Space segmentation radiotherapy radiation planning method, system, device and medium

Abstract

The invention relates to the technical field of medical data processing, and discloses a space segmentation radiotherapy radiation planning method, system, equipment and medium, which comprehensively considers irradiation parameter data of a space segmentation target region and the volume occupied by effective immunogenicity dead tumor cells to calculate required parameters and calibrated immune cell multiplication rate correction factors. A radioimmune effect unified quantification mode of irradiating different immunogenic tumors in different space division modes under ion beams / X-rays with different radiation qualities and different dose rate modes is accurately established, and a dynamic quantification evaluation model of immune cells of a subject after space division irradiation is formed; a tumor control probability model of a subject after space segmentation irradiation is established, tumor control probability quantification is realized, a more scientific and reasonable space segmentation radiotherapy radiation planning scheme is generated, clear guidance can be provided for a clinician to formulate a treatment scheme, and the treatment effect of a patient is remarkably improved.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of medical data processing, and in particular to a spatially fractionated radiotherapy radiation planning method, system, device and medium. BACKGROUND

[0002] Spatially fractionated radiotherapy is a new type of radiotherapy technique for cancer treatment, aiming to improve the effect of tumor treatment and reduce the damage to normal tissues by distributing the radiation dose on multiple spatial positions of the treatment area. The spatial fractionation technique divides the tumor target area into multiple small regions in space, so that different radiation doses are applied to each small region. This division can stimulate anti-tumor immunity in the tumor area and help the diffusion of immune cells and related molecules, improving the effect of tumor treatment while avoiding damage to surrounding healthy tissues. Compared with traditional radiotherapy, spatially fractionated radiotherapy is more targeted, as it can more finely adjust the angle and intensity of the radiation beam, allowing the focus of the radiotherapy to act directly on the tumor and reducing damage to healthy tissues.

[0003] Figure 1 Taking one of the spatially fractionated radiotherapy - lattice radiotherapy as an example, the related parameters required to be set in spatially fractionated radiotherapy are demonstrated: the attributes of Vertice (dose, position, number and size), the radiation quality of the beam (ion beam / X-ray), the dose rate (FLASH / CONV), the participation of conventional radiotherapy, the application of immunological drugs, and the response degree of different tumor types to spatially fractionated radiotherapy, etc. are all important factors affecting the final effect of spatially fractionated radiotherapy. However, there is currently a lack of a method for uniformly adjusting and planning the above-mentioned spatially fractionated radiotherapy related parameters. In the face of so many factors, how to set the corresponding parameters based on the actual situation of the patient in the clinical treatment process to achieve the best treatment effect, and how to review and summarize the treatment and prognosis data of patients treated with spatially fractionated radiotherapy to form expert consensus and standardized treatment guidelines, are all key defects in the current spatially fractionated irradiation based on experience.

[0004] Therefore, the present application proposes a spatially fractionated radiotherapy radiation planning method. SUMMARY

[0005] The present application provides a spatially fractionated radiotherapy radiation planning method, system, device and medium to solve the defect of the lack of a method for uniformly adjusting and planning the spatially fractionated radiotherapy related parameters.

[0006] The spatially fractionated radiotherapy radiation planning method provided by the present application comprises:

[0007] obtaining irradiation parameter data of a spatially fractionated target area;

[0008] Obtain experimental data from spatially fractionated irradiation experiments on subjects in spatially fractionated target areas, determine the parameters required to calculate the volume occupied by effective immunogenic dead tumor cells, and calibrate the correction factor for the immune cell multiplication rate, where the subjects are tumor-bearing animals;

[0009] Based on the irradiation parameter data of the spatially segmented target area, the parameters required to calculate the volume occupied by effective immunogenic dead tumor cells, and the calibrated immune cell multiplication rate correction factor, a dynamic quantitative assessment model for the subject's immune cells after spatially segmented irradiation was established;

[0010] Based on the dynamic quantitative evaluation model of immune cells after spatially fractionated irradiation, a tumor control probability model for subjects after spatially fractionated irradiation was established;

[0011] The tumor control probability model of the subject after spatial fractionation irradiation is used to iteratively optimize the tumor control probability of the subject after spatial fractionation irradiation until the optimization goal is reached, and the radiation planning scheme for spatial fractionation radiotherapy of the subject is obtained.

