Diffusing alpha-emitter radiation therapy for pancreatic cancer

Abstract

To provide an apparatus and method for providing tumor-specific radiation dosages in radiotherapy treatment.SOLUTION: A method for treating a tumor comprises identifying a tumor as a pancreatic cancer tumor and implanting, in the tumor identified as a pancreatic cancer tumor, as least one diffusing alpha-emitter radiation therapy (DaRT) source with a suitable radon release rate and for a given duration, such that the source provides during the given duration cumulated radioactivity of released radon between 5.6 mega becquerel (MBq) h and 11.6 MBq h, per centimeter length.SELECTED DRAWING: Figure 1

Description

Technical field

[0001] The present invention relates generally to radiotherapy, and more particularly to apparatus and methods for providing tumor-specific radiation doses in radiotherapy treatments. [Background technology]

[0002] Ionizing radiation is commonly used to treat certain types of tumors, including malignant cancerous tumors, and destroys cells. However, ionizing radiation can also damage healthy cells in the patient, so care should be taken to maximize the dose to the tumor while minimizing the radiation dose delivered to healthy tissue outside the tumor. be paid.

[0003] Ionizing radiation destroys cells by damaging their DNA. The biological effectiveness of different types of radiation in killing cells depends on the type and severity of DNA damage they produce. Alpha particles are a powerful means of radiotherapy because they induce clustered double-strand breaks in DNA that cells cannot repair. Unlike conventional types of radiation, the destructive effects of alpha particles are also largely unaffected by low cellular oxygen levels, and their presence in tumors is the main reason for the failure of conventional photon- or electron-based radiotherapy. It is also effective against hypoxic cells, which are the cause of In addition, the short range of alpha particles in tissue (less than 100 micrometers) protects surrounding healthy tissue when the alpha-emitting atoms are confined to the volume of the tumor. On the other hand, the short reach of alpha rays has so far limited their use in cancer therapy because there was no practical way to place sufficient concentrations of alpha-emitting atoms throughout the tumor volume.

[0004] Diffuse alpha-emitter radiotherapy (DaRT), described for example in Kelson U.S. Pat. No. 8,834,837, uses radium-223 or radium-224 atoms to extend the therapeutic range of alpha-emitter radiation. . Radium-224 has a half-life of 3.6 days and radium-223 has a half-life of 11.4 days. In DaRT, radium atoms attach with sufficient strength to a tumor-implanted source (also called a “seed”) and leave the source in a wasteful manner (by being removed from the tumor via blood). Instead, a significant proportion of the daughter radionuclides (radon-220 for radium-224 and radon-219 for radium-223) leave the source and enter the tumor upon radium decay. These radionuclides and their own radioactive daughter atoms spread around the source by diffusing to a radial distance of several millimeters before decaying by the alpha emitter. The extent of tumor destruction is therefore increased compared to the radionuclide remaining in the source with the daughter.

[0005] For tumor therapy to be effective, the DaRT seeds used to treat it must release a sufficient number of radon atoms to destroy the tumor with a high probability. Without sufficient doses of radiation, too many cancer cells remain in the tumor, and these cells can regenerate and reform into a malignant tumor. On the other hand, the seeds should not release too many radon atoms. Some of the daughters are cleared from the tumor through the blood and can damage distant healthy tissues of the patient, such as bone marrow, kidneys and ovaries.

[0006] The amount of radium atoms in a DaRT source is quantified in terms of radioactivity, the decay rate of radium. DaRT source radioactivity is measured in units of microcuries (μCi) or kilobecquerels (kBq). where 1 μCi = 37 kBq = 37,000 decays / sec. When using DaRT, the radiation dose delivered to tumor cells depends not only on the radium radioactivity of the source, but also on the probability that daughter radon atoms leave the source and enter the tumor upon alpha decay of radium. This probability is referred to herein as the "exit probability". Therefore, instead of referring to the radioactivity of the source, a measure of the DaRT-associated radioactivity of the source is the radon emission rate, defined herein as the product of the radioactivity at the source and the probability of radon leaving the source. ” can be used. Like radioactivity, radon emission rate is expressed in μCi or kBq. Radioactivity and radon emission rate values ​​given herein are for the source at the time of implantation of the source into the tumor unless otherwise specified.

[0007] Kelson, U.S. Pat. No. 8,834,837, supra, suggests using radioactivity "from about 10 nanocurie to about 10 microcurie, more preferably from about 10 nanocurie to about 1 microcurie." there is [Prior art documents] [Patent document]

[0008] [Patent document 1] U.S. Patent No. 8,834,837 [Outline of the invention]

[0009] Embodiments of the present invention relate to providing precisely controlled doses of radiation to tumors in radiation therapy treatments. Embodiments include kits containing radiation therapy sources designed to provide the appropriate amount of radiation and the appropriate number of sources for a tumor of a particular size. Further embodiments relate to methods of preparing kits of radiotherapy sources for specific tumors and methods of treating tumors.

[0010] Thus, according to an embodiment of the present invention, a method for treating a tumor comprises: identifying a pancreatic cancer tumor; Implanting two diffuse alpha emitter radiotherapy (DaRT) sources, wherein the sources emitted between 5.6 megabecquerel (MBq) hours and 8 MBq hours of radon per centimeter length during a predetermined period of time. and providing cumulative radioactivity.

[0011] Optionally implanting at least one radiation therapy source includes implanting an array of sources, each source being no more than 4 millimeters from an adjacent source in the array. Optionally implanting at least one radiation therapy source includes implanting an array of sources in a hexagonal arrangement, each source being no more than 4 millimeters from an adjacent source in the array. Optionally at least one radiation therapy source has a radon emission rate of between 1.2 and 2.5 microCuries per centimeter of length. Optionally at least one radiation therapy source has a radon emission rate between 1.4 and 1.9 microcuries per centimeter of length. Optionally, the method comprises selecting a given period of time prior to implanting at least one DaRT source in the tumor and removing the source from the tumor after the given period of time has elapsed since implantation of the source.

