Diffusing alpha-emitter radiotherapy for glioblastoma

Abstract

This application relates to diffuse alpha-emitter radiotherapy for glioblastoma. A method for treating a tumor includes identifying the tumor as a glioblastoma tumor, and implanting at least one diffuse alpha-emitter radiotherapy (DaRT) source (21) having a suitable radon release rate into the tumor identified as a glioblastoma tumor and sustaining it for a given duration, such that the source (21) provides a cumulative radon release activity between 6.5 megabecquerels (MBq) hours and 14.3 MBq hours per centimeter length during the given duration.

Description

[0001] This application is a divisional application of the application filed on June 8, 2022, with application number 202280005644.2 and invention title "Diffuse α-emitter radiotherapy for glioblastoma". Invention Field

[0002] The present invention relates generally to radiotherapy, and particularly to apparatus and methods for delivering tumor-specific radiation doses in radiotherapy treatment. Background of the Invention

[0003] Ionizing radiation is commonly used to treat certain types of tumors, including malignant cancers, by destroying their cells. However, ionizing radiation can also damage a patient's healthy cells, and therefore care must be taken to minimize the radiation dose delivered to healthy tissues outside the tumor while maximizing the dose delivered to the tumor.

[0004] Ionizing radiation damages cells by inflicting damage on their DNA. The bioeffectiveness of different types of radiation in killing cells is determined by the type and severity of DNA damage they cause. Alpha particles are a powerful tool in radiotherapy because they induce clusters of double-strand breaks in DNA that cells cannot repair. Unlike conventional types of radiation, the destructive effects of alpha particles are largely unaffected by low cellular oxygen levels, making them equally effective against hypoxic cells, the primary reason for the failure of conventional radiotherapy based on photons or electrons in tumors. Furthermore, the short distance (less than 100 micrometers) of alpha particles within tissue ensures that surrounding healthy tissue is spared if the emitting atoms are confined within the tumor volume. On the other hand, the short distance of alpha radiation has so far limited its application in cancer therapy because there is no practically feasible method to deploy alpha-emitting atoms at a sufficient concentration throughout the entire tumor volume.

[0005] For example, alpha-emitter radiation therapy (DaRT), described in Kelson's U.S. Patent 8,834,837, extends the therapeutic range of alpha radiation by using radium-223 or radium-224 atoms, which produce several chains of radioactive decay, with radium-224 having a dominant governing half-life of 3.6 days and radium-223 having a dominant half-life of 11.4 days. In DaRT, radium atoms attach to the source implanted in the tumor (also called "seeds") with enough intensity that they do not leave the source in a wasteful manner (removed from the tumor via the bloodstream), but a considerable percentage of their daughter radionuclides (radon-220 in the case of radium-224 and radon-219 in the case of radium-223) leave the source and enter the tumor upon radium decay. These radionuclides and their own radioactive daughter atoms diffuse over radial distances of up to several millimeters around the source before decaying through alpha radiation. Therefore, the extent of destruction within the tumor increases relative to the radionuclides that remain at the source along with their daughter atoms.

[0006] For tumor treatment to be effective, the DaRT seeds used in the treatment should release a sufficient number of radon atoms to destroy the tumor with a high probability. If the radiation dose used is insufficient, too many cancer cells will remain in the tumor, and these cells can proliferate and reform into malignant tumors. On the other hand, the seeds should not release too many radon atoms, because some of their progeny are cleared from the tumor through the bloodstream, and may therefore damage distant healthy tissues, including the patient's organs such as bone marrow, kidneys, and / or ovaries.

[0007] The amount of radium atoms on a DaRT source is quantified by its activity (i.e., the rate of radium decay). DaRT source activity is measured in microcuries (µCi) or kilobecquerels (kBq), where 1 µCi = 37 kBq = 37,000 decays per second. When using DaRT, the radiation dose delivered to tumor cells depends not only on the radium activity of the source but also on the probability that radon atoms, the daughter atoms, leave the source and enter the tumor during the alpha decay of radium. This probability is referred to in this paper as the "desorption probability." Therefore, instead of expressing it in terms of source activity, one can use the "radon release rate" as a measure of the source's DaRT-related activity, which in this paper is defined as the product of the source activity and the probability of radon desorption from the source. Similar to activity, the radon release rate is given in µCi or kBq. Unless otherwise stated, the activity and radon release rate values ​​given in this article are the activity and radon release rate values ​​of the source when the source is implanted into a tumor.

[0008] The aforementioned Kelson U.S. Patent 8,834,837 suggests using an activity of "about 10 nanocuries to about 10 microcuries, more preferably about 10 nanocuries to about 1 microcurie". Invention Overview

[0009] Embodiments of the present invention relate to providing a precisely tailored dose of radiation to a tumor during radiotherapy treatment. Embodiments include a radiotherapy source designed to provide an appropriate dose of radiation, and a kit comprising an appropriate number of sources for a tumor of a specific size. Further embodiments relate to methods for preparing a kit of radiotherapy sources for a specific tumor and methods for treating the tumor.

[0010] Therefore, according to embodiments of the present invention, a method for treating glioblastoma tumors is provided, the method comprising identifying the tumor as a glioblastoma tumor, and implanting at least one diffuse alpha emitter radiotherapy (DaRT) source having a suitable radon release rate into the tumor identified as a glioblastoma tumor and sustaining it for a given duration, such that the source provides a cumulative radon release activity between 6.5 megabecquerels (MBq) hours and 14.3 MBq hours per centimeter length during the given duration.

[0011] Optionally, implanting at least one radiotherapy source comprises an array of implanted sources, wherein each source in the array is spaced no more than 4 mm from its neighboring sources. In some embodiments, implanting at least one radiotherapy source comprises an array of implanted sources arranged in a hexagonal pattern, wherein each source in the array is spaced no more than 4 mm from its neighboring sources. Optionally, at least one radiotherapy source has a radon release rate between 1.4 microcuries and 3.1 microcuries per centimeter of length. Optionally, at least one radiotherapy source has a radon release rate between 1.9 microcuries and 2.6 microcuries per centimeter of length, preferably between 1.8 microcuries and 2.6 microcuries per centimeter of length. Optionally, the method includes selecting a given duration before implanting at least one DaRT source into a tumor, and removing the source from the tumor after the given duration has elapsed since the source implantation began.