[0012] In the present invention, the subjects are primarily mammals, as tumors commonly occur in mammals. Specifically, mammals can be classified by family, such as equines, bovines, and humans. Based on their intended use, mammals can be further categorized as experimental animals, pets, and livestock. These include, but are not limited to, common mice, guinea pigs, and rabbits. Given that the present invention utilizes experimental evaluation models, the test subjects are limited to non-human mammals.

[0013] Since the evaluation model is based on experiments, the test subjects can be further limited to non-human mammals.

[0014] According to a method for planning radiation therapy for spatially fractionated radiotherapy provided by the present invention, a dynamic quantitative evaluation model for immune cells of a subject after spatially fractionated irradiation is established based on irradiation parameter data of the spatially fractionated target area, parameters required for calculating the volume occupied by effective immunogenic dead tumor cells, and a calibrated immune cell multiplication rate correction factor, including:

[0015] Based on the irradiation parameter data of the spatially segmented target area, the parameters required for calculating the volume occupied by effective immunogenic dead tumor cells, and the calibrated immune cell multiplication rate correction factor, the dynamic change process of the subject's lymphocytes after spatially segmented irradiation was established, forming a dynamic quantitative evaluation model for the subject's immune cells after spatially segmented irradiation. The expression for the dynamic change process of the subject's lymphocytes after spatially segmented irradiation is:

[0016] CTL n+1 =(1-λ CTL )S CTL CTLn +ρCTL n +ψ∈A n T n

[0017] Where, CTL n+1 and CTL n represents the number of cytotoxic T lymphocytes in the tumor on day n+1 and day n; the first term (1-λ CTL )S CTL CTL n Describe the decrease in the number of cytotoxic T lymphocytes (S CTL ), and cytotoxic T lymphocytes follow the decay constant (λ CTL ) natural decrease process, the second term ρCTL n Describes the process of activation of primitive cytotoxic T lymphocytes (naive CTLs) in tumors under natural conditions. This process is proportional to the number of cytotoxic T lymphocytes in tumors. ρ represents the first proportional coefficient, and the third term ψ∈A n T n Describes the increase in the number of cytotoxic T lymphocytes in the tumor mediated by immunogenic death of tumor cells caused by spatially fractionated irradiation, where ψ is the doubling rate, A n Represents the density of lymphocytes that trigger immunity, ∈T n Indicates the number of tumor cells immunogenic death caused by radiation, T n represents the number of tumor cells on day n, and ∈ represents the second proportional coefficient.

[0018] According to a method for spatially segmented radiotherapy radiation planning provided by the present invention, the attenuation constant λ CTL The expression is:

[0019]

[0020] Where, τ CTL Represents the half-life of cytotoxic T lymphocytes.

[0021] According to a method for spatially fractionated radiotherapy radiation planning provided by the present invention, the expression of the multiplication factor ψ is:

[0022]

[0023] Where ψ0 represents the multiplication factor corresponding to moderately immunogenic tumor cells in X-ray CONV mode, as well as are the correction factors for the multiplication rate relative to X-rays, conventional irradiation dose rates, and moderately immunogenic tumor cells, respectively.

[0024] According to a method for spatially segmented radiotherapy radiation planning provided by the present invention, the expression of the second proportional coefficient ∈ is:

[0025] ∈=tanh((1-S T )V c-eff )

[0026] Where S T represents the survival fraction of tumor cells calculated according to the LQ model after irradiation, V c-eff It represents the volume of tumor cells that are effectively immunogenic and die due to radiation.

[0027] According to a spatial fractionation radiotherapy radiation planning method provided by the present invention, the volume V occupied by the effective immunogenic dead tumor cells caused by radiation is c-eff The expression is:

[0028]

[0029] Where, represents the volume of tumor cell immunogenic death in the i-th Vertex, and the parameter a is determined based on the experimental data of the subject undergoing spatially segmented irradiation experiment in the spatially segmented target area.