[0012] According to an embodiment of the present invention, there is further provided a method of preparing radiation therapy comprising: identifying a tumor as a pancreatic cancer tumor; receiving an image of the tumor; providing a layout of an emitter radiotherapy (DaRT) source, the source having a radon emission rate of 1.2-2.5 microcuries per centimeter of length. Providing layouts as options comprises providing layouts in which the spacing between sources within the tumor is 4 millimeters or less. Optionally, the source has a radon emission rate of between 1.4 and 1.9 microcuries per centimeter of length.

[0013] According to an embodiment of the present invention, there is further provided an apparatus for preparing radiation therapy comprising: an input interface for receiving information about a tumor; determining that the tumor is pancreatic cancer; A processor configured to generate a layout of radiation therapy (DaRT) sources, wherein the sources in the layout have a radon emission rate of 1.2-2.5 microCuries per centimeter of length and are adjacent to each other. a processor wherein the sources in the layout are arranged in a regular pattern with a distance between the sources of 5 millimeters or less; and an output interface for displaying the layout to a human operator. An apparatus is provided.

[0014] According to an embodiment of the present invention, there is further provided a method of preparing radiation therapy comprising: receiving a request for a diffuse alpha emitter radiotherapy (DaRT) source for a pancreatic cancer tumor; determining the number of therapy sources; and providing a kit containing the determined number of radiation therapy sources, the sources having a radon emission rate of 1.2 to 2.5 microcuries per centimeter of length. A method is provided comprising the steps of:

[0015] Optionally determining the number of radiation therapy sources required comprises determining the number of sources required such that the area of ​​the tumor is covered by sources having an inter-source spacing of 4 millimeters or less. have. Optionally, the source has a radon emission rate of between 1.4 and 1.9 microcuries per centimeter of length.

[0016] Further according to an embodiment of the present invention is a diffuse alpha emitter radiotherapy (DaRT) source for implantation into a pancreatic cancer tumor, wherein the DaRT source has 1.2-2.5 microCuries per centimeter length. A radon emitting rate is provided. An alternative is a radon emission rate between 1.4 and 1.9 microcuries per centimeter of length.

[0017] According to an embodiment of the present invention, there is further provided a kit of diffuse alpha emitter radiotherapy (DaRT) sources for implantation into a pancreatic cancer tumor comprising: a package; and a plurality of DaRT sources arranged in the package. and a DaRT source having a radon emission rate of 1.2 to 2.5 microcuries per centimeter of length. Alternatively, the source has a radon emission rate between 1.4 and 1.9 microcuries per centimeter of length.

[0018] According to an embodiment of the present invention, a method for treating a tumor further comprises: identifying the tumor as a pancreatic cancer tumor; and implanting an array of diffuse alpha emitter radiotherapy (DaRT) sources regularly spaced 3-4 millimeters between the sources. Optionally implanting the array of sources comprises implanting in a hexagonal arrangement, with each source being no more than 4 millimeters from a neighboring source in the array. [Brief description of the drawing]

[0019]

Figure 1

Figure 2

[0020] An aspect of some embodiments of the present invention relates to setting the radon emission rates of DaRT sources used in treating different types of tumors according to tumor characteristics. Applicants have developed a model that estimates the dose reaching the cells of the tumor as a function of the diffusion length of lead-212 in the tumor, the diffusion length of radon-220 in the tumor, and the leakage probability of lead-212. Diffusion length describes the general distance from the point at which the atom was produced in the decay of the parent radionuclide to the point at which the atom decays. It determines the spatial distribution of diffuse atoms around the seed; increasing the radial distance from the seed by one diffusion length reduces the alpha particle dose by about a factor of three. For the radon emitting rate seeds considered here, the diameter of the area around the seed that receives an alpha particle dose of 10 Gy is about 10 times the diffusion length. Methods for measuring the effective diffusion length and estimating the range of values ​​for the radon-220 and lead-212 diffusion lengths are given in the Appendix. The lead-212 leakage probability represents the likelihood that lead-212 atoms emitted from the source will leave the tumor via the blood system before decaying.

[0021] The diffusion length of radon-220 and the leakage probability of lead-212 have different values ​​depending on the cancer tumor type. In general, the shorter the diffusion length of radon-220, the more radioactivity required to achieve similar results. Applicants have estimated the diffusion length of radon-220 in various types of tumors and thus determined the radon release rates of the sources used to treat these tumor types.

[0022] FIG. 1 is a schematic diagram of a system 100 for planning radiation therapy, according to an embodiment of the invention. Treatment generally involves implantation of multiple sources into the tumor to be destroyed. System 100 includes an imaging camera 102 that acquires images of tumors requiring radiation therapy. 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. Alternatively or additionally, system 100 includes a communication interface 106 for receiving instructions and / or data from a remote computer or human operator. The system 100 was further configured to generate a layout plan of radiotherapy sources within the tumor, thus providing details of each kit of radiotherapy sources for treatment of the tumor via the output interface 110. A processor 108 is provided. Output interface 110 may be connected to a display and / or a communication network. Processor 108 optionally comprises a general-purpose hardware processor configured to execute software to perform the tasks described below. Alternatively or additionally, processor 108 comprises a dedicated processor such as a signal processor, digital signal processor (DSP) or vector processor, configured with appropriate software to perform its tasks as described herein. be. In other embodiments, processor 108 comprises a dedicated hardware processor configured in hardware, such as an FPGA or ASIC, to perform its tasks.

