Cross Reference to Related Application

[0002] This application claims priority to and the benefit of US Provisional Application No. 63135733, filed January 10, 2021, which is incorporated herein by reference in its entirety.

Technical Field

[0003] Neutron capture therapy (NCT) has been used for treating locally invasive malignant tumors such as primary brain tumors, recurrent head and neck cancer, and cutaneous and extracutaneous melanomas. It is a two-step procedure: first, the patient is injected with a tumor-localizing drug containing neutron-capturing material, such as the non-radioactive isotope boron-10 (10B), that has a high propensity to capture thermal neutrons. The probability of neutron capture (the absorption neutron cross section) of 10B is much higher than that of other elements present in tissues such as hydrogen, oxygen, and nitrogen. In the second step, the patient is radiated with epithermal neutrons. Neutron may be generated by different devices, such as reactor-based neutron sources or accelerator-based neutron sources. Referring to Figs, la-lb, after losing energy as they penetrate tissue, neutrons 001 are captured by the 10B 002, which subsequently emits high-energy alpha particle 003 and Li nuclei 004 that kill cancer cells 012 having sufficient quantities of 10B 002 inside. Both the alpha particle 003 and the lithium nuclei 004 cused ionizations in the immediate vicinity of the reaction, with a range of 5-9 μm, which is approximately the diameter of the target cell. Accordingly, the damage caused by the neutron capture reaction is limited to lOB-containing cancer cells 012. Normal cells Oil, without 10B inside, allow neutron 002 pass through and are unharmed. BNCT, therefore, can be considered as both a biologically and a physically targeted type of radiation therapy (targeted radiotherapy). [0004] In addition to 10B, other non-radioactive isotopes, such as gadolinium, has also been used for experimental studies but has not been used clinically yet. NCT that uses 10B as neutron capture material, called Boron Neutron Capture Therapy (BNCT), has been used clinically as an alternative to conventional radiotherapy for the treatment of high-grade gliomas, meningiomas, and recurrent, locally advanced cancers of the head and neck region and superficial cutaneous and extracutaneous melanomas.

Background Art

[0005] The success of BNCT depends on the selective delivery of sufficient amounts of 10B to the tumor while only small amounts of 10B localized in the surrounding normal tissues. Various boron delivery agents have been synthesized. BSH (Na2B12HllSH, sodium borocaptate), and BPA (a dihydroxyboryl derivative of phenylalanine) are well studied, and BPA has been used in many clinical trials.

[0006] Since both tumor and surrounding normal tissues are present in the neutron radiation field, even with an ideal epithermal neutron beam, there will be an unavoidable, nonspecific background dose, consisting of both high- and low-LET radiation. However, a higher concentration of 10B in the tumor will result in a higher total dose than that of adjacent normal tissues and caused irreparable damage to the tumor cells. Normal tissues, with none or small amount of 10B accumulation, sustains only minor damage and heals after the treatment. Accordingly, BNCT is an effective therapy against irregular-shaped tumors, multifocal tumors, or scattering cancer cells.

[0007] One problem for BNCT treatment is the poor tissue-penetrating properties of the thermai/epitherma! neutron beams. As thermal neutrons attenuate rapidly in tissues, external neutron beam will only be able to treat tumors located at or close to the surface. Epithermal neutron beam was utilized to provide a high flux of thermal neutrons at greater depths. However, the increase in tumor treatment depth (by using epithermal neutrons) is still very limited. Accordingly, most of the treatments in BNCT were limited to tumors close to the skin.

[0008] Doctors have tried to use BNCT to treat tumors that sit deep inside the body cavity in the past. Two patients with colon cancer, which had spread to the liver, have been treated with BNCT in Italy. The first was treated in 2001 and the second in mid-2003. The patients received an i.v. infusion of BPA, followed by removal of the liver (hepatectomy), irradiating the liver outside of the body (extracorporeal BNCT), and then re-transplanted into the patient. One of the patients survived, but it is unpractical to perform hepatectomy and re- transplant for every treatment. [0009] US5658233 patent described an improvement of BNCT. As seen in Fig. lc, a guide tube 6 is inserted into the target organ 7 , and a capillary neutron focusing lens 4 were used to direct neutrons to the tumor 1, and thereby avoiding damage to surrounding normal cells inside organ 7. By inserting a guide tube 6 into the target organ 7, a passageway through healthy tissue is provided for the cold neutrons concentrated by the neutron focusing lens 4. The 233 patent described a method that cold neutrons may be effectively administered to a tumor deeply embedded in healthy tissue without exposing the surrounding healthy tissue to neutrons. However, this method has never been adopted by the BNCT industry, probably because removing some healthy tissue from an organ to create a space for inserting the guide tube may cause serious harm to that organ. This prior art design also reduces or limits BNCT's ability of treating irregular-shaped tumors, multifocal tumors, or scattered cancer cells.