[0030] According to a method for spatially segmented radiotherapy radiation planning provided by the present invention, the density of lymphocytes A that triggers immunity n The expression of the change process is:

[0031] A n+1 =(1-∈)A n S i

[0032] Where A n+1 and A n S represents the density of lymphocytes that trigger immunity on day n+1 and day n. i represents the survival fraction of the i-th type of cells calculated by the LQ model, and 1-∈ represents the proportion of unactivated cytotoxic T lymphocytes.

[0033] According to a method for radiation planning for spatially fractionated radiotherapy provided by the present invention, a tumor control probability model for a subject after spatially fractionated irradiation is established based on a dynamic quantitative evaluation model of immune cells of the subject after spatially fractionated irradiation, comprising:

[0034] Based on the dynamic quantitative evaluation model of immune cells in subjects after spatially fractionated irradiation, expressions for surviving tumor cells and cells destined to die were established to form a tumor control probability model for subjects after spatially fractionated irradiation. The expression for surviving tumor cells is:

[0035]

[0036] Where, T n+1 and T n represents the number of surviving tumor cells on day n+1 and day n, μ represents the proliferation rate of tumor cells, μ = ln2 / τ pot , τ pot represents the tumor doubling time, S T represents the survival fraction of tumor cells calculated according to the LQ model after spatially fractionated irradiation, Z n represents the contribution of immune response to tumor cell death;

[0037] The expression for cells destined to die is:

[0038]

[0039] Where D n+1 and D n represents the cells destined to die on day n+1 and day n, λ D represents the decay / clearance constant of cells destined to die, (1-λ D )D n It represents the result of natural decay of cells destined to die, (1-S T )T n e μ Indicates tumor cell death directly caused by spatially fractionated irradiation, Indicates tumor cell death caused by immune response.

[0040] According to a spatial fractionation radiotherapy radiation planning method provided by the present invention, the contribution of immune response to tumor cell death is Z n There are two types of sources, represented as:

[0041] Z n =Z p,n +Z s,n

[0042]

[0043] Where Z p,n Indicates primary anti-tumor immune response, Z s,n represents secondary immune response / memory effect, w represents the number of CTL n The tumor cell killing rate of cytotoxic T lymphocytes, Describe the immunosuppressive effect, 1+p n Describes the effect of PD1-PDL1 immunotherapy on tumor control, γ represents the sensitivity coefficient, c i Describes the effect of CTLA4 immunotherapy on tumor control, r represents the normalization factor, Z p,i express…….

[0044] The present invention also provides a spatially segmented radiotherapy radiation planning system, comprising:

[0045] The irradiation parameter data acquisition module is used to: acquire irradiation parameter data of the spatially segmented target area;

[0046] An experimental data acquisition module is used to: obtain experimental data of a spatially segmented irradiation experiment performed on a subject in a spatially segmented target area, determine the parameters required for calculating the volume occupied by effective immunogenic dead tumor cells, and calibrate the correction factor for the immune cell multiplication rate, wherein the subject is a tumor-bearing animal;

[0047] The module for establishing a dynamic quantitative evaluation model for immune cells is used to establish a dynamic quantitative evaluation model for immune cells in subjects after spatially fractionated irradiation based on the irradiation parameter data of the spatially fractionated target area, the parameters required for calculating the volume occupied by effective immunogenic dead tumor cells, and the calibrated immune cell multiplication rate correction factor.

[0048] A tumor control probability model building module is used to: build a tumor control probability model for a subject after spatially fractionated irradiation based on a dynamic quantitative evaluation model of immune cells in the subject after spatially fractionated irradiation;

[0049] The tumor control probability iterative optimization module is used to iteratively optimize the tumor control probability of the subject after spatial fractionation irradiation using the tumor control probability model of the subject after spatial fractionation irradiation until the optimization target is reached, thereby obtaining a radiation planning scheme for spatial fractionation radiotherapy of the subject.

[0050] The present invention also provides an electronic device comprising a processor and a memory storing a computer program, wherein the processor implements any of the above-mentioned spatially fractionated radiotherapy radiation planning methods when executing the computer program.