[0023] In some embodiments, the processor 108 may include, for example, It is further configured to estimate the radiation dose expected to reach each point within the tumor, as described in PCT application PCT / IB2021 / 050034.

[0024] FIG. 2 is a flow chart of acts performed in preparing for radiation therapy treatment of a tumor, according to an embodiment of the present invention. The method of FIG. 2 generally begins with system 100 receiving input regarding a tumor, such as a tumor image and / or tumor type (202). The spacing between sources inserted into the tumor is selected (204) for the tumor and thus the number of sources to be included in the tumor treatment kit is determined (206). Additionally, a treatment period is selected (208). A radon emission rate for the source is also selected (210). In some embodiments, instructions regarding the layout of sources within the tumor are also provided (212). A kit containing a number of sources of selected parameters is then prepared (214) and packaged in a suitable sterile package. In some embodiments, the method further comprises a therapeutic procedure. In those embodiments, the method includes implanting (216) the source from the kit into the tumor, eg, according to a prepared (212) layout. In some embodiments, the method includes removing (218) the source after the selected (208) time period. In other embodiments, the source is not removed and remains with the patient.

[0025] In some embodiments, the type of tumor is determined clinically and / or by analysis of the amount and / or density of blood vessels within the tumor determined from biopsied portions of the tumor and / or imaging of the tumor. or determined based on histopathological observations. Tumor types are selected from a list including, for example, squamous cell carcinoma, basal cell carcinoma, glioblastoma, sarcoma, pancreatic cancer, lung cancer, prostate cancer, breast cancer, and colorectal cancer.

[0026] In some embodiments, the sources are arranged in a regular geometric pattern layout that achieves a relatively short distance between each point within the tumor and at least one of the sources.

[0027] FIG. 3 is a schematic diagram of a regular arrangement of sources in a hexagonal arrangement 160, according to an embodiment of the invention. In hexagonal arrangement 160, the surface through which the source enters the tumor to be treated is divided into hexagons 164, with the center 162 of each hexagon designated for insertion of the source. The center 162 for inserting the source is located at the vertex of the equilateral triangle between each two sources, and the distance 166 is referred to herein as the layout spacing. Hexagons 164 are formed by bisectors to lines connecting centers 162 to their nearest six adjacent centers 162 . The minimum doses of radiation from the source are at the centroids of the triangles and they are at the vertices of the hexagons. Optionally, the spacing between sources is less than 5 millimeters, 4.5 millimeters or less, 4 millimeters or less, 3.5 millimeters or less, or 3 millimeters or less. As explained below, the spacing between sources is very important in determining treatment plans for certain cancer types.

[0028] The spacing between sources should be combined with the desire to ensure tumor destruction without the use of radioactive levels that may approach the safe limit, which requires small spacing, and the simplicity of the simple procedure. is selected as an alternative (204) as a compromise between. In general, the largest interval is selected that is still believed to destroy tumors with seeds that are not too radioactive. The interval is chosen according to the tumor type because radon-220 and lead-212 have different diffusion lengths in different tumor types and thus DaRT sources have different effective ranges in different tumor types (204). . Furthermore, different tumor types require different radiation doses. In some embodiments, the interval is selected 204 according to the type of tumor treatment. One type of treatment aims to completely destroy the cells of the tumor. Another type of treatment is aimed at reducing a tumor mass to a sub-visible size or a size that makes the tumor resectable. Complete destruction usually requires either highly radioactive sources or close spacing between sources.

[0029] Alternatively or additionally, accessibility to the location of the tumor within the patient is considered when selecting 204 the spacing. For example, visceral tumors that require catheter or endoscopic access may prefer wider spacing than similar tumors that are easily accessible. In some embodiments, the spacing between sources is selected considering the time and complexity of implanting the sources. Smaller spacings require more sources and correspondingly longer source implantation times. Therefore, according to some embodiments of the present invention, the maximum spacing that still allows tumor destruction is used.

[0030] FIG. 4 is a schematic diagram of a DaRT source 21 kit 700 according to an embodiment of the invention. Kit 700 includes a sterile package 702 containing multiple alpha emitter radiotherapy sources 21 for insertion into a tumor.

[0031] Optionally, source 21 is provided in a vial or other casing 706 that prevents radiation from exiting the casing. In some embodiments, the casing is filled with a viscous liquid, such as glycerin, which is disclosed in PCT Application PCT / IB2019 / 051834, entitled "Radiation Therapy Seeds and Applicators," incorporated herein by reference. prevent radon atoms from escaping casing 706, as described in . In some embodiments, kit 700 further includes seed applicator 708 used to insert source 21 into a patient, as described in PCT Application PCT / IB2019 / 051834. Optionally, applicator 708 is provided with one or more feed line sources 21 pre-loaded therein. Following this option, separate sources 21 within casing 706 are provided for cases where more than the number of preloaded sources is required. Alternatively, source 21 in casing 706 is not provided in kit 700 and only source in applicator 708 is included in kit 700 .

[0032] The number of sources included in the tumor treatment kit 700 is determined 206 to cover the entire tumor according to the selected spacing and source layout. In some embodiments, an additional 10-20% source is provided in the treatment kit.

[0033] The duration of treatment (eg, how long the seeds remain in the tumor) is optionally selected by the operator according to the desired treatment (eg, complete destruction, mass reduction). In some embodiments, the duration of treatment is pre-selected 208 based on tumor parameters such as the location of the tumor within the patient and the patient's availability for removal of the source. Alternatively, a duration of treatment is selected 208 during treatment based on the progress of the treatment.

