Diffusing alpha-emitter radiation therapy source for prostate cancer

Abstract

The present invention discloses a method for treating a tumor, comprising: identifying a tumor as a prostate cancer tumor; and implanting at least one diffuse alkanes radiotherapy (DaRT) source (21) having a suitable radon release rate into the tumor identified as a prostate cancer tumor for a given duration, such that the source (21) provides a released radon accumulation activity between 7 MBq h / cm length and 14.7 MBq h / cm length during the given duration.

Description

Technical Field

[0001] This invention generally relates to radiotherapy, and more particularly to apparatus and methods for delivering tumor-specific radiation doses in radiotherapy treatments. Prior Technology

[0002] Ionizing radiation is typically used to treat certain types of tumors (including malignant cancerous tumors) by destroying the cells of these tumors. However, ionizing radiation can also damage a patient's healthy cells, and therefore care should be taken to minimize the radiation dose delivered to healthy tissue outside the tumor while maximizing the dose delivered to the tumor.

[0003] Ionizing radiation destroys cells by damaging their DNA. The bioeffectiveness of different types of radiation in killing cells is determined by the type and severity of the DNA damage they cause. Alpha particles are a powerful form of radiotherapy because they induce clustered double-strand breaks in DNA that cells cannot repair. Unlike conventional types of radiation, the destructive effect of alpha particles is largely unaffected by low cellular oxygen levels, making them equally effective on hypoxic cells, a major reason for the failure of conventional photon- or electron-based radiotherapy, which are present in tumors. Furthermore, short-range alpha particles (less than 100 micrometers) within tissues ensure that surrounding healthy tissue is spared if the atoms emitting these alpha particles are confined to the tumor volume. On the other hand, the use of short-range alpha radiation in cancer treatment has been limited so far because there is no practical way to deploy alpha-emitting atoms at a sufficient concentration throughout the entire tumor volume.

[0004] For example, diffused alpha radiation radiotherapy (DaRT) described in U.S. Patent 8,834,837 to Kelson extends the therapeutic range of alpha radiation by using radium-223 or radium-224 atoms. These atoms produce several radioactive decay chains with a dominant half-life of 3.6 days for radium-224 and 11.4 days for radium-223. In DaRT, radium atoms attach with sufficient strength to a source (also called a "seed") implanted in the tumor, such that these radium atoms do not leave the source by being discarded (by being cleared from the tumor through the blood), but a significant percentage of their progeny radionuclides (radon-220 in the case of radium-224 and radon-219 in the case of radium-223) immediately leave the source and enter the tumor after radium decay. These radionuclides and their own radioactive progeny atoms expand around the source by diffusing to a radial distance of a few millimeters before decaying due to alpha emission. Therefore, the extent of destruction in the tumor increases relative to the radionuclides that remain on the source along with their progeny.

[0005] For a tumor to be effectively treated, the DaRT seed used in the treatment should release a sufficient number of radon atoms to destroy the tumor with a high probability. If an insufficient dose of radiation is used, too many cancer cells will remain in the tumor, and these cells can proliferate and remodel into a malignant tumor. On the other hand, the seed should not release too many radon atoms, because some of its progeny will be cleared from the tumor through the bloodstream and may thus damage distant healthy tissues, including organs such as a patient's bone marrow, kidneys, and / or ovaries.

[0006] The atomic weight of radium on a DaRT source is quantified based on activity (i.e., radium decay rate). DaRT source activity is measured in microcuries (µCi) or kilobecquerels (kBq), where 1 µCi = 37 kBq = 37,000 decays / 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 progeny radon atoms will immediately leave the source and enter the tumor after the alpha decay of radium. This probability is referred to herein as the "desorption probability". Therefore, instead of the activity of a reference source, the "radon release rate," defined herein as the product of the activity on the source and the radon desorption probability from that source, can be used as one measure of the DaRT-related activity of a source. Like activity, the radon release rate is given in µCi or kBq. Unless otherwise stated, the source activity and radon release rate values ​​given herein refer to sources when implanted into tumors.

[0007] The U.S. Patent 8,834,837 granted to Kelson above recommends the use of one of the activities "from about 10 nanocuries to about 10 microcuries, more preferably from about 10 nanocuries to about 1 microcurie". Summary of the Invention

[0008] Embodiments of the present invention relate to the accurate delivery of a tailored dose of radiation to a tumor in a radiotherapy treatment. Embodiments include a radiotherapy source designed to deliver a suitable dose of radiation, and a kit containing a suitable number of sources for a tumor of a specific size. Other embodiments relate to methods for preparing a kit of radiotherapy sources for a specific tumor and methods for treating a tumor.

[0009] According to one embodiment of the present invention, a method for treating a prostate cancer tumor is further provided, comprising: identifying a tumor as a prostate cancer tumor; and implanting at least one diffuse alkanes radiotherapy (DaRT) source having a suitable radon release rate into the tumor identified as a prostate cancer tumor for a given duration, such that the source provides a released radon accumulation activity between 7 MBq hours / cm length and 14.7 MBq hours / cm length during the given duration.

[0010] Depending on the circumstances, implanting the at least one radiotherapy source comprises an array of implanted sources, each source being separated from its adjacent sources in the array by no more than 4 mm. In some embodiments, implanting the at least one radiotherapy source comprises an array of implanted sources arranged in a hexagonal pattern, each source being separated from its adjacent sources in the array by no more than 4 mm. Depending on the circumstances, the at least one radiotherapy source has a radon release rate between 1.5 microcuries / cm in length and 3.2 microcuries / cm in length. Depending on the circumstances, the at least one radiotherapy source has a radon release rate between 2 microcuries / cm in length and 2.7 microcuries / cm in length. Depending on the circumstances, the method includes selecting a given duration before implanting the at least one DaRT source into the tumor, and removing the source from the tumor after the given duration of implantation has elapsed.

[0011] According to one embodiment of the present invention, a method for preparing a radiotherapy treatment is further provided, comprising: identifying a tumor as a prostate cancer tumor; receiving an image of the prostate cancer tumor; and providing a layout of diffuse Alpha-radiotherapy (DaRT) sources for the prostate cancer tumor, wherein the sources have a radon release rate between 1.5 microcuries / cm in length and 3.2 microcuries / cm in length. Optionally, providing the layout includes providing a layout in which the spacing between the sources in the tumor is 4 millimeters or less. Optionally, the sources have a radon release rate between 2 microcuries / cm in length and 2.7 microcuries / cm in length.