[0051] The present invention also provides a non-transitory computer-readable storage medium having a computer program stored thereon, which, when executed by a processor, implements any of the above-mentioned spatially fractionated radiotherapy radiation planning methods.

[0052] The present invention also provides a computer program product, which includes a computer program. The computer program can be stored on a non-transitory computer-readable storage medium. When the computer program is executed by a processor, the computer can execute any of the above-mentioned spatially fractionated radiotherapy radiation planning methods.

[0053] The present invention provides a method, system, device and medium for spatially fractionated radiotherapy radiation planning, which comprehensively considers the irradiation parameter data of the spatially fractionated target area, the parameters required for calculating the volume occupied by effective immunogenic dead tumor cells, and the calibrated immune cell multiplication rate correction factor, accurately establishes a unified quantitative model of the radioimmune effect of irradiating different immunogenic tumors in different spatially fractionated modes under different radiation qualities of ion beams / X-rays and different dose rate modes, forms a dynamic quantitative evaluation model of immune cells in the subject after spatially fractionated irradiation, and then establishes a tumor control probability model for the subject after spatially fractionated irradiation, realizes tumor control probability quantification, and is used to generate a more scientific and reasonable spatially fractionated radiotherapy radiation planning scheme, which can provide clear guidance for clinicians to formulate treatment plans, significantly improve the treatment effect of patients, maximize the killing of tumor cells, while protecting normal tissues, and reducing unnecessary radiation doses and treatment side effects. The present invention can realize accurate planning of spatially fractionated radiotherapy, dynamic quantitative evaluation of immune effects and quantitative prediction of tumor control probability, provide strong technical support for improving radiotherapy effects and improving patient prognosis, and has important clinical application value and broad development prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0054] In order to more clearly illustrate the technical solutions in the present invention or the prior art, a brief introduction will be given below to the drawings required for use in the embodiments or the description of the prior art. Obviously, the drawings described below are some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0055] Figure 1 Schematic diagram of the irradiation target area in spatially fractionated radiotherapy (such as lattice radiotherapy).

[0056] Figure 2 A schematic flow chart of a method for spatially fractionated radiotherapy radiation planning provided by the present invention.

[0057] Figure 3 The calibration process of the immune cell multiplication rate correction factor is shown.

[0058] Figure 4 This is a structural schematic diagram of a spatially segmented radiotherapy radiation planning system provided by the present invention.

[0059] Figure 5 This is a schematic structural diagram of another spatially segmented radiotherapy radiation planning system provided by the present invention.

[0060] Figure 6 This is a schematic structural diagram of the electronic device provided by the present invention. DETAILED DESCRIPTION

[0061] In order to make the purpose, technical solutions and advantages of the present invention clearer, the technical solutions of the present invention will be clearly and completely described below in conjunction with the drawings in the present invention. Obviously, the embodiments described are part of the embodiments of the present invention, not all of the embodiments, and they should not be understood as limitations on the present invention. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention. In the description of the present invention, it should be understood that the terms used are only for descriptive purposes and cannot be understood as indicating or implying relative importance.

[0062] Figure 2 This is a flow chart of a method for spatially divided radiotherapy radiation planning provided by the present invention. The execution subject of the method for spatially divided radiotherapy radiation planning provided by the present invention can be any applicable terminal-side device or network-side device, such as a spatially divided radiotherapy radiation planning device.

[0063] See also Figure 2 The present invention provides a method for spatially segmented radiotherapy radiation planning, which may include:

[0064] S110 , obtaining irradiation parameter data of the spatially segmented target area. The irradiation parameter data may include the specific location of the target area, contour information, target area prescription dose, normal tissue limit, peak-to-valley ratio, etc.

[0065] like Figure 1 As shown in Figure 1, a spatially segmented target volume typically consists of a series of lattice target volumes (vertices) within the gross tumor target volume (GTV). These targets can be delineated manually or automatically using specialized software. Once delineated, they are stored in a universal format on a central server and can be accessed at any time by the spatially segmented radiotherapy planning system.

