well, and is biased to a substantially negative DC voltage. a titanium target disk and an electrically grounded metal cladding covering all exposed surfaces of the premoderator block;
Six neutron generators are positioned around the secondary moderator with the axis of each acceleration chamber passing through the center of the treatment chamber and the angled sides of the neutron generators being fully adjacent to each other. cancer treatment system. further comprising six generally rectangular spacing blocks of moderating material, one spacing block on each adjacent neutron generator with the side of the spacing block fully adjacent the angled side of the neutron generator; 9. The system of claim 8, placed between. 9. The system of claim 8, wherein the secondary moderator is shaped to fill the entire volume between the neutron generator and the central treatment chamber. 9. The system of claim 8, wherein the secondary moderator is a block or blocks of solid moderator material. 10. The system of claim 9, wherein the secondary moderator is a container filled with heavy water. 10. The system of claim 9, wherein the secondary moderator is a container filled with granular moderator material. A boron neutron cancer therapy system, comprising:
a secondary moderator having a central treatment chamber for the subject;
eight substantially identical neutron generators;
Each of eight substantially identical neutron generators has a top surface, a bottom surface, first and second ends, opposite sides angled inwardly by 22.5 degrees along at least a portion of its height, a first a pre-moderator block of moderator material having a length of one, a first width substantially less than the first length, and a first thickness; A cylindrical acceleration chamber having a first diameter substantially the first width of the pre-moderator block, sealed at one end to the top surface of the pre-moderator block adjacent the first end, the acceleration chamber comprising: The acceleration chamber is a cylindrical acceleration chamber having a height and a top cover at a second end remote from the premoderator block, and engaging the acceleration chamber at right angles to the vertical axis and pulling the acceleration chamber to a moderately high vacuum. a vacuum pump to bring about a state; a plasma ion chamber that opens into the acceleration chamber through an ion extraction iris through the top cover of the acceleration chamber on a vertical axis of the acceleration chamber; and a gas source that provides deuterium gas to the plasma ion chamber. a microwave energy source for ionizing gases in the plasma ion chamber; a cylindrical primary separation well centered on the vertical axis of the acceleration chamber and extending a substantial distance from the top surface into the premoderator block; a secondary separation well in the shape of a substantially hollow cylinder surrounding the primary separation well, to a depth somewhat less than the substantial distance of the primary separation well, and a target plane perpendicular to the axis of the acceleration chamber, within a first diameter of wherein the target disk has a diameter substantially smaller than the diameter of the isolation well, is positioned at the lower end of the isolation well and is biased to a substantially negative DC voltage , a water-cooled titanium target disk and an electrically grounded metal cladding covering all exposed surfaces of the premoderator block;
Eight neutron generators are positioned around the secondary moderator with the axis of each acceleration chamber passing through the center of the treatment chamber and the angled sides of the neutron generators being fully adjacent to each other. cancer treatment system. Further comprising eight generally rectangular spacing blocks of moderating material, one spacing block for each adjacent neutron generator with the side of the spacing block fully adjacent the angled side of the neutron generator. 15. The system of claim 14, placed between. 15. The system of claim 14, wherein the secondary moderator is shaped to fill the entire volume between the neutron generator and the central treatment chamber. 15. The system of claim 14, wherein the secondary moderator is a block or blocks of solid moderator material. 15. The system of claim 14, wherein the secondary moderator is a container filled with heavy water. 15. The system of claim 14, wherein the secondary moderator is a container filled with granular moderator material. A therapeutic system for evaluating a boron source for boron neutron cancer therapy (BNCT), comprising:
a substantially square secondary moderator having a central treatment chamber for the subject;
four substantially identical neutron generators;