[0012] According to embodiments of the invention, a method for preparing for radiotherapy treatment is also provided, the method comprising identifying a tumor as a glioblastoma tumor, receiving an image of the glioblastoma tumor; and providing an arrangement of diffuse alpha-emitter radiotherapy (DaRT) sources for the glioblastoma tumor, wherein the sources have a radon release rate between 1.4 microcuries and 3.1 microcuries per centimeter of length. Optionally, providing the arrangement includes providing an arrangement in which the spacing between the sources in the tumor is 4 millimeters or less. Optionally, the sources have a radon release rate between 1.8 microcuries and 2.6 microcuries per centimeter of length.

[0013] According to an embodiment of the invention, an apparatus for preparing radiotherapy treatment is also provided, the apparatus comprising an input interface for receiving information about a tumor; a processor configured to determine that the tumor is a glioblastoma tumor and generate an arrangement of diffuse alpha-emitter radiotherapy (DaRT) sources for the tumor, wherein the sources in the arrangement have radon release rates between 1.4 microcuries and 3.1 microcuries per centimeter of length, and the sources in the arrangement are arranged in a regular pattern with a distance of no more than 5 millimeters between adjacent sources; and an output interface for displaying the arrangement to a human operator.

[0014] According to embodiments of the invention, a method for preparing radiotherapy treatment is also provided, the method comprising receiving a request for a diffuse alpha-emitter radiotherapy (DaRT) source for glioblastoma tumors, determining the number of radiotherapy sources required for the glioblastoma tumors, and providing a sterile kit comprising the determined number of radiotherapy sources, wherein the sources have a radon release rate between 1.4 microcuries and 3.1 microcuries per centimeter of length.

[0015] Optionally, determining the required number of radiotherapy sources includes determining the number of sources required to cover the tumor area with a spacing between the sources not exceeding 4 mm. Optionally, the sources have a radon release rate between 1.8 microcuries and 2.6 microcuries per centimeter of length.

[0016] According to embodiments of the invention, a diffuse alpha-emitter radiotherapy (DaRT) source for implantation in glioblastoma tumors is also provided, wherein the DaRT source has a radon release rate between 1.4 microcuries and 3.1 microcuries per centimeter of length. Optionally, the radon release rate is between 1.8 microcuries and 2.6 microcuries per centimeter of length.

[0017] According to embodiments of the invention, a kit for implanting a diffuse alpha-emitter radiotherapy (DaRT) source into a glioblastoma tumor is also provided, the kit comprising packaging, preferably sterile packaging; and more than one DaRT source placed within the packaging, the source having a radon release rate between 1.4 microcuries and 3.1 microcuries per centimeter of length. Optionally, the radon release rate of the source is between 1.8 microcuries and 2.6 microcuries per centimeter of length.

[0018] According to embodiments of the invention, a method for treating a tumor is also provided, the method comprising identifying the tumor as a glioblastoma tumor, and implanting an array of diffuse alpha-emitter radiotherapy (DaRT) sources into the tumor identified as a glioblastoma tumor, the diffuse alpha-emitter radiotherapy (DaRT) sources being regularly arranged with a spacing between every two adjacent sources of 3 mm and 4 mm or 3.5 mm and 4.5 mm. Optionally, the array of implanted sources comprises implantation in a hexagonal arrangement, wherein each source in the array is spaced no more than 4 mm from its neighboring sources, preferably no more than 3.5 mm.

[0019] According to an embodiment of the invention, a diffuse alpha emitter radiotherapy (DaRT) source is also provided for use in treating glioblastoma tumors in patients, said source comprising: Support member, having a length of at least 1 mm; and Radium-224 atoms, coupled to the support, such that when the source is implanted into the tumor, no more than 20% of the radium-224 atoms leave the support and enter the tumor within 24 hours without decay, but upon decay, at least 5% of the radionuclides of the radium-224 atoms leave the support. The application mode of the source includes implanting the source throughout the entire tumor of the glioblastoma tumor, with the spacing between the sources between 3 and 4.5 mm. The radiotherapy source has a radon release rate between 1.4 microcuries and 3.1 microcuries per centimeter of length.

[0020] Optionally, the application mode of the source includes implanting the source throughout the entire tumor of the glioblastoma tumor, with the spacing between the sources between 3.1 and 3.9 mm. Optionally, the radiotherapy source has a radon release rate between 1.4 and 2.3 microcuries per centimeter of length. Optionally, the radiotherapy source has a radon release rate between 1.4 and 1.9 microcuries per centimeter of length. Optionally, the at least one radiotherapy source has a radon release rate between 1.9 and 2.6 microcuries per centimeter of length. Optionally, the application mode of the source includes implanting the sources into the entire tumor of the glioblastoma tumor in a hexagonal arrangement, with each source in the array spaced no more than 4 mm from its neighboring sources. Brief description of the attached diagram