[0034] The radioactivity of the sources and their detachment probabilities are selected as options (210) depending on the selected interval, treatment duration, and tumor type. In some embodiments, the radioactivity of the sources and their detachment probabilities are further selected in response to the type of tumor treatment. For example, if the operator indicates that complete cell destruction of a tumor should be aimed at, it may be necessary to remove the tumor from gross observation or reduce the size of the tumor to make it resectable. Optionally, the source radioactivity and source detachment probability are selected depending on the tumor type with the aim of achieving at least a certain radiation dose at each point across the tumor, which is described in more detail below.

[0035] Note that the risk of radiation overdose for a single small tumor is low, but when treating large tumors and / or multiple tumors, treatment may involve the implantation of hundreds of sources. . In such cases, it is important to precisely adjust the radioactivity of the source to avoid over-radiating the patient. It is generally considered undesirable to implant a patient with radioactivity levels exceeding a few millicuries (eg, 2-5) millicuries. However, just in case, a limit of about 1 millicurie is currently used. For large tumors requiring seeds of 170 centimeters or more, this sets a limit of about 6 microcuries on the radioactivity of a 1 centimeter long seed. As for the radon release rate, given a withdrawal rate of 38-45%, this sets a limit of about 2.5 microCuries. This limitation is not the same for all tumor types. Some tumor types, such as glioblastoma multiforme (GBM), prostate cancer, breast cancer, and squamous cell carcinoma, are generally expected to be treated with radiation if they are small. Therefore, the number of seeds used and their total length is expected to be less than 170 cm, allowing higher radon release rates to be used. Other types of cancer, such as the pancreas, are expected to require radiotherapy of large tumors. Additional cancer types, such as melanoma and colorectal, are expected to require radiation therapy for several different tumors. These types of cancer may require seeds that are 170 cm or longer in length.

[0036] Note that the acts in Figure 2 are not necessarily performed in the order presented. For example, if the radioactivity of the source is not selected 210 as a function of the treatment duration, the radioactivity of the source can be selected 210 before or in parallel with selecting 208 the treatment duration. As another example, layout preparation and kit preparation can be performed simultaneously or in any desired order.

[0037] FIG. 5 is a schematic diagram of a radiation therapy source 21, according to an embodiment of the invention. Radiation therapy source 21 includes support 22 configured for insertion into a subject's body. Radiation therapy source 21 further comprises radionuclide atoms 26 of radium-224 on outer surface 24 of support 22, for example, as described in US Pat. No. 8,894,969, which is incorporated herein by reference. . Note that atoms 26 as well as other components of radiation therapy source 21 are drawn disproportionately large for ease of illustration. Atoms 26 are generally bound to support 22 so that radionuclide atoms 26 do not leave the support, but upon radioactive decay their daughter radionuclides, symbolically shown as 28, are attributed to the decay. It can leave the support 22 for recoil. The percentage of daughter radionuclides 28 that leave the support due to decay is called the escape probability. Bonding of atoms 26 to support 22 is accomplished in some embodiments by heat treatment. Alternatively or additionally, coating 33 covers support 22 and atoms 26 in a manner that prevents release of radionuclide atoms 26 and / or modulates the release rate of daughter radionuclides 28 upon radioactive decay. The daughter radionuclides can pass through the coating 33 and exit the radiotherapy source 21 due to recoil, or recoil can bring them into the coating 33 from where they exit by diffusion. In some embodiments, in addition to coating 33, an inner coating 30 of thickness T1 is disposed on substrate 22, and radionuclide atoms 26 are attached to inner coating 30, as shown in FIG. However, not all embodiments include an internal coating 30, in which case the radionuclide atoms 26 are directly attached to the support 22. FIG.

[0038] In some embodiments, support 22 comprises a seed for implantation completely within a patient's tumor and may have any suitable shape such as a rod or plate. Support 22 is only partially implanted within the patient instead of being fully implanted, and is part of a needle, wire, endoscope tip, laparoscope tip, or any other suitable probe.

[0039] In some embodiments, support 22 is cylindrical and has a length of at least 1 millimeter, at least 2 millimeters, or at least 5 millimeters. Optionally, the seed length is 5-60 mm (millimeters). The support 22 optionally has a diameter of 0.7-1 mm, although larger or smaller diameter sources are optionally used. Particularly for small spacing treatment layouts, support 22 optionally has a diameter of less than 0.7 mm, less than 0.5 mm, less than 0.4 mm, or less than 0.3 mm.

[0040] The radioactivity of support 22 is here measured in units of microcuries per centimeter of source length. Since the radiation dose reaching the bulk of the tumor is dominated by the radionuclide leaving the source, a measure of "radon emission rate" is defined herein as the product of radioactivity at the source and the probability of escape. be. For example, a source with an activity of 2 microcuries per centimeter length and a probability of escape of 40% has a radon emission rate of 0.8 microcurie per centimeter length.

[0041] The detachment probability depends on the depth of radionuclide atoms 26 within the surface of support 22 and / or the type and thickness of coating 33 . Implantation of radionuclide atoms 26 into the surface of support 22 is generally accomplished by thermal treatment of radiotherapy device 21, and the depth of atoms 26 can be controlled by adjusting the temperature and / or duration of the thermal treatment. is. In some embodiments, the withdrawal probability is between about 38-45%. Alternatively, higher withdrawal probabilities are achieved, for example, using any of the methods described in PCT Publication WO2018 / 207105 entitled "Polymer Coatings for Brachytherapy Devices," the disclosure of which is incorporated herein by reference. incorporated herein. In other embodiments, as described in U.S. Provisional Patent Application No. 63 / 126,070, entitled "Diffuse Alpha Emitter Radiation Therapy with Enhanced Beta Therapy," the disclosure of which is incorporated herein by reference. , the lower exit probability is used.