[0012] According to one embodiment of the present invention, an apparatus for preparing a radiotherapy treatment is further provided, comprising: an input interface for receiving information about a tumor; a processor configured to determine that the tumor is a prostate cancer tumor and to generate a layout of diffuse Alpha radiation radiotherapy (DaRT) sources for the tumor, wherein the sources in the layout have a radon release rate between 1.5 μCurry / cm and 3.2 μCurry / cm and the sources in the layout are arranged in a regular pattern with a distance of no more than 5 mm between adjacent sources; and an output interface for displaying the layout to an operator.

[0013] According to one embodiment of the present invention, a method for preparing a radiotherapy treatment is further provided, comprising: receiving a request for a diffuse alkanes radiotherapy (DaRT) source for a prostate cancer tumor; determining the number of radiotherapy sources required for the prostate cancer tumor; and providing a sterile kit containing the determined number of radiotherapy sources, wherein the sources have a radon release rate between 1.5 microcuries / cm in length and 3.2 microcuries / cm in length.

[0014] As appropriate, determining the required number of radiotherapy sources includes determining a number of sources such that the tumor area is covered by the sources, wherein the interval between such sources is no greater than 4 mm. As appropriate, the source has a radon release rate between 2 microcuries / cm length and 2.7 microcuries / cm length.

[0015] According to one embodiment of the present invention, a diffuse albedo radiation radiotherapy (DaRT) source for implantation in a prostate cancer tumor is further provided, wherein the DaRT source has a radon release rate between 1.5 microcuries / cm in length and 3.2 microcuries / cm in length. Depending on the application, the radon release rate is between 2 microcuries / cm in length and 2.7 microcuries / cm in length.

[0016] According to one embodiment of the present invention, a kit for implantation of a diffuse albedo radiation radiotherapy (DaRT) source in a prostate cancer tumor is further provided, comprising: a sterile package; and a plurality of DaRT sources disposed within the sterile package, the sources having a radon release rate between 1.5 μCurry / cm length and 3.2 μCurry / cm length. Depending on the application, the radon release rate of the sources may be between 2 μCurry / cm length and 2.7 μCurry / cm length.

[0017] According to one embodiment of the present invention, a method for treating a tumor is further provided, comprising: identifying a tumor as a prostate cancer tumor; and implanting an array of diffuse Alpha-emission radiotherapy (DaRT) sources in the tumor identified as a prostate cancer tumor in a regular configuration, the regular configuration having a spacing between every two adjacent sources of between 3 mm and 4 mm. Optionally, the array of implanted sources may include implantation in a hexagonal configuration, with each source separated from its adjacent source in the array by no more than 3.5 mm. Simple Explanation of the Diagram

[0018] Figure 1 is a schematic illustration of a system for planning a radiotherapy treatment according to one embodiment of the present invention; Figure 2 is a flowchart of actions performed in preparing a radiotherapy treatment for a tumor according to an embodiment of the present invention; Figure 3 is a schematic illustration of a regular source configuration in a hexagonal arrangement according to one embodiment of the present invention; Figure 4 is a schematic illustration of a DaRT source assembly according to an embodiment of the present invention; Figure 5 is a schematic illustration of a radiotherapy source according to one embodiment of the present invention; Figures 6A to 6D are diagrams illustrating a wide range of radon release rate values ​​required to ensure at least one of the nominal alpha particle doses of 10 Grays (Gy) for different seed intervals, lead-212 leakage probabilities, and radon-220 and lead-212 diffusion lengths. Figure 6E is a contour plot showing the desired radon release rate values ​​for various possible radon-220 and lead-212 diffusion lengths within a range of interest, for a 4 mm interval, 50% lead-212 leakage, and a radiation dose of 10 Gy, according to an embodiment of the present invention. Figure 6F is a contour plot showing the minimum radiation dose expected to reach a tumor cell under the assumption of 50% lead-212 leakage for various possible radon-220 and lead-212 diffusion lengths according to an embodiment of the present invention, wherein seeds of 3 microcuries / cm length are implanted at 4 mm intervals; Figure 7 is a diagram illustrating a safety factor for various intervals and radon release rate ranges for prostate cancer according to an embodiment of the present invention; Figure 8A shows the spatial distribution of photostimulated light emission (PSL) signals in a tissue section of a 4T1 tumor, where the sampled data area is represented by white (0 mm to 4 mm) and the fitted area is represented by magenta dashed lines (0.5 mm to 3 mm); Figure 8B is a diagram of the radial activity distribution of the sampled data in Figure 8A. This radial activity distribution is fitted by a theoretical model to extract the effective diffusion length. Figure 8C shows the spatial distribution of PSL in another tissue section from the same tumor, where the seed location was automatically determined by calculating the intensity centroid. Figure 8D is a diagram of the radial activity distribution of the sampled data in Figure 8C. This radial activity distribution is fitted by a theoretical model to extract the effective diffusion length. Figures 9 to 14 show the effective spread length obtained for different tumor types based on tumor quality; Figure 15 shows four tissue sections of a DaRT tumor obtained using a digital automated radiography system to measure the diffusion length of radon-220. Figure 16A shows a single tissue slice used for measuring the diffusion length of radon-220; and Figure 16B shows the average count calculated based on the distance from a seed location, where a fitted model is used to measure the radon-220 diffusion length. Implementation

[0019] One aspect of certain embodiments of the present invention relates to setting the radon release rate of a DaRT source used when treating different types of tumors based on the characteristics of the tumor. The applicant has developed a model that estimates the dose reaching a tumor cell based on the diffusion length of lead-212 in the tumor, the diffusion length of radon-220 in the tumor, and the probability of lead-212 leakage. The diffusion length represents the typical distance from the point where an atom forms in the decay of its parent radionuclide to the point of decay of that atom. It determines the spatial distribution of diffusing atoms around the seed; when the radial distance from the seed increases by one diffusion length, the alpha particle dose decreases by approximately three times. For a seed with the radon release rate considered herein, the diameter of the region around the seed receiving an alpha particle dose of 10 Gy is approximately 10 times the diffusion length. A method for measuring an effective diffusion length and thus estimating a range of values ​​for the diffusion lengths of radon-220 and lead-212 is described in the appendix. The probability of lead-212 leakage represents the chance that a lead-212 atom released from its source will leave a tumor via the bloodstream before it decays.