[0010] Studies about using capillary neutron optics to change neutron paths have been published in the 90's. For example, an article titled "Capillary Neutron Optics For Boron Neutron Capture Therapy" by Q. F. Xiao, ... et al. was disclosed in Cancer Neutron Capture Therapy (edited by Yutaka Mishima, 1996 Edition). Glass capillaries with narrow channels can guide and bend thermal and cold neutrons. Capillary neutron optics, consisting of arrays of capillary fibers, can perform neutron focusing, neutron imaging, and filtering fast neutron and gamma rays.

[0011] Specific neutron guides for focusing neutron beam have also been disclosed. For example, the focusing effect of liner taping neutron guide 051, parabolic neutron guide 052, and elliptic neutron guide 053 were discussed in Neutron Guides (by Ken Anderson, published 2015/07/29, European Spallation Source). (Fig. Id)

[0012] Fig. 2a shows how a typical neutron capture treatment system operates. A typical neutron capture treatment system includes a neutron source 500 that generates neutron beam 100. Here we use a cyclone type accelerator-based neutron source as an example.

The neutron source 500 includes an accelerator 510, a transportation system 520, and a neutron irradiation system 530. The Cyclotron 511 generates proton beam 512 in accelerator 510. The beam transportation system 520, including arrays of magnets 521, transports and reshapes proton beam 512 to hit the target 531. The target 531, after being hit by the proton beam 512, generates neutrons with different energy levels. Moderator desired energy level, such as epithermal neutrons, to pass through. The epithermal neutrons that emitted from opening 540 form neutron beam 100. The neutron beam 100 penetrates the cavity wall 230 and enters the body cavity 200. Although we use accelerator-based neutron source as an example, the neutron source can be reactor-based neutron source or any other devices that generate neutron beams.

[0013] Referring to Fig. 2b. Organ 212, with tumor 211 inside, is embedded within body cavity 200. When the patient is irradiated with neutron beam 100, the neutron beam 100 passes through cavity wall 230, healthy organs 220, and body fluid inside the body cavity 200. Because thermal/epithermal neutrons attenuate rapidly in tissues and in body fluids, neutron beam 100 can only effectively treat tumors within a limited distance from the surface (the effective distance D). And because tumor 211 is located outside the effective distance D, BNCT treatment cannot be used to treat this tumor 211 effectively.

Summary of the Invention

[0014] The present invention provides a neutron capture treatment system to increase the flux of thermal neutrons at deeper locations surrounded by fluids, tissues and organs. The present invention also provides a device to guide the neutron beam into the body cavity.

Brief Description of Drawings

[0015] Figs, la-lb show the basic theory of BNCT.

[0016] Fig. lc shows a neutron focusing lens to direct cold neutron into deep tumor. [0017] Fig. Id shows how neutrons travel inside different neutron guides.

[0018] Fig. 2a illustrates how BNCT treatment is performed.

[0019] Fig. 2b illustrates the treatment depth limitation of existing BNCT technology. [0020] Figs. 3a-3c show one embodiment of the invention.

[0021] Fig. 4 shows another embodiment of the invention.

[0022] Fig. 5a-5b show another embodiment of the invention. [0023] Fig. 6a-6b show another embodiment of the invention.

[0024] Fig. 7a-7b show another embodiment of the invention.

[0025] Fig. 8 shows several expandable structures.

[0026] Fig. 9 shows another embodiment of the invention.

[0027] Figs. 1Oa-1Ob show another embodiment of the invention.

[0028] Fig. 11 shows how neutron beam can be directed through the neck of a neutron tunnel.

[0029] Figs. 12a-12b show another example for directing neutron beam through the neck of a neutron tunnel.

[0030] Fig. 13 shows how a neutron guide changes the direction of a neutron beam.

[0031] Fig. 14 shows another embodiment of the invention.

Modes for Carrying Out the Invention

[0032] The present invention provides a NCT treatment system to increase the flux of thermal neutrons at deeper locations surrounded by fluids, tissues and organs. The present invention also provides a device to guide the neutron beam into the body cavity.

[0033] To overcome the penetration depth limitation for traditional NCT treatment, a NCT treatment system of the present invention is disclosed in Fig. 3a. The NCT treatment system of the invention includes a neutron source 500 to generate neutron beam 100 and a neutron tunnel 310, inserted into the body cavity 220, to create a neutron pathway for neutron beam 100.

[0034] Fig. 3b explains how the neutron tunnel 310 works. By creating a passage inside the patient's body cavity, neutron beam 100 passes through neutron tunnel 310 without significant attenuation and thh tumor 211 is now within the effective distance D. There is no need to insert the neutron tunnel 310 into the organ 212.

[0035] Although the neutron tunnel can be a solid block, preferably the neutron tunnel 310 includes an outer shell to define an enclosed hollow space. The neutron tunnel 310 can also block the opening on cavity wall 230 to prevent pathogens from entering the patient's body cavity during BNCT treatment time. The outer shell of neutron tunnel 310 can be solid or flexible, and the hollow space may be filled with fluids like gas or liquid. The outer shell, nonetheless, may also be an open structure like a tube or a frame.

[0036] As seen in Fig. 3c, neutron tunnel 310 needs not be positioned in close proximity to the organ 212. Healthy organ 220 may sit between neutron tunnel 310 and tumor 211, as long as the tumor 211 is still withing the effective distance D from neutron tunnel 310.