[0066] S120. Obtain experimental data of spatially fractionated irradiation experiments performed on subjects in spatially fractionated target areas, determine the parameters required for calculating the volume occupied by effective immunogenic dead tumor cells, and calibrate the immune cell multiplication rate correction factor, wherein the subjects are tumor-bearing animals.

[0067] In one embodiment, biological experimental technology can be used to conduct in vivo experiments on small animals to determine the parameters required for calculating the volume occupied by effective immunogenic dead tumor cells and to calibrate the correction factor for the immune cell multiplication rate.

[0068] This embodiment uses biological experimental techniques to conduct in vivo experiments on small animals to determine the parameters required for subsequent calculation of the volume occupied by effective immunogenic dead tumor cells. Tumor-bearing small animals are subjected to spatially segmented irradiation, and existing biological experimental techniques (such as flow cytometry, immunofluorescence, etc.) are used to quantify the effects of different segmentation patterns (such as vertex position, size, and number) on key indicators in the tumor immune microenvironment (such as CD8+, NK, neutrophil counts, TNF-α, TNF-γ, and other cytokines or chemokine concentrations). Combined with experimental data, a functional relationship between these key indicators and different segmentation patterns is established to determine the parameters required for calculation of the volume occupied by effective immunogenic dead tumor cells.

[0069] This example uses biological experimental techniques to conduct in vivo small animal experiments to calibrate the subsequent immune cell multiplication rate correction factors involved. Tumor-bearing small animals are subjected to spatially fractionated irradiation, and biological experimental techniques (such as flow cytometry and immunofluorescence) are used to quantify the effects of different radiation qualities of ion beams / X-rays, ultra-high / conventional dose rates, and the level of tumor cell immunogenicity on key indicators in the tumor immune microenvironment. Combined with the experimental data, the immune cell multiplication rate correction factor is calibrated.

[0070] S130. Based on the irradiation parameter data of the spatially segmented target area, the parameters required to calculate the volume occupied by effective immunogenic dead tumor cells, and the calibrated immune cell multiplication rate correction factor, a dynamic quantitative evaluation model for the subject's immune cells after spatially segmented irradiation is established.

[0071] Spatially fractionated high-dose irradiation can produce systemic immune-mediated antitumor effects through immunogenic cell death (ICD). ICD promotes the release of tumor-associated antigens and damage-associated molecular patterns (DAMPs). Furthermore, the production and release of cytokines and chemokines within the tumor microenvironment (TME) triggers the chemotaxis of dendritic cells (DCs), macrophages, and cytotoxic T lymphocytes (CTLs) to the microenvironment, leading to the antitumor effects of CTLs.

[0072] In one embodiment, S130 may include:

[0073] Based on the irradiation parameter data of the spatially segmented target area, the parameters required for calculating the volume occupied by effective immunogenic dead tumor cells, and the calibrated immune cell multiplication rate correction factor, the dynamic change process of the subject's lymphocytes after spatially segmented irradiation was established, forming a dynamic quantitative evaluation model for the subject's immune cells after spatially segmented irradiation. The expression for the dynamic change process of the subject's lymphocytes after spatially segmented irradiation is:

[0074] CTL n+1 =(1-λ CTL )S CTL CTL n +ρCTL n +ψ∈A n T n

[0075] Where, CTL n+1 and CTL n represents the number of cytotoxic T lymphocytes in the tumor on day n+1 and day n; the first term (1-λ CTL )S CTL CTL n Describe the decrease in the number of cytotoxic T lymphocytes (S CTL ), and cytotoxic T lymphocytes follow the decay constant (λ CTL ) natural reduction process, S CTL The second term ρCTL represents the survival rate of cytotoxic T lymphocytes after cells are irradiated on day n+1. n Describes the process of activation of primitive cytotoxic T lymphocytes (naive CTLs) in tumors under natural conditions. This process is proportional to the number of cytotoxic T lymphocytes in tumors. ρ represents the first proportional coefficient, and the third term ψ∈A n T n Describes the increase in the number of cytotoxic T lymphocytes in the tumor mediated by immunogenic death of tumor cells caused by spatially fractionated irradiation, where ψ is the doubling rate, A n Represents the density of lymphocytes that trigger immunity, ∈T n Indicates the number of tumor cells immunogenic death caused by radiation, T n represents the number of tumor cells on day n, and ∈ represents the second proportional coefficient.