[0020] The diffusion length of radon-220 and the probability of lead-212 leakage vary in different types of cancerous tumors. Generally, the shorter the diffusion length of radon-220, the more activities are required to achieve similar results. The applicant has estimated the diffusion length of radon-220 in various types of tumors and has therefore determined the radon release rate of the source to be used in treating these tumor types.

[0021] Figure 1 is a schematic illustration of a system 100 for planning a radiotherapy treatment according to an embodiment of the present invention. The treatment typically involves implanting a plurality of sources 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 an operator (e.g., a physician). Alternatively, system 100 includes a communication interface 106 for receiving instructions and / or data from a remote computer or operator. System 100 further includes a processor 108 configured to generate a layout plan of radiotherapy sources in the tumor and thus provide details of individual sets 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 may, as appropriate, include a general-purpose hardware processor configured to run software to perform the tasks described below. Alternatively, processor 108 may include a dedicated processor configured with software suitable for performing one of its tasks described herein, such as a signal processing processor, a digital signal processor (DSP), or a vector processor. In other embodiments, processor 108 may include a dedicated hardware processor configured with hardware (such as an FPGA or ASIC) to perform its tasks.

[0022] In some embodiments, the processor 108 is further configured to estimate the radiation dose expected to reach each of several points in the tumor, for example as described in PCT / IB2021 / 050034, filed January 5, 2021, entitled “Treatment Planning for Alpha Particle Radiotherapy,” the disclosure of which is incorporated herein by reference.

[0023] Figure 2 is a flowchart of actions performed in preparing a radiotherapy treatment for a tumor according to an embodiment of the present invention. The method of Figure 2 generally begins with system 100 receiving (step 202) input about the tumor (such as an image of the tumor and / or a type of the tumor). For the tumor, a gap is selected (step 204) to be inserted between sources of the tumor and thus determined (step 206) the number of sources to be included in the treatment kit for the tumor. Additionally, (step 208) the duration of the treatment is selected. The radon release rate of the sources is also selected (step 210). In some embodiments, instructions for the layout of the sources in the tumor are also prepared (step 212). Thereafter, (step 214) a kit containing the number of sources with the selected parameters is prepared and the kit is packaged in a suitable sterile package. In some embodiments, the method further includes a processing procedure. In those embodiments, the method includes, for example, implanting (step 216) the kit of sources into the tumor according to the prepared (step 212) layout. In some embodiments, the method includes removing (step 218) the source after a selected (step 208) duration. In other embodiments, the source is not removed and remains in the patient.

[0024] In some embodiments, the type of tumor is determined based on clinical and / or pathological histological observations (such as an analysis of a portion of a tumor obtained during a physical examination and / or an analysis of the quantity and / or density of blood vessels in the tumor, as determined from an image of the tumor). For example, the type of tumor is selected from a list including one of the following: squamous cell carcinoma, basal cell carcinoma, glioblastoma multiforme, sarcoma, pancreatic cancer, lung cancer, prostate cancer, breast cancer, and colorectal cancer.

[0025] In some embodiments, the sources are arranged in a layout with a regular geometric pattern, thereby achieving a relatively low distance between each point in the tumor and at least one of the sources.

[0026] Figure 3 is a schematic illustration of a regular source configuration in a hexagonal arrangement 160 according to one embodiment of the present invention. In the hexagonal arrangement 160, a surface of a tumor to be treated is divided into hexagons 164 through which a source enters, and the center 162 of each hexagon is designated for inserting a source. The center 162 for inserting a source is located at the vertex of an equilateral triangle, and the distance 166 between any two sources is referred to herein as the layout spacing. The hexagon 164 is formed by the bisectors of the lines connecting the center 162 to its six nearest neighbor centers 162. The minimum radiation dose from the source is located at the centroid of the triangle, which is located at the vertex of the hexagon. Depending on the situation, 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. The spacing between the sources is important in determining a treatment plan for a particular type of cancer, as discussed below.

[0027] The spacing between the sources is selected (step 204) as a trade-off between ensuring the desired destruction of the tumor (by a smaller spacing) without using an activity level close to safety limits and the simplicity of the implantation procedure (by a larger spacing). Generally, the largest spacing is chosen that is still believed to destroy the tumor using a seed with a relatively low activity level. The spacing (step 204) is selected in response to the type of tumor because radon-220 and lead-212 have different diffusion lengths in different tumor types, and therefore DaRT sources have different effective ranges in different tumor types. In addition, different tumor types have different required radiation doses. In some embodiments, the spacing (step 204) is selected according to one type of tumor treatment. One type of treatment is aimed at completely destroying the cells of the tumor. Another type of treatment is aimed at reducing the mass of the tumor to a size that is not visible to the naked eye, or to a size that makes the tumor resectable. Complete destruction usually requires a higher activity level of the sources and / or a smaller spacing between the sources.

[0028] Another option, or alternative, is to consider the accessibility of the tumor's location within the patient's body when selecting the interval (step 204). For example, a larger interval is preferable for tumors located in visceral organs that require access via a catheter or endoscope, compared to similar tumors that are easily accessible. In some embodiments, the interval between sources is selected while considering the time and complexity of implantation. Smaller intervals require more sources and therefore increase the implantation time. Therefore, according to some embodiments of the invention, a maximum interval that still allows for tumor destruction is used.

[0029] Figure 4 is a schematic illustration of a DaRT source 21 kit 700 according to an embodiment of the present invention. The kit 700 includes a sterile package 702 containing a plurality of Alpha-emitting radiotherapy sources 21 for insertion into a tumor.