[0042] Note that not all alpha rays reaching the tumor are due to daughter radionuclides 28 of radon-220 leaving the support 22 upon decay. A portion of the radon-220 daughter radionuclide 28 produced from the decay of the radionuclide atom 26 remains on the support 22 . When the daughter radionuclide 28 decays, the daughter radionuclide, eg protonium-216, may leave the support 22 due to recoil. The lead-212 produced during the decay of protonium-216 can leave the support 22 due to recoil.

[0043] Generally, radionuclide atom 26 is bound to support 22 in a manner that prevents radionuclide atom 26 from leaving support 22 itself. In other embodiments, the radionuclide atom 26 is not decayed, e.g., by diffusion, e.g. Radionuclide atoms 26 are bound to support 22 in a manner that allows them to leave the support using any of the methods described. Diffusion is optionally achieved by using a bioabsorbable coating that initially prevents premature release of the radionuclide atoms, but which collapses after implantation into the tumor to allow diffusion.

[0044] The total amount of radiation emitted by a source within the tumor is referred to herein as the "cumulative radioactivity of emitted radon" and depends on the radon emission rate of the source and the time the source remains within the tumor. If the source is left in the tumor for an extended period of time, e.g., more than a month for a radium-224 source, the cumulative activity of the radon released will affect the radon emission rate of the source over the life expectancy of radium. The multiplied product is reached, which is 63 days or 87.12 hours divided by ln2, 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 activity of emitted radon of about 4.651 megabecquerels (MBq) hours. Note that the same amount of cumulative radioactivity of emitted radon can be achieved by implanting a source with a higher radon emission rate for a shorter period of time. For such a short period of time, the cumulative radioactivity is:

number

number

[0045] The amount of source radioactivity required to achieve tumor destruction varies greatly with tumor type and source spacing. Therefore, for each tumor type, it is important to specify the radioactivity required for that particular tumor type. A method for calculating the radiation dose reaching each point in a tumor according to the radioactivity of the implanted source is a U.S. patent application entitled "Treatment Planning for Alpha Particle Radiation Therapy," filed January 5, 2021. Publication No. 17 / 141,251, the disclosure of which is incorporated herein by reference. Using these calculation methods, the required radon emission rate is determined by the diffusion length of lead-212 in the tumor, the diffusion length of radon-220 in the tumor, the distance between sources implanted in the tumor, and the distance from the tumor to It can be calculated as a function of the lead-212 leakage probability and the radiation dose required to reach each location within the tumor.

[0046] Figures 6A-6D are graphs showing a wide range of radon emission rate values ​​required to ensure a nominal alpha particle dose of at least 10 Grays (Gy) for different values ​​of the above parameters. The 10 Gy level is chosen as a reference because the nominal alpha particle dose required varies by tumor type and can be as high as 20-30 Gy. To obtain the required seed radioactivity for target doses other than 10 Gy, the 10 Gy seed radioactivity needs to be multiplied by the ratio of the target dose and 10 Gy. FIG. 6A shows the required radon emission rate as a function of lead-212 diffusion length for three different values ​​of radon-220 diffusion length for a lead leakage probability of 80% and a spacing of 3.5 mm. FIG. 6B is a similar graph for a lead leakage probability of 40%. FIG. 6C shows the same graph for 4 mm spacing and 80% lead leakage probability, and FIG. 6D shows the required radon emission rate for 4 mm spacing and 40% lead leakage probability. The reader will appreciate that the range of possible radon emission rate values ​​is very large, and the discussion below provides guidance on the narrow ranges to be used for specific tumor types.

[0047] FIG. 6E shows the required for 4 mm spacing, 50% lead-212 leakage, and 10 Gy radiation dose for various possible radon-220 and lead-212 diffusion lengths over the range of interest, according to an embodiment of the present invention. 2 is a contour graph showing various radon emission rate values;

[0048] FIG. 6F shows the potential for various radon-220 and lead-212 diffusion lengths in cells of a tumor implanted with 3 microcurie seeds per cm length and 4 mm spacing, according to embodiments of the present invention. Contour graph showing minimum radiation dose expected to reach, assuming 50% lead-212 leakage.

[0049] As can be seen in FIG. 6E, the required radon emission rate is significantly different for different diffusion lengths. Since different tumor types have different diffusion lengths, different tumor types require different radon release rates.

[0050] To estimate the diffusion lengths of lead-212 and radon-220 in different types of tumors, applicants performed two classes of experiments on different types of tumors and different sizes. . In a first class of experiments, Applicants implanted radiation sources within tumors generated in mice, dissected the tumors several days later, and measured the actual radioactivity that reached various points in the tumor. These measurements fit the above equation, thus estimating the effective long-term diffusion length within the tumor. This effective diffusion length is the larger of the diffusion lengths of radon-220 and lead-212.

[0051] Tumors were removed from the mice and frozen so that the tumors could be sliced ​​immediately after removal from the mice. Tumors were then cut into slices approximately 10 microns thick. Formalin fixation was performed briefly (min) directly on histological slices placed on glass slides immediately after sectioning. After fixation, the slides were placed on the Fuji Phosphor Imaging Plate in a closed box for 1 hour. The slide was separated from the plate by a thin Mylar foil to avoid contamination of the plate with radioactive decay. Subsequently, plates were scanned with a fluorescence imaging autoradiography system (Fuji FLA-9000) to record the spatial distribution of lead-212 within histological slices.

[0052] Details of effective long-term diffusion length measurements are provided in Appendix A below.