[0076] Among them, the decay constant λ CTL The expression is:

[0077]

[0078] Where, τ CTL Represents the half-life of cytotoxic T lymphocytes.

[0079] The multiplication factor ψ is affected by radiation quality, dose rate, and tumor cell immunogenicity, and its expression is:

[0080]

[0081] Where ψ0 represents the multiplication factor corresponding to moderately immunogenic tumor cells in X-ray CONV mode, as well as They represent the multiplication factor correction factors relative to X-ray, conventional irradiation dose rate and moderate immunogenic tumor cells, respectively. These factors can be calibrated by the animal tumor-bearing spatial fractionation irradiation experiment involved in this embodiment, such as Figure 3 shown.

[0082] The second proportional coefficient ∈ is related to the spatial division illumination mode, and its expression is:

[0083] ∈=tanh((1-S T )V c-eff )

[0084] Where S T represents the survival fraction of tumor cells after irradiation calculated according to the well-known linear quadratic (LQ) model, V c-eff It represents the volume of tumor cells that are effectively immunogenic and die due to radiation.

[0085] The volume of effectively immunogenic dead tumor cells caused by radiation V c-eff The expression is:

[0086]

[0087] Where, represents the volume of tumor cells immunogenic death in the i-th Vertex. The reason for effectively calculating the volume occupied by tumor cells immunogenic death caused by radiation here is that the current experimental results show that the effect of two spatially segmented irradiations of 10% tumor volume is significantly better than that of one spatially segmented irradiation of 20% tumor volume, indicating that the effectiveness of tumor cell immunogenic death caused by different spatial segmentation modes is different. Therefore, this embodiment intends to use the volume occupied by effective immunogenic death tumor cells to describe this phenomenon. The parameter a is determined based on the experimental data of the spatially segmented irradiation experiment of the subject in the spatially segmented target area. For example, V can be calculated based on the change in the number of CD8+ cells under different spatial segmentation modes. c-eff Perform regression fitting to determine.

[0088] As some cytotoxic T lymphocytes are activated or die due to irradiation, the density of lymphocytes that trigger immunity increases. N The density of lymphocytes that trigger immunity will also change. N The expression of the change process is:

[0089] A N+1 =(1-∈)A N S i

[0090] Where A N+1 and A nS represents the density of lymphocytes that trigger immunity on day n+1 and day n. i represents the survival fraction of the i-th type of cells calculated by the LQ model, and 1-∈ represents the proportion of unactivated cytotoxic T lymphocytes.

[0091] Thus, this embodiment has achieved a dynamic quantitative description of the radioimmune effects of ion beam and X-ray CONV / FLASH spatial segmentation on the tumor immune microenvironment.

[0092] S140. Based on the dynamic quantitative evaluation model of immune cells of subjects after spatially fractionated irradiation, a tumor control probability model of subjects after spatially fractionated irradiation is established.

[0093] Based on the dynamic quantitative evaluation model of immune cells in subjects after spatially fractionated irradiation, this embodiment extends the observation endpoint to tumor control, that is, establishes a method for calculating the tumor control probability (TCP) in ion beam / X-ray CONV / FLASH spatially fractionated radiotherapy. This embodiment considers the four main types of cells in the tumor: viable cancer cells, T cells, and viable tumor cells. n , doomed cells n , activated cytotoxic T lymphocytes CTL n and the density of lymphocytes that trigger immunity A n .