[0030] Depending on the application, source 21 may be housed within a vial or other enclosure 706 that prevents radiation from escaping. In some embodiments, the enclosure is filled with a viscous liquid (such as glycerin) that prevents radon atoms from escaping the enclosure 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 further includes a seed applicator 708 for inserting source 21 into a patient, as described in PCT application PCT / IB2019 / 051834. Depending on the application, applicator 708 may be provided pre-loaded with one or more sources 21. According to this option, individual sources 21 in the enclosure 706 are supplied for cases where more than the pre-loaded number of sources is required. Another option is to not provide the source 21 in the housing 706 in the kit 700 and to include the source in the device 708 only in the kit 700.

[0031] The number of sources to be included in one of the treatment kits 700 for tumor treatment is determined based on the selected interval and source layout (step 206) to cover the entire tumor. In some embodiments, an additional 10% to 20% of sources are provided in the treatment kit.

[0032] The operator selects the duration of treatment (e.g., the time the seed remains in the tumor) as appropriate, based on the desired outcome (e.g., complete destruction, mass reduction). In some embodiments, the duration of treatment is pre-selected (step 208) based on tumor parameters (such as its location in the patient's body and the patient's availability of the removal source). Alternatively, the duration of treatment is selected during treatment based on the progress of the treatment (step 208).

[0033] The activity and desorption probability of the source are selected as appropriate (step 210) in response to the selected interval, treatment duration, and tumor type. In some embodiments, the activity and desorption probability of the source are further selected in response to a treatment type of the tumor. For example, if an operator instructs that the goal is to completely destroy the cells of the tumor, a higher activity and / or desorption probability is used compared to an instruction to remove the tumor from visual monitoring or reduce its size to make it resectable. Depending on the tumor type, one goal of selecting the activity and source probability is to achieve at least a specific radiation dose at every point in the entire tumor (or at least at points in the entire tumor exceeding a certain threshold percentage), as discussed in more detail below.

[0034] Note that while the risk of over-radiation for a single small tumor is low, treatment of larger and / or multiple tumors may involve the implantation of hundreds of sources. In such cases, it is important to precisely adjust the activity of the sources to prevent the administration of an over-radiation dose to the patient. It is generally considered undesirable to implant more than a few millicuries (e.g., 2 to 5 millicuries) of activity level in a patient. However, for safety reasons, a limit of approximately 1 millicurie is currently used. For larger tumors requiring a seed size of 170 cm or more, this sets a limit of approximately 6 microcuries for the activity of a single seed unit of a certain length. Regarding radon release rates, this sets a limit of approximately 2.5 microcuries given a desorption rate of 38% to 45%. This limit is not the same for all tumor types. Certain 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, allowing for a higher radon release rate. Other cancer types, such as pancreatic cancer, are expected to require radiation therapy to larger tumors. Other cancer types, such as melanoma and colorectal cancer, are expected to require radiation therapy to several different tumors. These cancer types may require seeds with a total length of 170 cm or even longer.

[0035] Note that the actions in Figure 2 are not necessarily performed in the order they are presented. For example, in cases where the activity of selecting a source (step 210) is not in response to the processing duration, the activity of selecting a source (step 210) can be performed before or concurrently with selecting (step 208) the processing duration. As another example, the preparation of the layout and the preparation of the set can be performed simultaneously or in any desired order.

[0036] Figure 5 is a schematic illustration of a radiotherapy source 21 according to one embodiment of the present invention. The radiotherapy source 21 includes a support 22 configured for insertion into a body of a host. The radiotherapy source 21 further includes radioactive seed atoms 26 of radium-224 located on an outer surface 24 of the support 22, for example as described in U.S. Patent 8,894,969, which is incorporated herein by reference. Note that for illustrative purposes, the atoms 26 and other components of the radiotherapy source 21 are drawn disproportionately large. The atoms 26 are typically coupled to the support 22 in a manner that prevents the radioactive seed atoms 26 from leaving the support, but upon radioactive decay, the daughter radioactive seeds (symbolically shown as 28) of these radioactive seed atoms may immediately leave the support 22 due to the recoil generated by decay. The percentage of daughter radioactive seeds 28 that leave the support due to decay is called the desorption probability. In some embodiments, coupling of the atom 26 to the support 22 is achieved by heat treatment. Alternatively, or additionally, a coating 33 covers the support 22 and the atom 26 in a manner that prevents the release of the radioactive seed atom 26 and / or immediately modulates the release rate of one of the progeny radioactive seeds 28 after radioactive decay. The progeny radioactive seeds may pass through the coating 33 and be transferred from the radiotherapy source 21 due to recoil, or recoil may carry the progeny radioactive seeds into the coating 33, which then leaves the coating by diffusion. In some embodiments, as shown in FIG. 5, in addition to the coating 33, an inner coating 30 of thickness T1 is also placed on the support 22, and the radioactive seed atom 26 is attached to the inner coating 30. However, note that not all embodiments include an inner coating 30 and alternatively, the radioactive seed atom 26 is directly attached to the support 22. [ ]

[0037] In some embodiments, the support 22 includes a seed for complete implantation within a tumor of a patient and may have any suitable shape, such as a rod or plate. Instead of being fully implanted, the support 22 may be partially implanted within a patient and may be part of a needle, a lead, the tip of an endoscope, the tip of a laparoscope, or any other suitable probe.

[0038] In some embodiments, the support member 22 is cylindrical and has a length of at least 1 mm, at least 2 mm, or even at least 5 mm. Depending on the case, the seed has a length between 5 mm and 60 mm. The support member 22 may have a diameter of 0.7 mm to 1 mm, but in some cases, a source with a larger or smaller diameter is used. Specifically, for processing layouts with smaller intervals, the support member 22 may have a diameter of less than 0.7 mm, less than 0.5 mm, less than 0.4 mm, or even no more than 0.3 mm. [ ]

[0039] In this paper, activity on support 22 is measured in microcuries per centimeter of source length. Since the radiation dose reaching most of the tumor is controlled by the radioactive nuclei leaving the source, the measurement of "radon release rate" is defined in this paper as the product of source activity and desorption probability. For example, a source with 2 microcuries of activity per centimeter and a 40% desorption probability has a radon release rate of 0.8 microcuries per centimeter. [ ]

[0040] The desorption probability depends on the depth of the radionuclear seed atom 26 within the surface of the support 22 and / or on the type and thickness of the coating 33. Implantation of the radionuclear seed atom 26 into the surface of the support 22 is typically achieved by heat treatment of the radiotherapy device 21, and the depth of the atom 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 can be achieved, for example, by using any of the methods described in PCT disclosure WO 2018 / 207105 entitled "Polymer Coatings for Brachytherapy Devices," the disclosure of which is incorporated herein by reference. In other embodiments, a lower desorption probability is used, as described in U.S. Provisional Patent Application No. 63 / 126,070 entitled "Diffusing Alpha-emitters Radiation Therapy with Enhanced Beta Treatment," the disclosure of which is incorporated herein by reference.