[0053] A second class of experiments was similar to the first class, but instead of waiting several days, the tumor was removed approximately 30 minutes after source insertion. The distribution of radioactivity after such a short period is believed to be primarily due to the diffusion of radon-220. This suggests that while the spatial distribution of radon-220 stabilizes very quickly, the contribution arising from lead-212 increases from zero to a maximum 1.5–2 days after source insertion, and is sufficient at 30 min after source insertion. because it is very low. Details for measuring the diffusion length of Radon-220 are provided in Appendix B below.

[0054] Early measurements of the diffusion length of radon-220 detected values ​​between 0.23 and 0.31 mm. However, the number of measurements was relatively small. Recent results of the above measurements surprisingly showed no significant difference between long-term and short-term experiments. Applicants therefore assume that the diffusion length of lead-212 is shorter than that of radon-220. Applicants therefore assume that lead-212 is about 0.2 millimeters. This assumption is used because, in the range of values ​​for the diffusion length of radon-220, the dependence on the diffusion length of lead-212 is weak, as seen in FIG. 6E. The measured radon-220 diffusion lengths are summarized for several cancer types in Table 1 below.

[0055] As is known in the art, different tumor types require different doses of radiation to destroy their cells. Table 1 shows the biological effective dose (BED) required for various types of cancer tumors in gray equivalents (GyE). These dose values ​​are for photon-based radiation (X-rays or gamma rays). Alpha rays are thought to be more lethal to cells, so the dose of alpha rays at Gray is multiplied by a correction factor called Relative Biological Effectiveness (RBE), currently estimated at 5, to Convert to equivalent BED (GyE). DaRT's BED is the alpha dose multiplied by the RBE plus the beta dose produced by Radium-224 and his daughter.

[0056] Leakage probability of lead-212 is relatively low in the center of the tumor, but reaches about 80% in the periphery of the tumor. To ensure cell destruction throughout the tumor, Applicants used an 80% leakage probability value in choosing the radon emission rate of the source.

[0057] To estimate the desired spacing and radon emission rate of seeds for a particular tumor type, Applicants provided the dose required for the tumor type, the beta radiation dose provided by the span of radioactivity levels, and the alpha radiation Estimate the remaining dose required. The alpha dose is estimated for the span of the interval and the radon emission rate, and the safety factor, which is the ratio of the estimated delivered dose to the required dose, is calculated for the span of the interval and the radon emission rate. A safety factor is necessary to overcome possible inaccuracies in source placement, so that some sources may be separated by more than the specified spacing. There is Furthermore, tumors are heterogeneous and there may be some local variation in diffusion length.

[0058] Applicants have chosen a safety factor range of 1.5-4 to define the interval and radon release range required for treatment. This safety factor is thought to provide sufficient safety for tumors to be destroyed by the radiation provided, while leakage of lead-212 from tumors via blood and subsequent uptake in various organs not high enough to endanger the patient from whole-body radiation resulting from

[0059] For a given tumor type, the same safety margin can be achieved with different interval pairs and radon release rates. If the sources are spaced relatively large, such as 4.5 mm or 5 mm, the radon emission rate of the source should be high, such as greater than 1.5 microCuries per centimeter of length. In contrast, when the spacing between sources is less than 4 mm, the sources can be assigned relatively low radon emission rates.

[0060] Given the range of safety factors chosen, an appropriate source spacing is chosen. As above, the largest interval is selected that is still considered to destroy the tumor with seeds that are not too radioactive. Applicants limit the selection of spacing to steps of 0.5 millimeters. This is believed to be close to the level of seed placement inaccuracy. These inaccuracies are taken into account in the safety factor.

[0061] After selecting the interval, a range of radon emission rates is selected that corresponds to the interval and safety factor. Radon release rates in this range are believed to provide the best results in treating tumors of the tumor types for which the calculations were performed. The selected range of radon emission rates is not limited to being used with the particular interval used to select the range, but rather the range of intervals surrounding the selected interval for a margin of safety. Note that you can use

table 1

[0062] As listed in Table 1, the effective long-term diffusion length for pancreatic cancer is estimated to be about 0.29 mm, and the required dose is about 100 GyE.

[0063] Table 2 shows beta doses, corresponding required alpha doses, estimated alpha doses, and resulting safety margins for several intervals and radon emission rates in pancreatic cancer. FIG. 7 is a graph showing the safety factor for various intervals and ranges of radon release rates in pancreatic cancer, according to embodiments of the invention.

[0064] From Figure 7, Applicants determined that a 4 millimeter spacing would require seeds with a radon release rate substantially greater than 2.5 microCuries. To avoid such high levels of radioactivity, a spacing of 3.5 millimeters is assumed when choosing the radon emission rate of the source. The spacing actually used is optionally less than 3.9 mm, less than 3.8 mm, less than 3.7 mm, or even less than 3.6 mm. On the other hand, the actual spacing used may optionally be greater than 3.1 mm, greater than 3.2 mm, greater than 3.3 mm, or greater than 3.4 mm. [Table 2]

[0065] At 3.5 millimeter intervals, a radon emission rate of 1.2-2.5 microCuries per centimeter of length is chosen to sufficiently destroy the tumor without exposing the patient to unnecessary radiation. For long-term treatment, this corresponds to a cumulative radioactivity of emitted radon between about 5.6 MBq hours and 11.6 MBq hours per centimeter.

[0066] In some embodiments, at least 1.4 microcuries per centimeter of length, at least 1.5 microcuries per centimeter of length, at least 1.7 microcuries per centimeter of length, to increase the likelihood of successful treatment. , and even radon emission rates of at least 1.8 are used for pancreatic cancer. On the other hand, in some embodiments, the radon emission rate is 2.2 or less, 2.0 or less, 1.8 or less, or even 1.75 microcuries per centimeter of length to reduce the amount of radiation to which the patient is exposed. . In other embodiments, a safety factor of 1.5-2.5 is used, so the radon emission rate is 1.2-1.85 microcuries per centimeter of length. In still other embodiments, a safety factor of between 3 and 4 is used, so the seed 21 has a radon emission rate of 2.1 to 2.5 microcuries per centimeter of length.