[0021] Figure 1 This is a schematic diagram of a system for planned radiotherapy treatment according to an embodiment of the present invention; Figure 2 This is a flowchart illustrating the actions performed in preparation for radiotherapy treatment of a tumor according to an embodiment of the present invention; Figure 3 This is a schematic diagram showing the regular arrangement of sources in a hexagonal pattern according to an embodiment of the present invention; Figure 4 This is a schematic diagram of a DaRT source kit according to an embodiment of the present invention; Figure 5 This is a schematic diagram of a radiotherapy source according to an embodiment of the present invention; Figures 6A-6D This is a graph illustrating a wide range of radon release rate values ​​required to ensure a nominal alpha particle dose of at least 10 Gy for different seed spacing, lead-212 leakage probability, and radon-220 and lead-212 diffusion distances. Figure 6E This is a contour plot showing the values ​​of the radon release rate required for various possible radon-220 and lead-212 diffusion distances within the range of interest, for a 4 mm spacing, 50% lead-212 leakage, and a radiation dose of 10 Gy, according to an embodiment of the invention. Figure 6F This is a contour map showing the minimum radiation dose expected to reach tumor cells by various possible diffusion distances of radon-220 and lead-212, assuming a 50% lead-212 leak, according to an embodiment of the invention, in which seeds of 3 microcuries per centimeter length are implanted in the tumor at a spacing of 4 millimeters. Figure 7 This is a graph illustrating the safety factors for various spacings and a series of radon release rates for glioblastoma according to embodiments of the present invention; Figure 8A The spatial distribution of photoexcited emission (PSL) signals in histological sections of 4T1 tumors is shown, where the areas of sampled data are represented in white (0-4 mm) and the fitted areas are represented by magenta dashed lines (0.5-3 mm). Figure 8B yes Figure 8A The radial activity distribution map of the sampled data was fitted with a theoretical model to extract the effective diffusion distance; Figure 8C The spatial distribution of PSL in another histological section from the same tumor is shown, where the seed locations are automatically determined by calculating the intensity center-of-gravity. Figure 8D yes Figure 8C The radial activity distribution map of the sampled data was fitted with a theoretical model to extract the effective diffusion distance; Figures 9-14 The effective diffusion distance obtained for different tumor types as a function of tumor quality is shown. Figure 15Four histological sections of DaRT-treated tumors, acquired using a digital autoradiography system, are shown for measuring radon-220 diffusion distance. Figure 16A A single histological section used to measure the diffusion distance of radon-220 is shown; and Figure 16B The average count, calculated as a function of distance from the grain location, and the fitted model used to measure the diffusion distance of radon-220 are shown. Detailed implementation plan

[0022] Some embodiments of the present invention relate to setting the radon release rate of a DaRT source for treating different types of tumors according to the characteristics of the tumor. The applicant has created a model to estimate the dose reaching tumor cells, which varies with the diffusion distance of lead-212 in the tumor, the diffusion distance of radon-220 in the tumor, and the leakage probability of lead-212. The diffusion distance represents the typical distance from the point where the atom is produced in the decay of its parent radionuclide to the point where the atom decays. The diffusion distance determines the spatial distribution of diffusing atoms around the seed; as the radial distance from the seed increases by one diffusion distance, the alpha particle dose decreases to about 1 / 3. For a seed with the radon release rate considered herein, the diameter of the region around the seed receiving a 10 Gy alpha particle dose is approximately 10 times the diffusion distance. Methods for measuring the effective diffusion distance and thereby estimating the range of radon-220 and lead-212 diffusion distance values ​​are described in the appendix. The leakage probability of lead-212 represents the probability that lead-212 atoms released from the source leave the tumor via the bloodstream before decaying.

[0023] The diffusion distance of radon-220 and the leakage probability of lead-212 differ in different types of cancerous tumors. Generally, the shorter the diffusion distance of radon-220, the greater the activity required to achieve similar results. The applicant estimated the diffusion distance of radon-220 in various types of tumors and accordingly determined the radon release rate of the source for treating these types of tumors.

[0024] Figure 1This is a schematic diagram of a system 100 for planning radiotherapy treatment according to an embodiment of the present invention. Treatment typically involves implanting more than one source into a tumor to be destroyed. System 100 includes an imaging camera 102 that acquires images of the tumor requiring radiotherapy. Additionally, system 100 includes an input interface 104, such as a keyboard and / or mouse, for receiving input from a human operator (such as a physician). Optionally or additionally, system 100 includes a communication interface 106 for receiving instructions and / or data from a remote computer or human operator. System 100 also includes a processor 108 configured to generate a plan of the placement of radiotherapy sources in the tumor and, accordingly, provide details of the various kits of radiotherapy sources for treating the tumor via an output interface 110. Output interface 110 may be connected to a display and / or a communication network. Processor 108 optionally includes a general-purpose hardware processor configured to run software to perform the tasks described below. Optionally or additionally, processor 108 includes a dedicated processor, such as a signal processing processor, digital signal processor (DSP), or vector processor, configured with suitable software to perform the tasks described herein. In other embodiments, processor 108 includes a dedicated hardware processor, such as an FPGA or ASIC, configured in hardware to perform its tasks.

[0025] In some embodiments, processor 108 is also configured to estimate the radiation dose expected to reach each point in the tumor, as described, for example, in PCT application PCT / IB2021 / 050034, filed January 5, 2021, entitled “Treatment Planning for Alpha Particle Radiotherapy,” the disclosure of which is incorporated herein by reference.

[0026] Figure 2 This is a flowchart of the actions performed in preparing for radiotherapy treatment of a tumor according to an embodiment of the present invention. Figure 2The method typically begins with system 100 receiving input about the tumor (such as an image of the tumor and / or the type of the tumor) (202). The spacing between sources to be inserted into the tumor is selected (204), and the number of sources to be included in the treatment kit for the tumor is determined accordingly (206). Furthermore, the duration of treatment is selected (208). The radon release rate of the sources is also selected (210). In some embodiments, a description of the arrangement of the sources in the tumor is also prepared (212). Subsequently, a kit (214) of sources including the selected number of parameters is prepared and packaged in a suitable sterile package. In some embodiments, the method also includes a treatment procedure. In these embodiments, the method includes, for example, implanting the sources from the kit into the tumor according to the prepared arrangement (212) (216). In some embodiments, the method includes removing the sources after the selected duration (208) (218). In other embodiments, the sources are not removed but remain in the patient.

[0027] In some implementations, the type of tumor is determined based on clinical and / or histopathological observations, such as analysis of a portion of the tumor obtained from a biopsy and / or the amount and / or density of blood vessels in the tumor, as determined from images of the tumor. Tumor types are selected, for example, from a list including squamous cell carcinoma, basal cell carcinoma, glioblastoma, sarcoma, pancreatic cancer, lung cancer, prostate cancer, breast cancer, and colorectal cancer.

[0028] In some implementations, the sources are arranged in a regular geometric pattern, which achieves a relatively low distance between each point in the tumor and at least one of the sources.