[0041] Note that not all alpha radiation reaching the tumor is due to the radon-220 progeny radionuclides 28 that immediately leave the support 22 after decay. Some of the radon-220 progeny radionuclides 28 produced from the decay of the radionuclide atom 26 remain on the support 22. When the progeny radionuclides 28 decay, their progeny radionuclides (e.g., plutonium-216) may leave the support 22 due to recoil, or lead-212 produced immediately after the decay of plutonium-216 may leave the support 22 due to recoil.

[0042] Typically, the radionuclides 26 are coupled to the support 22 in a manner that prevents the radionuclides 26 from escaping from the support 22 itself. In other embodiments, the radionuclides 26 are coupled to the support 22 in a manner that allows the radionuclides 26 to, for example, use any of the methods described in PCT Publication WO 2019 / 193464 entitled "Controlled Release of Radionuclides" (e.g., by diffusion away from the support without decay), the disclosure of which is incorporated herein by reference. Diffusion may also be achieved by using a bioabsorbable coating, which initially prevents premature escape of the radionuclides 26 but decomposes and allows diffusion after implantation in a tumor.

[0043] The total radiation emitted from a source within a tumor (referred to herein as "cumulative radon activity") depends on the radon emission rate of the source and the time the source remains in the tumor. If the source remains in the tumor for a relatively long period (for example, more than one month for a radium-224 source), the cumulative radon activity is the product of: the radon emission rate of the source multiplied by the average lifetime of radium-224 (which is 3.63 days or 87.12 hours) divided by ln² (which is approximately 0.693). For example, a radium-224 source with a radon emission rate of 1 microcurie (μCi) = 37,000 becquerels (Bq) has a cumulative radon activity of approximately 4.651 megabecquerels (MBq) hours. Note that the same amount of cumulative radon activity can be achieved by implanting a source with a higher radon emission rate within a shorter period. For this shorter period, the cumulative activity is given by: Where S(0) represents the radon release rate of the source when it is inserted into the tumor. The average radium-224 lifetime is given by t, which is the processing duration in hours. For example, a two-week processing provides the following cumulative activity: The amount of activity required at the source to achieve tumor destruction varies significantly depending on the type of tumor and the source-source intervals. Therefore, it is important to identify the activity required for a specific tumor type for each type of tumor. A method for calculating the radiation dose reaching each point in a tumor based on the activity of the implanted source 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 those calculation methods, the required radon release rate can be calculated based on the diffusion length of lead-212 in the tumor, the diffusion length of radon-220 in the tumor, the interval 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.

[0044] Figures 6A to 6D are diagrams illustrating 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. A 10 Gy level is chosen as a reference because the required nominal alpha particle dose depends on the tumor type and can be as high as 20 to 30 Gy. To obtain the seed activity required for a target dose other than 10 Gy, the seed activity for 10 Gy should be multiplied by the ratio between the target dose and 10 Gy. Figure 6A shows the required radon release rate for three different values ​​of radon-220 diffusion length based on lead-212 diffusion length when the lead leakage probability is 80% and the spacing is 3.5 mm. Figure 6B is a similar diagram for a lead leakage probability of 40%. Figure 6C shows the same diagram for a 4 mm spacing and an 80% lead leakage probability, while Figure 6D shows the required radon release rate for a 4 mm spacing and a 40% lead leakage probability. Readers will understand that the range of radon release rate values ​​can be very wide and the following discussion provides guidance on a narrow range of applications for specific tumor types.

[0045] Figure 6E is a contour plot showing the desired radon release rate values ​​for various possible radon-220 and lead-212 diffusion lengths within a range of interest, for a 4 mm interval, 50% lead-212 leakage, and a radiation dose of 10 Gy, according to an embodiment of the present invention.

[0046] Figure 6F is a contour plot showing the minimum radiation dose expected to reach a tumor cell under the assumption of 50% lead-212 leakage for various possible radon-220 and lead-212 diffusion lengths according to an embodiment of the present invention, wherein seeds of 3 microcurie / cm length are implanted at 4 mm intervals.

[0047] As shown in Figure 6E, the required radon release rate varies depending on the diffusion length. Since different tumor types have different diffusion lengths, the required radon release rate differs for each tumor type.

[0048] To estimate the diffusion lengths of lead-212 and radon-220 in different tumor types, the applicant conducted two categories of experiments on various types and sizes of tumors. In a first experimental category, the applicant implanted the sources into tumors induced in mice and dissected the tumors several days later, measuring the actual activity reaching various points within the tumor. These measurements conformed to the aforementioned equation, thus estimating one effective long-term diffusion length in the tumor. This effective diffusion length is the larger of the diffusion lengths of radon-220 and lead-212.

[0049] The tumor was removed from the mouse and frozen, allowing for sectioning shortly after removal. The tumor was then cut into slices approximately 10 micrometers thick. Immediately following sectioning, the tissue slices, placed directly on glass slides, were fixed with formalin for a short period (several minutes). 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 using a thin Mylar foil to prevent radioactive contamination. The plate was then scanned using an automated phosphorescent radiography system (Fuji FLA-9000) to record the spatial distribution of lead-212 within the tissue slices.

[0050] Further details on the measurement of effective long-term diffusion length are discussed in Appendix A below.

[0051] The second experimental category is similar to the first, but the tumor is removed approximately half an hour after source insertion rather than waiting several days. Following this shorter period, the distribution of radioactivity is believed to be primarily due to the diffusion of radon-220, as its spatial distribution stabilizes very rapidly, while the contribution from lead-212 increases from zero to a maximum within approximately 1.5 to 2 days after source insertion and remains sufficiently low within 30 minutes. Details regarding the measurement of the radon-220 diffusion length are discussed below in Appendix B.