each of four substantially identical neutron generators having a top surface, a bottom surface, first and second ends, opposing parallel sides, a first length and a first width substantially less than the first length , and a pre-moderator block of moderator material having a first thickness and at one end to the top surface of the pre-moderator block adjacent the first end of the pre-moderator block, with a vertical axis perpendicular to the top surface A sealed cylindrical acceleration chamber having a first diameter substantially a first width of the pre-moderator block, the acceleration chamber having a height and a width at a second end remote from the pre-moderator block. A cylindrical acceleration chamber having a top cover, a vacuum pump engaging the acceleration chamber perpendicular to the vertical axis to bring the acceleration chamber to a medium high vacuum, and a top of the acceleration chamber on the vertical axis of the acceleration chamber. A plasma ion chamber opening into an acceleration chamber through an ion extraction iris through a cover, a gas source providing deuterium gas to the plasma ion chamber, a microwave energy source ionizing the gas in the plasma ion chamber, and an acceleration chamber. a cylindrical primary separation well extending a substantial distance into the pre-moderator block from the top surface centered on the vertical axis of and within a first diameter of the acceleration chamber somewhat less than the substantial distance of the primary separation well A secondary separation well in the shape of a substantially hollow cylinder surrounding the primary separation well to depth, and a water-cooled titanium target disk having a target surface perpendicular to the axis of the acceleration chamber, the target disk extending into the separation well. A water-cooled titanium target disk having a diameter substantially smaller than the diameter, positioned at the lower end of the isolation well and biased to a substantially negative DC voltage, and all exposed surfaces of the pre-moderator block. an electrically grounded metal cladding covering;
A treatment system wherein four neutron generators are positioned around a substantially square secondary moderator with the axis of each acceleration chamber passing through the center of the treatment chamber. 21. The system of claim 20, wherein the secondary moderator is a block or blocks of solid moderator material. 21. The system of claim 20, wherein the secondary moderator is a container filled with heavy water. 21. The system of claim 20, wherein the secondary moderator is a container filled with granular moderator material. A boron neutron cancer therapy system, comprising:
a moderator chamber filled with a liquid or particulate moderator material except for a central treatment chamber and having parallel upper and lower surfaces;
a plurality of neutron generators;
a mechanically adjustable carrier for the neutron generator;
Each of the plurality of neutron generators has a top surface, a bottom surface, first and second ends, opposing sides, a first length, a first width substantially less than the first length, and a first thickness. and a first pre-moderator block sealed at one end to the top surface of the pre-moderator block adjacent the first end of the pre-moderator block with a vertical axis perpendicular to the top surface A cylindrical acceleration chamber having a diameter substantially the first width of the pre-moderator block, the acceleration chamber having a height and a top cover at a second end remote from the pre-moderator block. a vacuum pump that engages the acceleration chamber and places it in a medium high vacuum, and an ion extraction iris through the top cover of the acceleration chamber on the vertical axis of the acceleration chamber and into the acceleration chamber. a plasma ion chamber opening into, a gas source providing deuterium gas to the plasma ion chamber, a microwave energy source ionizing the gas in the plasma ion chamber, and a pre-deceleration from the top surface about the vertical axis of the acceleration chamber. A cylindrical primary separation well extending a substantial distance into the block of material and a substantially hollow surrounding the primary separation well within the first diameter of the acceleration chamber to a depth somewhat less than the substantial distance of the primary separation well. A water-cooled titanium target disk having a secondary separation well in the shape of a cylinder and a target surface perpendicular to the axis of the acceleration chamber, the target disk having a diameter substantially smaller than the diameter of the separation well, a water-cooled titanium target disk positioned at the lower end of the isolation well and biased to a substantially negative DC voltage, and an electrically grounded metal cladding covering all exposed surfaces of the pre-moderator block; with
mechanically adjustable carriers for the neutron generators, each carrier supporting one neutron generator and translating the neutron generator towards and away from the central treatment chamber; and allowing the neutron generator to rotate in a plane parallel to the planes of the parallel upper and lower surfaces of the moderator chamber,
A boron neutron cancer therapy system in which a modular generator and a mechanically adjustable carrier are fully immersed in a liquid or particulate moderator material in a moderator chamber.

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