[0029] Figure 3 This is a schematic diagram of a regular arrangement of sources in a hexagonal arrangement 160 according to an embodiment of the invention. In the hexagonal arrangement 160, the surface through which the source enters the tumor to be treated is divided into hexagons 164, and the center 162 of each hexagon is designated for the insertion of the source. The center 162 for inserting the source is located at the vertex of an equilateral triangle, and the distance 166 between every two sources is referred to herein as the arrangement spacing. The hexagons 164 are formed by the bisectors of the lines connecting the centers 162 to their six nearest neighboring centers 162. The minimum dose of radiation from the source is at the centroid of the triangle, which is located at the vertex of the hexagon. Optionally, the spacing between the sources is less than 5 mm, no more than 4.5 mm, no more than 4 mm, no more than 3.5 mm, or even no more than 3 mm. As described below, the spacing between the sources is very important in determining the treatment plan for a specific cancer type.

[0030] The spacing between sources is optionally selected (204) as a trade-off between the need to destroy the tumor without using activity levels that may approach safety limits (requiring a small spacing) and the simplicity of the implantation procedure (requiring a larger spacing). Typically, the largest spacing considered to destroy the tumor with seed particles that are not excessively high in activity is selected. Since radon-220 and lead-212 have different diffusion distances in different tumor types, and therefore DaRT sources have different effective ranges in different tumor types, the spacing (204) is selected in response to the type of tumor. Furthermore, different tumor types have different required radiation doses. In some embodiments, the spacing (204) is selected based on the type of tumor to be treated. One type of treatment aims to completely destroy tumor cells. Another type of treatment aims to reduce the tumor mass to a size that is not visible to the naked eye, or to a size that makes the tumor resectable. Complete destruction typically requires a higher source activity level and / or a smaller source spacing.

[0031] Optionally or additionally, the accessibility of the tumor location within the patient's body is considered when selecting the spacing (204). For example, a larger spacing is preferred for tumors in internal organs that require access via catheters or endoscopes than for similar tumors that are easily accessible. In some embodiments, the spacing between sources is selected while taking into account the time and complexity of source implantation. The smaller the spacing, the more sources are required, and therefore the time for source implantation increases. Therefore, according to some embodiments of the invention, a maximum spacing that still allows for tumor destruction is used.

[0032] Figure 4 This is a schematic diagram of a kit 700 for a DaRT source 21 according to an embodiment of the present invention. Kit 700 includes a sterile package 702 comprising more than one alpha-emitter radiotherapy source 21 for insertion into a tumor.

[0033] Optionally, source 21 is provided within a vial or other housing 706, which prevents radiation from escaping the housing. In some embodiments, the housing is filled with a viscous liquid, such as glycerol, which prevents radon atoms from escaping the housing 706, as described in PCT application PCT / IB2019 / 051834 entitled “Radiotherapy Seeds and Applicators,” the disclosure of which is incorporated herein by reference. In some embodiments, kit 700 also includes a seed applicator 708 for inserting source 21 into a patient, as described in PCT application PCT / IB2019 / 051834. Optionally, applicator 708 is provided to pre-load one or more sources 21 therein. According to this option, for cases requiring more sources than the pre-loaded number, individual sources 21 are supplied in housing 706. Optionally, instead of sources 21 being provided in housing 706, kit 700 includes only sources within applicator 708.

[0034] To cover the entire tumor, the number of sources to be included in the treatment kit 700 for the tumor is determined (206) based on the selected spacing and source arrangement. In some embodiments, an additional 10%-20% of sources are provided in the treatment kit.

[0035] The duration of treatment (e.g., the time the seed remains in the tumor) is optionally selected by the operator based on the desired treatment outcome (e.g., complete destruction, mass reduction). In some embodiments, the duration of treatment (208) is pre-selected based on tumor parameters, such as its location within the patient and the patient's availability of the removal source. Optionally, during treatment, the duration of treatment (208) is selected based on the progress of treatment.

[0036] The source activity and its desorption probability are optionally selected in response to the chosen spacing, treatment duration, and tumor type (210). In some embodiments, the source activity and its desorption probability are also selected in response to the type of tumor being treated. For example, if the operator instructs that the goal is to completely destroy tumor cells, a higher activity and / or desorption probability is used than for an instruction that the tumor needs to be removed based on visual monitoring or reduced in size to make it resectable. Optionally, depending on the type of tumor, the purpose of selecting the activity and source probability is to achieve at least a specific radiation dose at each point throughout the tumor (or to achieve at least a threshold percentage of radiation dose at points throughout the tumor), as discussed in more detail below.

[0037] It should be noted that while the risk of radiation overdose is low for a single small tumor, treatment can involve the implantation of hundreds of sources when treating large and / or multiple tumors. In such cases, it is important to precisely adjust the source activity to prevent excessive radiation exposure to the patient. It is generally considered undesirable to implant activity levels exceeding a few millicuries (e.g., 2–5) in the patient. However, for safety reasons, a limit of approximately 1 millicurie is currently used. For large tumors requiring seeds of 170 cm or longer, this sets a limit of approximately 6 microcuries for the activity of a 1 cm seed. In terms of radon release rate, given a desorption rate of 38%–45%, this sets a limit of approximately 2.5 microcuries. This limit is not uniform for all tumor types. Some tumor types, such as glioblastoma multiforme (GBM), prostate cancer, breast cancer, and squamous cell carcinoma, are often intended to be treated with radiation when they are smaller. Therefore, the number of seeds used and their total length are expected to be less than 170 cm to allow for the use of higher radon release rates. Other cancer types, such as pancreatic cancer, are expected to require radiation therapy for large tumors. Other cancer types, such as melanoma and colorectal cancer, are expected to require radiation therapy for several different tumors. These cancer types may require seeds with a total length of 170 cm or even longer.

[0038] It should be noted that Figure 2 The actions in the process do not have to be performed in the order they are presented. For example, where the activity of the source is not selected in response to the duration of treatment (210), the activity of the source (210) can be selected before or in parallel with the selection of the duration of treatment (208). As another example, the preparation of the arrangement and the preparation of the kit can be performed simultaneously or in any desired order.