[0052] Early measurements of the diffusion length of radon-220 found values ​​between 0.23 mm and 0.31 mm. However, the number of measurements was relatively small. The most recent results of the measurements described above unexpectedly showed no significant difference between long-term and short-term experiments. Therefore, the applicant hypothesizes that the diffusion length of lead-212 is less than that of radon-220. Thus, the applicant hypothesizes that lead-212 is approximately 0.2 mm. This hypothesis is used because, as shown in Figure 6E, the dependence of lead-212 diffusion length is weaker within the range of radon-220 diffusion length values. Table 1 below summarizes the measured radon-220 diffusion lengths for several cancer types.

[0053] As is known in this technique, different tumor types require different radiation doses to destroy their cells. Table 1 contains the required bioeffective dose (BED) for various types of cancer tumors in Gy equivalents (GyE). These dose values ​​are for photon-based radiation (X-rays or gamma rays). Alpha radiation is considered more lethal to cells, and therefore the alpha radiation dose in Gy is multiplied by a correction factor called the relative biological effect (RBE) (currently estimated to be 5) to convert the alpha radiation dose to a BED in Gy equivalents (GyE). The BED in DaRT is the sum of the alpha dose multiplied by the RBE and the beta dose generated from radium-224 and its progeny.

[0054] The probability of lead-212 leakage is relatively low in the center of the tumor, but reaches about 80% in the periphery of the tumor. In order to ensure cell destruction throughout the tumor, the applicant has used an 80% leakage probability value when selecting the radon release rate of the source.

[0055] To estimate the required interval and radon release rate for seeds used in a specific tumor type, the applicant estimates the required dose for that tumor type, the beta radiation dose provided by a certain range of active levels, and a remaining required dose to be provided by alpha radiation. The alpha radiation dose is estimated for a certain range of intervals and radon release rates, and a safety factor is calculated for that range of intervals and radon release rates, representing the ratio between the estimated provided dose and the required dose. A safety factor is needed to overcome inaccuracies that can occur in source placement, allowing some sources to be separated beyond a specified interval. Furthermore, the tumor may be heterogeneous, exhibiting some local variations in diffusion length.

[0056] The applicant has selected a safety factor range of 1.5 to 4 when defining the desired interval and radon release range for treatment. This safety factor is believed to provide sufficient safety for the tumor to be destroyed by the provided radiation, without being too high to expose the patient to the risk of systemic radiation from lead-212 leakage through the bloodstream from the tumor and subsequent absorption in various organs.

[0057] For a given tumor type, the same safety factor can be achieved by using different spacings between sources and radon release rates. If the sources are 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 above 1.5 microcuries / cm length. In contrast, when the spacing between sources is less than 4 mm, the sources can be assigned a relatively low radon release rate.

[0058] Given the chosen safety factor range, a suitable source interval is selected. As mentioned above, the largest interval is chosen that is still believed to utilize a seed with a relatively low activity level to disrupt the tumor. The applicant limits the interval selection to a step size of 0.5 mm, which is believed to be close to an inaccuracy level in seed placement. This inaccuracy is taken into account in the safety factor. [ ]

[0059] After selecting an interval, select a radon release rate range that corresponds to that interval and the safety factor. This radon release rate range is believed to provide optimal results when dealing with tumors of the type against which calculations are performed. Note that the selected radon release rate range is not limited to use with the specific interval used to select that range, but can be used with a range of intervals surrounding the selected interval due to safety margins. Table 1 Tumor types Effective long-term diffusion length in millimeters (all sizes) Required dosage (Bioeffective dose (BED) in gray equivalents) squamous cell carcinoma 0.44 60 colon and rectum 0.44 120 Glioblastoma multiforme (GBM) 0.27 100 Melanoma 0.40 150 prostate 0.32 173 Breast (triple negative) 0.35 60 pancreatic cancer 0.29 100

[0060] As shown in Table 1, the effective long-term spread length for prostate cancer is estimated to be approximately 0.32 mm and the required dose is approximately 173 GyE.

[0061] Table 2 presents the beta dose for several intervals and radon release rates for prostate cancer, the corresponding required alpha radiation dose, the estimated alpha radiation dose, and the obtained safety factor.

[0062] Figure 7 is a diagram illustrating the safety factors based on radon release rate for various intervals and for prostate cancer according to embodiments of the present invention.

[0063] From Figure 7, the applicant determined that a 4 mm interval would require a seed with a radon emission rate substantially higher than 2.5 microcuries. To avoid this higher activity level, a 3.5 mm interval was assumed when selecting the radon emission rate of the source. The actual interval used was shorter than 3.9 mm, shorter than 3.8 mm, shorter than 3.7 mm, or even shorter than 3.6 mm, depending on the situation. On the other hand, the actual interval used was greater than 3.1 mm, greater than 3.2 mm, greater than 3.3 mm, or even greater than 3.4 mm, depending on the situation. Table 2 Interval (mm) 3 3.5 4 Beta-dosage [0.9 μCi] 16.3 11.5 8.0 [1.35 μCi] 24.4 17.3 12.0 [1.8 μCi] 32.6 23.1 16.0 [2.25 μCi] 40.7 28.8 20.0 [2.7 μCi] 48.9 34.6 24.0 Required nominal alpha dose [0.9 μCi] 31.3 32.3 33.0 [1.35 μCi] 29.7 31.1 32.2 [1.8 μCi] 28.1 30.0 31.4 [2.25 μCi] 26.5 28.8 30.6 [2.7 μCi] 24.8 27.7 29.8 Alpha dose [0.9 μCi] 74.7 28.2 10.7 [1.35 μCi] 112.0 42.2 16.0 [1.8 μCi] 149.4 56.3 21.4 [2.25 μCi] 186.7 70.4 26.7 [2.7 μCi] 224.0 84.5 32.0 Safety factor [0.9 μCi] 2.38 0.87 0.32 [1.35 μCi] 3.77 1.36 0.50 [1.8 μCi] 5.32 1.88 0.68 [2.25 μCi] 7.06 2.44 0.87 [2.7 μCi] 9.03 3.05 1.07

[0064] For a 3.5 mm interval, a safety factor between 1.5 and 4 corresponds to a radon release rate between 1.5 μCurry / cm length and 3.2 μCurry / cm length. Although the upper half of this range is relatively high, this range of radon release rates is reasonable given the relatively small size of prostate cancer tumors. For long-term treatment, this corresponds to cumulative radon activity between approximately 7 MBq / cm and 14.7 MBq / cm.