[0067] Alternatively or additionally, the radiation source may optionally include at least 5.9 MBq hours per centimeter, at least 6.4 MBq hours per centimeter, at least 6.8 MBq hours per centimeter, or even at least 7.3 MBq hours per centimeter. Includes MBq hours. Sources, on the other hand, include options of less than 10.5 MBq hours per centimeter, or less than 9 MBq hours per centimeter.

[0068] Alternatively, if a spacing of less than 3.5 millimeters can be achieved with reasonable accuracy, e.g. , or less than 1.4 microcuries per centimeter of length.

[0069] (Conclusion) It will be appreciated that the methods and devices described above should be interpreted as including methods of using the devices and devices for carrying out the methods. Features and / or things described with respect to one embodiment may be used with other embodiments, and all embodiments of the invention are shown in particular figures, in one particular embodiment. It should be understood that not all features and / or things described with respect to one may be present. Tasks are not necessarily performed in the exact order presented.

[0070] Note that some of the above embodiments may not be essential to the invention and may include structures, acts or details of structures and acts described as examples. Structure and acts described herein are interchangeable with equivalents that perform the same function even if the structure or acts are different, as known in the art. The above embodiments are cited as examples, and the invention is not limited to that specifically shown and described herein. Rather, the scope of the invention includes combinations and subcombinations of the various features described above and variations and modifications thereof.

[0071] (Appendix A) (measurement of effective diffusion length) 7-20 days after tumor inoculation, when the lateral diameter of the tumor is about 6-15 mm, 2-3 uCi 224 Insert a single DaRT seed (6.5 mm long, 0.7 mm outer diameter) carrying Ra into the center of the mouse-mediated tumor. After 4-5 days, the tumor is excised (whole) and divided into two halves perpendicular to the seed axis at the presumed location of the seed center. The seeds are then pulled out using surgical tweezers and placed in water-filled tubes for measurement in a gamma counter. Tumors are kept at about 80°C for 1 hour. Then put it in dry ice and measure it with the same gamma counter, containing 212 Measure the radioactivity of Pb. Seed and tumor radioactivity measurements 212 Used to determine the leakage probability of Pb.

[0072] Immediately following the gamma measurements, one-half of the tumor therapy undergoes histological sectioning on a cryostat microtome. Sections are cut at 250–300 µm intervals at 10 µm thickness, placed on positively charged glass slides, and fixed with 4% paraformaldehyde. There are usually 5-15 sections per tumor, 1.5-5 mm in length. Immediately after preparation, the slides are placed face down on a phosphor imaging plate (Fujifilm TR2040S) protected with 12 μm Mylar foil for 1 hour and placed in a light tight case. 212 Pb progeny atoms, 212 Bi and 212 Alpha particles emitted from the Po decay section penetrate the foil and deposit energy in the emissive layer of the phosphorescent imaging plate. The plate is then read on a fluorescence imaging scanner (Fujifilm FLA-9000).

[0073] For each tumor section, the results are local 212 2D intensity map proportional to Pb radioactivity. Using an appropriate calibration sample measured at the same time as the slide, the intensity (unit of photostimulated luminescence) was 212 Converted to radioactive Pb. The points where the seed crosses the section are identified by either marking a "hole" in the radioactivity map or by obtaining the centroid of the radioactivity distribution. Examples are shown in 8A-8D. Define a region of interest (ROI) centered on the estimated seed position and divide it into concentric rings of width 0.1 mm with radii ranging from 0.5 to 3 mm. Calculate the average radioactivity for each ring. If the ROI extends beyond the range of the tumor section, or contains tissue or areas of reduced image quality, ring averaging is acquired over a limited azimuthal sector. The curves of radioactivity obtained as a function of radial distance from the origin (estimated seed position) are then numerically fitted by a function representing the distribution of radioactivity radially from the seed, based on a diffusion leakage model. be. The calculation describes the seed as a source perpendicular to the image. The source is divided into a number of point-like segments, each radioactive to a specific pixel in the plane of the image:

number

[0074] Figure 8A shows the spatial distribution of photostimulated luminescence (PSL) signals in tissue sections of 4T1 tumors, where the area of ​​sampled data is shown in white (0–4 mm) and the fitted area is the magenta dashed line ( 0.5-3 mm). Seed positions are determined manually. FIG. 8B is a graph of the radial radioactivity distribution of the sampled data of FIG. 8A fitted by a diffuse leakage model. Figure 8C shows the PSL spatial distribution in another tissue section of the same tumor. Here, the seed positions are automatically determined by calculating the centroid of the intensity. FIG. 8D is a graph of the radial radioactivity distribution of the sampled data of FIG. 8C fitted by a diffuse leakage model. FIG. 9 shows measurements of effective diffusion length as a function of tumor mass for pancreatic tumors. FIG. 10 shows measurements of effective diffusion length as a function of tumor mass for prostate tumors. FIG. 11 shows measurements of effective diffusion length as a function of tumor mass for melanoma tumors. FIG. 12 shows effective diffusion length measurements as a function of tumor burden for squamous cell carcinoma tumors. FIG. 13 shows measurements of effective diffusion length as a function of tumor burden for triple-negative breast cancer. FIG. 14 shows effective diffusion length measurements as a function of tumor burden for GBM tumors.