[0037] In another embodiment of the invention, the neutron tunnel 310 is affixed to the cavity wall 230 by fixing members 401. (See Fig. 4) Fixing members 401 can be constructed with flexible materials (such as tapes), rigid materials (such as plastic or metal), or both. Please note that although we use plural fixing members 401 as example, it is intended to also cover single fixing member as well. For example, fixing members 401 can be a clamp or a clip.

[0038] Figs. 5a and 5b show another embodiment of the invention. Fixing members 401 keeps the opening on the cavity wall 230 open and neutron tunnel 310 can slide along the fixing members 401. When the patient breathes, the cavity wall 230 moves from position A (Fig. 5a) to position B (Fig. 5b) and fixing members 401 move with the cavity wall 230. The neutron tunnel 310 remains at substantially the same position comparing to the tumor 211. Neutron tunnel 310 can be temporarily attached to the surface of organ 212 using existing methods. For example, MIT engineers developed a double-sided detachable adhesive that can affix devices to the surfaces of organs and the result was published in the Proceedings of the National Academy of Sciences in June 2020.

[0039] Figs. 6a and 6b show another embodiment of the invention. The neutron tunnel 310 includes an expandable structure 311 and a connecting structure 312. After been inserted into the body cavity 200, the expandable structure 311 expends and creates a proper pathway for neutron beam. Although the neutron beam still passes through cavity wall 230, tumor 211 is still within the effective distance D.

[0040] Figs. 7a and 7b show yet another embodiment of the invention. After being inserted into the body cavity 200, the neutron tunnel 310 expends and pushes healthy organs 220 and/or body fluid away. The opening on the cavity wall 230 is also widened. [0041] The expandable structure of the embodiments of the invention can be any available structure. For example, an inflatable plastic bag with a predetermined shape, a retractor, a speculum, or a spreader. Fig. 8 shows some expandable frames that can be used as the expandable structure. Neutron tunnel 310 may include an expandable structure and an elastic shell or a membrane covering the expandable structure, wherein the shell/membrane keeps body fluid outside the neutron tunnel 310.

[0042] In another embodiment of the invention, neutron tunnel 310 also includes a neutron lens 510 to alter the direction of neutron beans. See Fig. 9.

[0043] It may be desirable that the opening on cavity wall 230 can be as small as possible, and under certain conditions it may be necessary to insert the neutron tunnel 310 between two healthy organs 220 (or ribs). Referring to Fig. 10a, another embodiment of the invention shows a neutron tunnel 310 with a narrower "neck". Neutron tunnel 310 can transform between a first shape 3101 and a second shape 3102. See Fig. 10b. When in the first shape 3101, the smaller end of the neutron tunnel 310 can be inserted easily through the opening on the cavity wall 230. After insertion, the neutron tunnel 310 transforms into the second shape 3102 to create propel neutron pathway. After BNCT treatment, the neutron tunnel 310 transforms back to the first shape 3101 and can be removed easily.

[0044] Fig. 11 shows how neutron beam can be directed through the neck of the neutron tunnel 310 when treating a tumor 211 that is larger than the opening of the neck. Area A and area B are at opposite ends of tumor 211. In this embodiment, a neutron lens 510 is introduced to focus the neutron beam 100. If the neutron lens 510 is positioned so that the focal point of neutron lens 501 is close to or is approximately at the neck of neutron tunnel 310, the focused neutron beam 101 passes through the neck and widens after passing through the neck, thereby both area A and area B of the tumor 211 can be irradiated by neutron beam 101. Please be noted that neutron lens 501 can be capillary neutron optics, neutron guides, or any device that can change the neutron beam's pattern.

[0045] In another embodiment of the invention, irradiation of areas A and B of tumor 211 is achieved by changing the irradiation direction of neutron beams or by changing the patient's position. When neutron beam 100 comes from a first angle (Fig. 12a), neutron beam reaches area A of tumor 211. When neutron beam 100 comes from a second angle (Fig. 12b), neutron beam reaches area B of tumor 211. By changing the position of the patient (using a movable treatment seating area), it is possible to change the incoming angle of neutron beam 100 thereby all areas of tumor 211 receives enough neutron irradiation.

[0046] In another embodiment of the invention, neutron tunnel 310 is a curved neutron guide. As seen in Fig. 13, one end of the neutron tunnel 310 may be widened to cover more area. But it is not necessary to have one widened end.

[0047] The incoming neutron beam 100 may be wider than the neutron tunnel 310. In yet another embodiment, neutron shield 520, made of neutron blocking or absorbing materials, is introduced to protect the tissues or organs close to the neutron tunnel 310. (See Fig. 14)

[0048] The invention also includes combination of the features of all embodiments. For example, fixing member 401 of Fig.5a can be used with the neutron tunnel 310 of Fig. 10a.

In this setup, the fixing member 401 is attached to the organ 312, and inner end (the end inside the body cavity 200) of the tunnel 310 can slide alone fixing member 401 to keep the neutron pathway open.