[0065] In some embodiments, to increase the success rate of treatment, a radon release rate of at least 1.6 microcuries / cm, at least 1.7 microcuries / cm, at least 1.8 microcuries / cm, or even at least 2.0 microcuries / cm is used for prostate cancer. In some embodiments, to reduce the radiation dose to which the patient is exposed, the radon release rate is no greater than 3.0 microcuries / cm, no greater than 2.8 microcuries / cm, no greater than 2.5 microcuries / cm, or even no greater than 2.2 microcuries / cm. In other embodiments, a safety factor between 1.5 and 2.5 is used, and therefore the radon release rate is between 1.5 and 2.3 microcuries / cm. In other embodiments, a safety factor between 3 and 4 is used, and thus the radon release rate of seed 21 is between 2.7 microcuries per centimeter and 3.2 microcuries per centimeter.

[0066] Alternatively, the source may contain at least 8 MBq / hour / cm, at least 8.8 MBq / hour / cm, at least 9.6 MBq / hour / cm, or even at least 10.4 MBq / hour / cm. On the other hand, the source may contain less than 12 MBq / hour / cm or even less than 11 MBq / hour / cm.

[0067] [in conclusion] [, , ] It will be understood that the methods and apparatus described above are to be interpreted as including apparatus for performing methods and methods of using apparatus. It should be understood that features and / or steps described with respect to one embodiment may sometimes be used in other embodiments, and not all embodiments of the invention have all features and / or steps shown in a particular figure or described with respect to one of a particular embodiment. Tasks may not be performed in the exact order described.

[0068] Note that some embodiments described above may include structures, actions, or details of structures and actions that are not essential to the invention and are described by way of example. The structures and actions described herein may be replaced by equivalents that perform the same function, even if the structures or actions are different, as is known in the art. The embodiments described above are cited 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 that would immediately occur to those skilled in the art upon reading the foregoing description and not disclosed in the prior art. Therefore, the scope of the invention is limited only by the elements and limitations as used in the claims, wherein the terms "comprise," "include," "have," and their variants, when used in the claims, mean "including but not limited to."

[0069] [appendix] [A, ] [Effective Diffusion Length Measurement] [ ] When the tumor diameter was ~6 mm to 15 mm, a single DaRT seed (6.5 mm in length, 0.7 mm in outer diameter) carrying 2-3 uCi 224Ra was inserted into the center of a murine tumor 7 to 20 days after tumor inoculation. Four to five days later, the tumor (as a whole) was excised and cut in half at the estimated location perpendicular to the seed axis at the seed center. The seed was then pulled out using surgical forceps and placed in a water-filled tube for subsequent measurement using a gamma counter. The tumor was kept at -80°C for one hour. It was then placed in dry ice for measurement using the same gamma counter to determine its 212Pb activity. The probability of 212Pb leakage from the tumor was determined using measurements of seed and tumor activity.

[0070] Following gamma measurement, both halves of the tumor underwent tissue sectioning using a cryogenic microtome. Sections were cut to a thickness of 10 μm at intervals of 250 μm to 300 μm, placed on positively charged glass slides, and fixed with 4% paraformaldehyde. Typically, 5 to 15 sections were prepared per tumor, spanning a length of 1.5 mm to 5 mm. Shortly after preparation, the glass slides were placed face down on a phosphor imaging plate (Fujifilm TR2040S) for one hour, protected by a 12 μm Maillard foil and enclosed in an opaque shell. Alpha particles emitted from the sections during the decay of 212Pb descendant atoms, 212Bi, and 212Po penetrate the foil and deposit energy into the active layer of the phosphor imaging plate. The plate was then read out using a phosphor imaging scanner (Fujifilm FLA-9000).

[0071] For each tumor slice, the result is a two-dimensional intensity map proportional to local 212Pb activity. Intensity (in units of photoluminescence) is converted to 212Pb activity using suitable calibration samples measured simultaneously with the slide. The point where the seed passes through the section can be identified by the appearance of a "hole" in the activity map or by obtaining the centroid of the activity distribution. Examples are shown in Figures 8A to 8D. A region of interest (ROI) centered on the estimated seed location is defined, and this ROI is divided into concentric rings 0.1 mm wide with a radius ranging from 0.5 mm to 3 mm. For each ring, the average activity is calculated. If the ROI extends beyond the tumor slice area or contains an area with degraded tissue or image quality, the ring average is obtained within a finite azimuth sector. Then, based on a diffusion leakage model, a curve of activity based on radial distance from the origin (estimated seed location) is numerically fitted using a function describing the radial activity distribution from the seed. The seed is calculated as a line source perpendicular to the image. The source is divided into a large number of point segments, each segment contributing an activity to a given pixel in the image plane. In this expression, The distance between the source segment and the pixel under consideration, and and These are free parameters, the values ​​of which are adjusted to optimize the fit to the entire curve (Figures 8A to 8D). This will be addressed in... The obtained value is considered as an estimate of the effective diffusion length of the slice. This will be applied to all slices. The average value is considered to represent the effective (or primary) spread length of the tumor, where the uncertainty is equal to the standard deviation of the values ​​obtained across all slices.

[0072] Figure 8A shows the spatial distribution of photostimulated light emission (PSL) signals in a tissue section of a 4T1 tumor, where the sampled data area is represented by white (0 mm to 4 mm) and the fitted area is represented by magenta dashed lines (0.5 mm to 3 mm). Seed location was manually determined.

[0073] Figure 8B is a graph of the radial activity distribution of the sampled data in Figure 8A, fitted by the diffusion leakage model.

[0074] Figure 8C shows the spatial distribution of PSL in another tissue slice from the same tumor, where the seed location is automatically determined by calculating the intensity centroid.

[0075] Figure 8D is a graph of the radial activity distribution of the sampled data in Figure 8C, fitted by the diffusion leakage model.

[0076] Figure 9 shows the measured value of effective diffusion length based on tumor quality of pancreatic tumors.