[0094] In one embodiment, S140 may include:

[0095] Based on the dynamic quantitative evaluation model of immune cells in subjects after spatially fractionated irradiation, expressions for surviving tumor cells and cells destined to die were established to form a tumor control probability model for subjects after spatially fractionated irradiation. The expression for the number of surviving tumor cells is:

[0096]

[0097] Where, T n+1 and T n represents the number of surviving tumor cells on day n+1 and day n, μ represents the proliferation rate of tumor cells, μ = ln2 / τ pot , τ pot represents the tumor doubling time, S T represents the survival fraction of tumor cells calculated according to the LQ model after spatially fractionated irradiation, Z n represents the contribution of immune response to tumor cell death, where the contribution of immune response to tumor cell death is Z n There are two types of sources, represented as:

[0098] Z n= Z p,n + Z s,n

[0099]

[0100] where Z p,n represents the primary anti-tumor immune response, Z s,n represents the secondary immune response / memory effect, w represents the tumor cell killing rate of cytotoxic T lymphocytes with number of CTL n cells, describes the immune suppression effect, 1 + p n describes the effect of PD1-PDL1 immunotherapy on tumor control, γ represents the sensitivity coefficient, c i describes the effect of CTLA4 immunotherapy on tumor control, r represents the normalization factor, Z p,i represents the contribution of the primary anti-tumor immune response to tumor cell death on the i-th day;

[0101] The expression of the number of cells destined to die is:

[0102]

[0103] where D n+1 and D n represent the number of cells destined to die on the (n+1)-th day and the n-th day, λ D represents the decay / removal constant of cells destined to die, (1-λ D )D n represents the result of natural decay of cells destined to die, (1-S T )T n e μ represents the tumor cell death directly caused by spatially fractionated irradiation, represents the tumor cell death caused by immune response (the number of immune cells is in a negligible amount compared to D n , which can be ignored here to ensure the simplicity of the model).

[0104] Since dead cells are often cleared by the body after about 1-2 weeks, the total number of tumor cells is counted as T n + D n , and the change in the total number of cells in each voxel of the tumor is calculated according to different spatially fractionated irradiation modes, and finally the change in the macroscopic volume of the tumor is obtained, thereby realizing the construction of the tumor control probability model in ion beam and X-ray FLASH / CONV spatially fractionated radiotherapy.

[0105] S150. Using the tumor control probability model of the subject after spatially fractionated irradiation, iteratively optimize the tumor control probability of the subject after spatially fractionated irradiation until the optimization goal is reached (the optimization goal may be to control the tumor control probability within a certain range), and obtain a radiation planning plan for the spatially fractionated radiotherapy of the subject.

[0106] After iteratively optimizing the tumor control probability and obtaining the final radiation planning scheme for spatially segmented irradiation, the irradiation planning scheme generated in a general format can be sent and stored in the central server. The radiation planning scheme can be retrieved at the irradiation implementation terminal. Under certain conditions, a specific beam delivery device can also be prepared and installed at the irradiation terminal. The terminal controls the irradiation device to generate and deliver the relevant beam according to the plan to irradiate the terminal target, such as Figure 4 shown.

[0107] One embodiment of the present invention is a radiation planning scheme for lattice irradiation (a type of spatially segmented irradiation) for huge solid tumors. First, the immunogenicity of solid tumor cells and the radiation quality of the irradiation terminal are clarified based on pathological examination. A mouse tumor-bearing experiment is carried out using tumor cells with similar immunogenicity, and a beam with the same radiation quality as the irradiation terminal is used to irradiate the mouse tumor in different spatially segmented modes through a special metal block. After irradiation, flow cytometry is used to measure the level of CD8+ immune cells inside the mouse tumor. Based on the spatially segmented irradiation parameters of different segmentation modes and the experimentally measured CD8+ immune cell levels inside the mouse tumor, the method of the present invention is used to perform regression fitting to determine the specific value of the parameter a required for calculating the volume occupied by effective immunogenic dead tumor cells, and to calibrate the immunogenic tumor cell multiplication rate (this embodiment uses X-rays with a conventional dose rate, so ), so it is only necessary to determine the level of CD8+ immune cells in the tumor of mice after spatially divided irradiation based on the immunogenicity of tumor cells. Based on the parameters obtained from the above experiments, the CD8+ immune cell level of the solid tumor after irradiation can be further evaluated according to the spatially fractionated irradiation target mode parameters of this case, thereby obtaining the corresponding tumor control probability. Through iterative adjustment and optimization of the radiation plan, a spatially fractionated irradiation plan for this solid tumor can be finally obtained.