[0039] Figure 5This is a schematic diagram of a radiotherapy source 21 according to an embodiment of the present invention. The radiotherapy source 21 includes a support 22 configured for insertion into a subject. The radiotherapy source 21 also includes radioactive nuclides 26 of radium-224 on the outer surface 24 of the support 22, as described, for example, in U.S. Patent 8,894,969, which is incorporated herein by reference. It should be noted that, for ease of illustration, the atoms 26 and other components of the radiotherapy source 21 are drawn disproportionately large. The atoms 26 are generally coupled to the support 22 in such a manner that the radioactive nuclides 26 do not leave the support, but upon radioactive decay, their daughter radionuclides (symbolically shown as 28) may leave the support 22 due to the recoil generated by decay. The percentage of daughter radionuclides 28 that leave the support due to decay is called the desorption probability. In some embodiments, the coupling of the atoms 26 to the support 22 is achieved by heat treatment. Optionally or additionally, coating 33 covers the support 22 and atoms 26 in a manner that prevents the release of radionuclide atoms 26 and / or modulates the release rate of progeny radionuclides 28 during radioactive decay. Progeny radionuclides may pass through coating 33 and leave the radiotherapy source 21 due to recoil, or recoil may carry them into coating 33, where they leave by diffusion. In some embodiments, such as Figure 5 As shown, in addition to coating 33, an inner coating 30 of thickness T1 is placed on support 22, and radioactive nuclide atoms 26 are attached to the inner coating 30. However, it should be noted that not all embodiments include an inner coating 30, but rather the radioactive nuclide atoms 26 are directly attached to support 22.

[0040] In some implementations, the support 22 includes a seed for complete implantation within the patient's tumor, and the support 22 can have any suitable shape, such as a rod or plate. Alternatively, the support 22 may be partially implanted within the patient and may be part of a needle, suture, endoscope tip, laparoscopic tip, or any other suitable probe.

[0041] In some embodiments, the support 22 is cylindrical and has a length of at least 1 mm, at least 2 mm, or even at least 5 mm. Optionally, the seed has a length between 5 and 60 mm. The support 22 optionally has a diameter of 0.7-1 mm, although in some cases, sources with larger or smaller diameters are used. In particular, for fine-pitch treatment arrangements, the support 22 optionally has a diameter of less than 0.7 mm, less than 0.5 mm, less than 0.4 mm, or even no greater than 0.3 mm.

[0042] The activity on support 22 is measured in microcuries per centimeter of source length in this paper. Since most of the radiation dose reaching the tumor is determined primarily by the radionuclide leaving the source, the measure of “radon release rate” is defined as the product of the activity on the source and the desorption probability. For example, a source with an activity of 2 microcuries per centimeter of length and a desorption probability of 40% has a radon release rate of 0.8 microcuries per centimeter of length.

[0043] The desorption probability depends on the depth of the radionuclide atoms 26 within the surface of the support 22 and / or the type and thickness of the coating 33. Implanting the radionuclide atoms 26 into the surface of the support 22 is typically achieved by heat treatment of the radiotherapy device 21, and the depth of the atoms 26 can be controlled by adjusting the temperature and / or duration of the heat treatment. In some embodiments, the desorption probability is between approximately 38% and 45%. Alternatively, a higher desorption probability may be obtained using any of the methods described, for example, in PCT Publication WO 2018 / 207105 entitled “PolymerCoatings for Brachytherapy Devices,” the disclosure of which is incorporated herein by reference. In other embodiments, a lower desorption probability is used, such as that described in U.S. Provisional Patent Application 63 / 126,070 entitled “Diffusing Alpha-emitters Radiation Therapy with Enhanced BetaTreatment,” the disclosure of which is incorporated herein by reference.

[0044] It should be noted that not all alpha radiation reaching the tumor is due to the radon-220 daughter radionuclides 28 that leave the support 22 upon decay. Some radon-220 daughter radionuclides 28 produced by the decay of radionuclides 26 remain on the support 22. When the daughter radionuclides 28 decay, their daughter radionuclides, such as polonium-216, may leave the support 22 due to recoil, or lead-212 produced during the decay of polonium-216 may leave the support 22 due to recoil.

[0045] Typically, the radionuclide 26 is coupled to the support 22 in a manner that prevents the radionuclide 26 from escaping from the support 22 itself. In other embodiments, the radionuclide 26 is coupled to the support 22 in a manner that allows the radionuclide 26 to leave the support without decaying (e.g., by diffusion), for example using any of the methods described in PCT publication WO 2019 / 193464 entitled “Controlled Release of Radionuclides,” which is incorporated herein by reference. Alternatively, diffusion can be achieved by using a bioabsorbable coating that initially prevents the radionuclide 26 from escaping prematurely but disintegrates and allows diffusion after implantation into the tumor.

[0046] The total amount of radiation released by the source in the tumor (referred to herein as the “cumulative radon activity”) depends on the radon release rate of the source and the time the source remains in the tumor. If the source remains in the tumor for a long period, such as a radium-224 source for more than a month, the cumulative radon activity is approximately 0.693, which is the product of the radon release rate of the source multiplied by the average lifetime of radium-224 (3.63 days or 87.12 hours) divided by ln2. For example, a radium-224 source with a radon release rate of 1 microcurie (μCi) = 37,000 becquerels (Bq) has a cumulative radon activity of approximately 4.651 megabecquerels (MBq) hours. It should be noted that an equivalent cumulative radon activity can be achieved by implanting a source with a higher radon release rate over a shorter period of time. For such a shorter period of time, the cumulative activity is given by:

[0047] Where S(0) is the radon release rate when the source is inserted into the tumor. t represents the average lifespan of radium-224, and t is the duration of treatment in hours. For example, two weeks of treatment provides the following cumulative activity:

[0048] The required activity on the sources to achieve tumor destruction varies greatly depending on the type of tumor and the distance between the sources. Therefore, it is important to identify the activity required for that specific tumor type. A method for calculating the radiation dose reaching each point in the tumor based on the activity of the implanted sources is described in U.S. Patent Application 17 / 141,251, filed January 5, 2021, entitled “Treatment Planning for Alpha Particle Radiotherapy,” the disclosure of which is incorporated herein by reference. Using these calculation methods, the required radon release rate can be calculated as a function of the diffusion distance of lead-212 in the tumor, the diffusion distance of radon-220 in the tumor, the distance between the sources implanted in the tumor, the probability of lead-212 leakage from the tumor, and the radiation dose required to reach each location in the tumor.