[0077] Figure 10 shows the measured value of effective spread length based on tumor quality of prostate tumors.

[0078] Figure 11 shows the measured value of effective spread length based on tumor quality in melanoma tumors.

[0079] Figure 12 shows the measured value of effective spread length based on tumor quality of squamous cell carcinoma tumors.

[0080] Figure 13 shows the measured value of effective spread length based on tumor quality in triple-negative breast tumors.

[0081] Figure 14 shows the measured value of effective spread length based on the tumor quality of GBM tumors.

[0082] [appendix] [B, ] [Rn] [Measurement Method] [, , ] A DaRT seed is inserted into a tumor for a relatively short time—30 minutes—after which the seed is removed (to prevent Pb accumulation within the tumor). The tumor is then frozen and cut into 10 µm thick sections perpendicular to the seed axis. These sections are placed on glass slides and fixed with formaldehyde. The tumor sections are then fed into a digital automated radiography system (iQID Alpha camera, QScint Imaging Solutions, LLC), which records the Alpha particle impacts one by one, providing their xy coordinates (with ~20 µm accuracy), a timestamp, and a signal proportional to the deposited energy.

[0083] Figure 15 shows an example of an image consisting of four tissue slices from a DaRT-treated tumor, acquired using the iQID system. The image is cropped so that each slice is analyzed independently, as shown in Figure 16A, which shows a single tissue slice used for analysis. For each slice, a center is selected (either by a centroid method or by identifying a "hole" in the motion map), and the average number of alpha particle counts is calculated at an increasing radial distance from the center. The resulting image is then numerically fitted by assuming the recorded motion map is superimposed along an infinitesimal segment of the DaRT seed, where Equation 1 is used to calculate each segment: In this expression, The radial distance between the seed segment and the point of interest on the image. Radon diffusion length and It is a free parameter. These two parameters ( The value was found using a least squares fitting method.

[0084] The fitting is performed within a finite region of the active distribution to avoid artificial "holes" at the center (where the DaRT seed is located) and far ends of the distribution where statistical variation is too large. Figure 16B shows an example of a fitted curve, which displays the average count calculated based on the distance from the seed location (including the fitted function).

[0085] 21: Diffused Alpha Emission Radiation Therapy Source / Source / Alpha Emission Radiation Therapy Source / Radiotherapy Source / Radiotherapy Device / Seed 22: Support component 24: Outer surface 26: Radioactive nuclei / atoms 28: Progeny radioactive nuclei 30: Inner coating 33: Coating 100: System 102: Imaging camera 104: Input Interface 106: Communication Interface 108: Processor 110: Output Interface 160: Array / Hexagonal Configuration 162: Center 164: Hexagon 166: Distance 202: Steps 204: Steps 206: Steps 208: Steps 210: Steps 212: Steps 214: Steps 216: Steps 218: Steps 700: Set / Processing Set 702: Aseptic Packaging 706: Small bottle / Other outer casing / Outer casing 708: Seed Therapy Device / Therapy Device T1: Thickness

Claims

1. A diffuse alpha-emitter radiation therapy (DaRT) source for the treatment of a prostate cancer tumor in one of the patients, the DaRT source comprising: A support having a length of at least 1 millimeter; and radium-224 atoms coupled to the support such that when the DaRT source is implanted in the prostate cancer tumor, no more than 20% of the radium-224 atoms leave the support and enter the prostate cancer tumor within 24 hours without decaying, but after decay, at least 5% of the daughter radionuclides of the radium-224 atoms leave the support; characterized in that an administration pattern of the DaRT source includes implanting the DaRT source in the prostate cancer tumor for a given duration, wherein the DaRT source provides cumulated activity of released radon between 7 megabecquerels (MBq) hours / cm length and 14.7 MBq hours / cm length.

2. The DaRT source of claim 1, wherein the mode of administration of the DaRT source includes implanting the DaRT source and other DaRT sources into the entire prostate cancer tumor, wherein a space between the DaRT sources is between 3 mm and 4.5 mm.

3. The DaRT source of claim 2, wherein the mode of administration of the DaRT source includes implanting the DaRT source and other DaRT sources into the entire prostate cancer tumor, wherein a spacer between the DaRT sources is between 3.1 mm and 3.9 mm.

4. The DaRT source of claim 3, wherein the mode of administration of the DaRT source includes implanting the DaRT source and other DaRT sources into the entire prostate cancer tumor, wherein a space between the DaRT sources is between 3.3 mm and 3.7 mm.

5. The DaRT source of any one of claims 1 to 4, wherein the mode of administration of the DaRT source includes implanting the DaRT source and other DaRT sources in a hexagonal configuration throughout the prostate cancer tumor.

6. A DaRT source as claimed in any of claims 1 to 4, wherein the administration mode of the DaRT source includes selecting the given duration before implanting the DaRT source and removing the DaRT source from the prostate cancer tumor after the given duration since the implantation of the DaRT source has elapsed.

7. A DaRT source as described in any of claims 1 to 4, wherein the DaRT source has a radon release rate between 1.5 microcurie / cm length and 3.2 microcurie / cm length.

8. The DaRT source as claimed in claim 7, wherein the DaRT source has a radon release rate between 1.5 microcurie / cm length and 2.3 microcurie / cm length.

9. The DaRT source of claim 7, wherein the DaRT source has a radon release rate between 2.7 microcurie / cm length and 3.2 microcurie / cm length.

10. A diffuse albedo radiation therapy (DaRT) source for the treatment of a prostate cancer tumor in one of the patients, the DaRT source comprising: A support having a length of at least 1 millimeter; and radium-224 atoms coupled to the support such that, upon decay, at least 5% of the progeny radioactive nuclei of the radium-224 atoms leave the support, characterized in that one application mode of the DaRT source includes implanting the DaRT source into the prostate cancer tumor in a regularly configured array, the regularly configured array having a spacing between 3 millimeters and 4 millimeters between every two adjacent DaRT sources.

11. The DaRT source of claim 10, wherein the DaRT source is implanted in the prostate cancer tumor in a hexagonal array, and each DaRT source is separated from its adjacent DaRT source in the hexagonal array by a distance between 3 and 3.5 mm.

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