[0075] (Appendix B) (Rn measurement method) DaRT seeds are inserted into the tumor for a relatively short time (30 minutes), after which the seeds are removed (to prevent accumulation of Pb within the tumor). Tumors are then frozen and cut into 10 μm thick sections perpendicular to the seed axis. These are placed on glass slides and fixed using formaldehyde. Tumor sections are sent to a digital autoradiography system (iQID alpha camera by QScint Imaging Solutions, LLC). The system records alpha particle hits one by one, providing xy coordinates (~20 µm accuracy), time stamps, and a signal proportional to the accumulated energy.

[0076] An example of an image obtained using the iQID system from four tissue sections of a DaRT-treated tumor is shown in FIG. It shows four tissue sections of DaRT-treated tumors acquired using the iQID autoradiography system. For analysis, images are cropped so that each section is analyzed independently, as seen in Figure 16A, which shows a single histological section used for analysis. For each section, a center is chosen (either by the centroid method or by identifying "holes" in the radioactivity map) and at increasing radial distances from the center the average number of alpha particle counts is calculated. The resulting plots are then fitted numerically, assuming that the recorded radioactivity map is a superposition of microsegments along the DaRT seed. Each segment is calculated using Equation 1 below:

number

[0077] The fit is performed over a limited range of the radioactive distribution to avoid artificial 'holes' in the center (where the DaRT seeds were) and the far ends of the distribution where the statistical variation is too large. An example of a fitted curve is shown in Figure 16B. It shows the calculated average counts as a function of distance from the seed location, including the fit function.

Claims

1. 1. A diffuse alpha emitter radiotherapy (DaRT) source for use in treating a pancreatic cancer tumor in a patient, the DaRT source comprising: a support having a length of at least 1 millimeter; and radium-224 atoms bound to said support, wherein when said DaRT source is implanted in said tumor, no more than 20% of said radium-224 atoms leave said support and enter the tumor within 24 hours without decaying, but upon decay, at least 5% of the daughter radionuclides of said radium-224 atoms leave said support; having a pattern of administration of the DaRT source comprising implanting the DaRT source in the pancreatic cancer tumor for a predetermined period of time; the source provides a cumulative radioactivity of emitted radon per centimeter of length of 5.6 megabecquerel (MBq)-hours to 11.6 MBq-hours during the predetermined time period. A DaRT source characterized in that

2. The DaRT source described in claim 1, characterized in that the administration pattern of the DaRT source includes a step of embedding the DaRT source within a pancreatic cancer tumor, together with other DaRT sources, throughout the tumor with a spacing of 3 to 4.5 millimeters between the DaRT sources.

3. 3. The DaRT source of claim 2, wherein the administration pattern of the DaRT source comprises implanting the DaRT source in a pancreatic cancer tumor with other DaRT sources throughout the tumor with spacing of 3.1 to 3.9 millimeters between the DaRT sources.

4. The DaRT source of any one of claims 1 to 3, characterized in that the administration pattern of the DaRT source comprises implanting the DaRT source in the pancreatic cancer tumor in a hexagonal arrangement with other DaRT sources throughout the tumor, each DaRT source being separated by 4 millimeters or less from an adjacent DaRT source in the hexagonal arrangement.

5. A DaRT source described in any one of claims 1 to 4, characterized in that the administration pattern of the DaRT source includes the steps of selecting the predetermined period before implanting the DaRT source, and removing the DaRT source from the pancreatic cancer tumor after the predetermined period has elapsed since implantation of the DaRT source.

6. A DaRT source described in any one of claims 1 to 5, characterized in that the DaRT source has a radon emission rate of between 1.2 and 2.5 microcuries per centimeter of length.

7. 7. The DaRT source of claim 6, wherein the DaRT source has a radon emission rate between 1.2 and 1.85 microcuries per centimeter of length.

8. 7. The DaRT source of claim 6, wherein the DaRT source has a radon emission rate between 1.4 and 1.9 microcuries per centimeter of length.

9. 7. The DaRT source of claim 6, wherein the DaRT source has a radon emission rate of between 2.1 and 2.5 microcuries per centimeter of length.

10. 1. A method of preparing radiation therapy comprising: identifying the tumor as a pancreatic cancer tumor; receiving input regarding said pancreatic cancer tumor; and A layout of a diffuse alpha emitter radiotherapy (DaRT) source for the pancreatic cancer tumor; and a kit having a determined number of said DaRT sources required for said pancreatic cancer tumors; and providing one or more having The DaRT source has a radon emission rate of 1.2 to 2.5 microcuries per centimeter of length. A method comprising:

11. The method of claim 10, wherein receiving input regarding the pancreatic cancer tumor comprises receiving an image of the tumor.

12. 12. The method of claim 10 or 11, wherein providing the layout comprises providing a layout in which the spacing between the DaRT sources in the tumor is 4 millimeters or less.

13. 12. The method of claim 10 or 11, wherein the DaRT source has a radon emission rate between 1.4 and 1.9 microcuries per centimeter of length.

14. The method of claim 10 or 11, further comprising a step of determining the number of DaRT sources required such that the area of ​​the tumor is covered by the DaRT sources with spacing between the DaRT sources of 4 millimeters or less.

15. A diffuse alpha emitter radiotherapy (DaRT) source for use in treating a pancreatic cancer tumor in a patient, comprising: a support having a length of at least 1 millimeter; and radium-224 atoms bound to said support, wherein upon decay at least 5% of the daughter radionuclides of said radium-224 atoms leave said support; having The administration pattern of the DaRT source includes implanting the DaRT sources in the pancreatic cancer tumor in a regular array with a distance between every two adjacent DaRT sources of 3.1 to 3.9 millimeters. A DaRT source characterized in that 16. The DaRT source of claim 15, wherein the DaRT sources are embedded in the pancreatic cancer tumor in an array in a hexagonal configuration, each DaRT source being spaced 3.7 millimeters or less from an adjacent DaRT source in the array.

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