[0049] Figures 6A-6D This graph illustrates a wide range of radon release rate values ​​required to ensure a nominal alpha particle dose of at least 10 Gy for different values ​​of the above parameters. The 10 Gy level is chosen as a reference because the required nominal alpha particle dose varies depending on the tumor type and can be as high as 20–30 Gy. To obtain the seed activity required for a target dose beyond 10 Gy, the seed activity at 10 Gy should be multiplied by the ratio between the target dose and 10 Gy. Figure 6A The required radon release rate varies with the lead-212 diffusion distance for three different radon-220 diffusion distance values, when the lead leakage probability is 80% and the spacing is 3.5 mm. Figure 6B This is a similar graph to one showing a 40% probability of lead leakage. Figure 6C The same graph is shown for a 4mm pitch and an 80% probability of lead leakage, while Figure 6D The required radon release rate is shown for a 4mm spacing and a 40% lead leakage probability. The reader will understand that the range of possible radon release rate values ​​is very large, and the discussion below provides guidance on a narrower range to be used for specific tumor types.

[0050] Figure 6E This is a contour plot showing the values ​​of the radon release rate required for various possible radon-220 and lead-212 diffusion distances within the range of interest, for a 4 mm spacing, 50% lead-212 leakage, and a radiation dose of 10 Gy, according to an embodiment of the invention.

[0051] Figure 6F This is a contour map illustrating the minimum radiation dose expected to reach tumor cells by various possible diffusion distances of radon-220 and lead-212, assuming a 50% lead-212 leak, according to an embodiment of the invention, in which seeds of 3 microcuries per centimeter length are implanted in the tumor at a spacing of 4 millimeters.

[0052] like Figure 6E As can be observed, the required radon release rate varies greatly for different diffusion distances. Since different tumor types have different diffusion distances, the required radon release rate also differs for each tumor type.

[0053] To estimate the diffusion distances of lead-212 and radon-220 in different types of tumors, the applicant conducted two categories of experiments on tumors of different types and sizes. In the first category, the applicant implanted the sources into tumors generated in mice and dissected the tumors several days later to measure the actual activity reaching various points within the tumor. These measurements conformed to the equations described above, and the effective long-term diffusion distance in the tumor was estimated accordingly. This effective diffusion distance was the larger of the diffusion distances for radon-220 and lead-212.

[0054] Tumors were removed from mice and frozen to allow for sectioning shortly after removal. The tumors were then sectioned into pieces approximately 10 micrometers thick. Immediately after sectioning, the tissue sections were fixed with formalin for a short duration (minutes) directly onto a glass slide. After fixation, the slides were placed on a Fuji phosphorescent imaging plate in a sealed container for one hour. The slides were separated from the plate by a thin Mylar foil to prevent radioactive contamination. The plate was then scanned using a phosphorescent autoradiography system (Fuji FLA-9000) to record the spatial distribution of lead-212 within the tissue sections.

[0055] Further details on effective long-term diffusion distance measurements are discussed in Appendix A below.

[0056] The second category of experiments was similar to the first, but instead of waiting several days, the tumor was removed approximately half an hour after source insertion. The radioactive distribution following this short period is thought to be primarily due to radon-220 diffusion, as its spatial distribution stabilizes very rapidly, while the contribution from lead-212 increases from zero to its maximum approximately 1.5–2 days after source insertion and remains sufficiently low 30 minutes after insertion. Details of measuring the radon-220 diffusion distance are discussed in Appendix B below.

[0057] Early measurements of the diffusion distance of radon-220 found values ​​between 0.23 mm and 0.31 mm. However, the number of measurements was relatively small. Surprisingly, the most recent results of the measurements described above show no significant difference between long-term and short-term experiments. Therefore, the applicant hypothesizes that the diffusion distance of lead-212 is less than that of radon-220. Thus, the applicant hypothesizes that the diffusion distance of lead-212 is approximately 0.2 mm. This hypothesis is used because, as in... Figure 6EAs can be observed, the dependence on the diffusion distance of lead-212 is very weak within the range of radon-220 diffusion distance values. Table 1 below summarizes the measured radon-220 diffusion distances for various cancer types.

[0058] As is known in the art, different tumor types require different doses of radiation to destroy their cells. Table 1 lists the bioeffective doses (BEDs) required for various types of cancer tumors in gray equivalents (GyE). These dose values ​​apply to photon-based radiation (X-rays or gamma rays). Alpha radiation is considered more lethal to cells, and therefore the alpha radiation dose in gray is multiplied by a correction factor called the relative biological effect (RBE) (currently estimated at 5) to convert it to a BED in gray equivalents (GyE). The BED in DaRT is the sum of the alpha dose multiplied by the RBE and the beta dose produced by radium-224 and its daughters.

[0059] The lead-212 leakage probability is relatively low at the tumor center, but reaches approximately 80% around the tumor periphery. To ensure cellular destruction throughout the tumor, the applicant used an 80% leakage probability value when selecting the radon release rate of the source.

[0060] To estimate the required spacing and radon release rate for seeds used in a specific tumor type, the applicant estimated the required dose for the tumor type, the beta radiation dose provided by a span of activity levels, and the remaining required dose to be provided by alpha radiation. The alpha radiation dose was estimated for the span of spacing and radon release rate, and a safety factor (the ratio between the estimated provided dose and the required dose) was calculated for this span of spacing and radon release rate. The safety factor is needed to overcome potential inaccuracies in source placement, allowing some sources to be spaced beyond the specified spacing. Furthermore, tumors may be heterogeneous, causing some local variations in diffusion distance.

[0061] The applicant selected a safety factor range of 1.5-4 as the definition of the required spacing and radon release range for treatment. This safety factor is considered to provide sufficient safety so that the tumor will be destroyed by the radiation provided, without being too high to expose the patient to the risk of systemic radiation from lead-212 leaking from the tumor through the blood and subsequently being absorbed into various organs.

[0062] For a given tumor type, the same safety margin can be achieved using different spacing and radon release rate pairs. If the sources are to be placed with a relatively high spacing between them (such as 4.5 mm or 5 mm), the sources should have a high radon release rate, such as more than 1.5 microcuries per centimeter of length. Conversely, when the spacing between the sources is less than 4 mm, the sources can be configured with a relatively low radon release rate.

[0063] Given the chosen safety margin range, an appropriate source spacing was selected. As stated above, the maximum spacing considered sufficient to destroy tumors with seed grains that do not have excessively high activity levels was chosen. The applicant limited the spacing selection to a 0.5 mm step, which was considered close to the level of imprecision in seed placement. These imprecisions were taken into account in the safety margin.

[0064] After selecting the spacing, a range of radon release rates corresponding to that spacing and a safety factor is selected. This range of radon release rates is considered to provide optimal results for treating tumors of the type for which calculations were performed. It should be noted that the selected range of radon release rates is not limited to use at a specific spacing used for selection, but can be used at a range of spacings around the selected spacing due to a safety margin.

[0065] Table 1

[0066] As stated in Table 1, the effective long-term spread distance for glioblastoma is estimated to be approximately 0.27 mm, and the required dose is approximately 100 GyE.

[0067] Table 2 presents the β dose, corresponding required α radiation dose, estimated α radiation dose, and obtained safety factor for several intervals and radon release rates used in glioblastoma.

[0068] Figure 7 This is a graph showing the safety factor for various spacings in glioblastoma according to embodiments of the present invention, as a function of radon release rate.

[0069] from Figure 7 The applicant determined that a 4 mm spacing would require the grains to have a radon release rate significantly higher than 2.5 microcuries. To avoid such high levels of radioactivity, a 3.5 mm spacing was assumed when selecting the radon release rate of the source. The actual spacing used is optionally shorter than 3.9 mm, 3.8 mm, 3.7 mm, or even 3.6 mm. On the other hand, the actual spacing used is optionally greater than 3.1 mm, 3.2 mm, 3.3 mm, or even 3.4 mm.

[0070] Table 2 - Glioblastoma

[0071] For a 3.5 mm spacing, a safety factor between 1.5 and 4 corresponds to radon release rates between 1.4 and 3.1 microcuries per centimeter of length. While the upper end of this range is relatively high, this range of radon release rates is reasonable given the importance of success in tumors within the patient's head, the difficulty of access, and the fact that the tumor is expected to be relatively small. For long-term treatment, this equates to cumulative radon activity released between approximately 6.5 MBqh per centimeter and 14.3 MBqh per centimeter.

[0072] In some embodiments, to increase the probability of treatment success, radon release rates of at least 1.5 microcuries per centimeter length, at least 1.7 microcuries per centimeter length, at least 1.8 microcuries per centimeter length, or even at least 2.0 microcuries per centimeter length are used for glioblastoma. In some embodiments, to reduce the radiation exposure of the patient, radon release rates are no greater than 3.0 microcuries per centimeter length, no greater than 2.8 microcuries per centimeter length, no greater than 2.5 microcuries per centimeter length, or even no greater than 2.2 microcuries per centimeter length. In other embodiments, a safety factor between 1.5 and 2.5 is used, and therefore the radon release rate of seed 21 is between 1.4 and 2.3 microcuries per centimeter length. In still other embodiments, a safety factor between 3 and 4 is used, and therefore the radon release rate of seed 21 is between 2.65 and 3.1 microcuries per centimeter length.

[0073] Optionally or additionally, the source may optionally include at least 7 MBq hours per centimeter, at least 8 MBq hours per centimeter, at least 9 MBq hours per centimeter, or even at least 10 MBq hours per centimeter. On the other hand, the source may optionally include less than 12 MBq hours per centimeter or even less than 11 MBq hours per centimeter.

[0074] in conclusion It should be understood that the above-described methods and apparatus are to be interpreted as including the apparatus for performing the method and the method of using the apparatus. It should be understood that features and / or steps described for one embodiment may sometimes be used in conjunction with other embodiments, and not all embodiments of the invention have all the features and / or steps shown in a particular drawing or described for one particular embodiment. Tasks are not necessarily performed in the exact order described.

[0075] It should be noted that some of the above embodiments may include details of structure, behavior, or structure and behavior that may not be essential to the present invention and are described as examples. As is known in the art, the structures and behaviors described herein may be replaced by equivalents that perform the same function, even if the structure or behavior differs. The above embodiments have been mentioned by way of example, and the invention is not limited to what has been specifically shown and described above. Rather, the scope of the invention includes both combinations and sub-combinations of the various features described above, as well as variations and modifications thereof not disclosed in the prior art that would arise to those skilled in the art upon reading the foregoing description. Therefore, the scope of the invention is defined only by the elements and limitations used in the claims, wherein the terms “comprise,” “include,” “have,” and their variations, when used in the claims, should mean “including but not necessarily limited to.” Appendix A

[0076] Effective diffusion distance measurement 7-20 days after tumor inoculation, when the tumor's transverse diameter is ~6-15 mm, it will carry 2-3 uCi 224 A single Ra DaRT seed (6.5 mm long, 0.7 mm outer diameter) was inserted into the center of a mouse tumor. Four to five days later, the tumor (as a whole) was excised and cut in half perpendicular to the seed axis at the estimated location in the seed center. The seed was then removed with surgical forceps and placed in a water-filled tube for subsequent gamma counter measurements. The tumor was stored at -80°C for one hour. It was then removed in dry ice for measurements with the same gamma counter to determine its contents. 212 Pb activity. Measurements of grain and tumor activity are used to determine the origin of Pb from tumors. 212 Probability of Pb leakage.

[0077] Immediately after gamma measurement, the tumor halves were sectioned histologically using a cryostat. Sections were cut at 250–300 μm intervals and 10 μm thickness, placed on positively charged glass slides, and fixed with 4% paraformaldehyde. Typically, 5–15 sections were prepared per tumor, spanning 1.5–5 mm in length. Shortly after preparation, the glass slides were placed face down on a phosphorescent imaging plate (Fujifilm TR2040S) for one hour, protected by 12 μm Mylar foil and enclosed in an opaque housing. 212 Pb sub-atoms ( 212 Bihe 212Alpha particles emitted from the slice during the decay of phosphorescent phosphor (P) penetrate the foil and deposit energy into the active layer of the phosphorescent imaging plate. The plate is then read out by a phosphorescent imaging scanner (Fujifilm FLA-9000).

[0078] For each tumor slice, the results are compared with local... 212 A two-dimensional intensity map proportional to Pb activity. Intensity (in units of photoexcited luminescence) is converted using a suitable calibration sample measured simultaneously with the slide. 212 Pb activity. Points where grains penetrate the slice are identified by the appearance of "holes" in the activity map, or by taking the centroid of the activity distribution. An example is... Figures 8A-8D As shown in the diagram, we defined a region of interest (ROI) centered on the estimated seed location and divided it into concentric rings 0.1 mm wide with radii ranging from 0.5 to 3 mm. For each ring, we calculated the average activity. If the ROI extended beyond the area of ​​the tumor slice, or included areas with degraded tissue or reduced image quality, the average activity of the rings was taken over a finite azimuthal sector. Then, based on a diffusion-leakage model, we numerically fitted the resulting curve of activity as a function describing the radial activity distribution from the seed to the origin (estimated seed location). The calculation described the seed as a line source perpendicular to the image. The source was divided into numerous point segments, each contributing activity to a given pixel in the image plane. In this expression, It is the distance between the source segment and the pixel under consideration, and as well as These are free parameters whose values ​​are adjusted to optimize the fit to the entire curve. Figures 8A-8D ). Get the obtained The value is used as an estimate of the effective diffusion distance of the slice. Take the values ​​on all slices... The average value is used to represent the effective (or primary) spread distance of the tumor, where the uncertainty is equal to the standard deviation of the values ​​obtained across all slices.

[0079] Figure 8A The spatial distribution of photoexcited emission (PSL) signals in histological sections of 4T1 tumors is shown, with the sampled data areas indicated in white (0–4 mm) and the fitted areas indicated by magenta dashed lines (0.5–3 mm). Seed locations were determined manually.

[0080] Figure 8B yes Figure 8A The radial activity distribution of the sampled data was fitted using a diffusion-leakage model.

[0081] Figure 8CThe spatial distribution of PSL in another histological section from the same tumor is shown, where the seed locations are automatically determined by calculating the intensity centroid.

[0082] Figure 8D yes Figure 8C The radial activity distribution of the sampled data was fitted using a diffusion-leakage model.

[0083] Figure 9 The effective diffusion distance for pancreatic tumors is shown as a function of tumor mass.

[0084] Figure 10 The effective diffusion distance for prostate tumors is shown as a function of tumor mass.

[0085] Figure 11 The effective diffusion distance for melanoma tumors is shown as a function of tumor mass.

[0086] Figure 12 The effective diffusion distance for squamous cell carcinoma tumors is shown as a function of tumor mass.

[0087] Figure 13 The effective diffusion distance for triple-negative breast tumors is shown as a function of tumor mass.

[0088] Figure 14 The effective diffusion distance for GBM tumors is shown as a function of tumor mass. Appendix B

[0089] Rn measurement method DaRT seeds were inserted into the tumor for a relatively short time (30 minutes), after which they were removed (to prevent Pb buildup within the tumor). The tumor was then frozen and sectioned into 10 µm thick slices perpendicular to the seed axis. These slices were placed on glass slides and fixed with formaldehyde. The tumor slices were then fed into a digital autoradiography system (iQID alpha camera, manufactured by QScint Imaging Solutions, LLC), which records alpha particle impacts one by one, providing their xy coordinates (accurate to ~20 μm), timestamps, and signals proportional to the deposition energy.

[0090] exist Figure 15 The image shown is an example of a tumor processed by DaRT consisting of four histological sections and acquired using the iQID system. Figure 15Four histological sections of a DaRT-treated tumor, acquired using an iQID autoradiography system, are shown. For analysis, the images were cropped so that each section could be analyzed independently, as shown in [the original text]. Figure 16A As can be observed, it shows a single histological section used for analysis. For each section, a center was selected (either by the centroid method or by identifying “holes” in the activity map), and the average alpha particle count was calculated at radially increasing distances from the center. The resulting map was then numerically fitted by assuming that the recorded activity map was a superposition of infinitely small segments along the DaRT grains, where each segment was calculated using Equation 1:

[0091] In this expression, It is the radial distance between the grain segment and the point of interest on the image. It is the radon diffusion distance, and These are free parameters. These two parameters ( The findings were obtained using the least squares fitting method.

[0092] The fitting was performed over a finite activity distribution area to avoid artificial “holes” in the center of the distribution (where DaRT grains are located) and at the far ends, where statistical variation is too large. Figure 16B An example of a fitted curve is shown, which illustrates the calculated average count as distance from the grain position, including the fitted function.

Claims

1. A diffuse alpha emitter radiotherapy source for implantation in glioblastoma tumors, comprising: Radium-224 mounted on the support, The diffuse alpha emitter radiotherapy source described herein has a radon release rate between 1.4 microcuries and 3.1 microcuries per centimeter of length.

2. The source according to claim 1, wherein the diffuse alpha emitter radiotherapy source has a radon release rate between 1.4 microcuries and 2.3 microcuries per centimeter of length.

3. The source according to claim 1, wherein the diffuse alpha emitter radiotherapy source has a radon release rate between 1.9 microcuries and 2.6 microcuries per centimeter of length.

4. A kit for implantation of a diffuse alpha emitter radiotherapy source in a glioblastoma tumor, wherein the kit includes a diffuse alpha emitter radiotherapy source having radium-224 mounted on a support, wherein the diffuse alpha emitter radiotherapy sources are implanted in an array, wherein each diffuse alpha emitter radiotherapy source in the array is spaced no more than 3.9 mm from its neighboring diffuse alpha emitter radiotherapy sources.

5. The kit of claim 4, wherein the diffuse alpha emitter radiotherapy source is implanted in a hexagonal arrangement.

6. The kit of claim 4, wherein the spacing between each diffusing alpha emitter radiotherapy source and its neighboring diffusing alpha emitter radiotherapy source in the array is between 3.1 mm and 3.9 mm.

7. The kit of claim 4, wherein the distance between each diffusing alpha emitter radiotherapy source and its neighboring diffusing alpha emitter radiotherapy source in the array does not exceed 3.5 mm.

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