[0108] The present invention provides a method, system, device and medium for spatially fractionated radiotherapy radiation planning, which comprehensively considers the irradiation parameter data of the spatially fractionated target area, the parameters required for calculating the volume occupied by effective immunogenic dead tumor cells, and the calibrated immune cell multiplication rate correction factor, accurately establishes a unified quantitative model of the radioimmune effect of irradiating different immunogenic tumors in different spatially fractionated modes under different radiation qualities of ion beams / X-rays and different dose rate modes, forms a dynamic quantitative evaluation model of immune cells in the subject after spatially fractionated irradiation, and then establishes a tumor control probability model for the subject after spatially fractionated irradiation, realizes tumor control probability quantification, and is used to generate a more scientific and reasonable spatially fractionated radiotherapy radiation planning scheme, which can provide clear guidance for clinicians to formulate treatment plans, significantly improve the treatment effect of patients, maximize the killing of tumor cells, while protecting normal tissues, and reducing unnecessary radiation doses and treatment side effects. The present invention can realize accurate planning of spatially fractionated radiotherapy, dynamic quantitative evaluation of immune effects and quantitative prediction of tumor control probability, provide strong technical support for improving radiotherapy effects and improving patient prognosis, and has important clinical application value and broad development prospects.

[0109] The following describes the spatially divided radiotherapy radiation planning system provided by the present invention. The spatially divided radiotherapy radiation planning system described below and the spatially divided radiotherapy radiation planning method described above can be referenced to each other.

[0110] See also Figure 5 The present invention provides a spatially segmented radiotherapy radiation planning system, which may include:

[0111] The irradiation parameter data acquisition module is used to: acquire irradiation parameter data of the spatially segmented target area;

[0112] An experimental data acquisition module is used to: obtain experimental data of a spatially segmented irradiation experiment performed on a subject in a spatially segmented target area, determine the parameters required for calculating the volume occupied by effective immunogenic dead tumor cells, and calibrate the correction factor for the immune cell multiplication rate, wherein the subject is a tumor-bearing animal;

[0113] The module for establishing a dynamic quantitative evaluation model for immune cells is used to establish a dynamic quantitative evaluation model for immune cells in subjects after spatially fractionated irradiation based on the irradiation parameter data of the spatially fractionated target area, the parameters required for calculating the volume occupied by effective immunogenic dead tumor cells, and the calibrated immune cell multiplication rate correction factor.

[0114] A tumor control probability model building module is used to: build a tumor control probability model for a subject after spatially fractionated irradiation based on a dynamic quantitative evaluation model of immune cells in the subject after spatially fractionated irradiation;

[0115] The tumor control probability iterative optimization module is used to iteratively optimize the tumor control probability of the subject after spatial fractionation irradiation using the tumor control probability model of the subject after spatial fractionation irradiation until the optimization target is reached, thereby obtaining a radiation planning scheme for spatial fractionation radiotherapy of the subject.

[0116] Figure 6 An example of a physical structure diagram of an electronic device is shown below. Figure 6 As shown, the electronic device may include: a processor 810, a communication interface 820, a memory 830, and a communication bus 840, wherein the processor 810, the communication interface 820, and the memory 830 communicate with each other via the communication bus 840. The processor 810 may call the logic instructions in the memory 830 to perform the following steps:

[0117] Obtaining irradiation parameter data of spatially segmented target areas;

[0118] Obtain experimental data from spatially fractionated irradiation experiments on subjects in spatially fractionated target areas, determine the parameters required to calculate the volume occupied by effective immunogenic dead tumor cells, and calibrate the correction factor for the immune cell multiplication rate, where the subjects are tumor-bearing animals;

[0119] Based on the irradiation parameter data of the spatially segmented target area, the parameters required to calculate the volume occupied by effective immunogenic dead tumor cells, and the calibrated immune cell multiplication rate correction factor, a dynamic quantitative assessment model for the subject's immune cells after spatially segmented irradiation was established;

[0120] Based on the dynamic quantitative evaluation model of immune cells after spatially fractionated irradiation, a tumor control probability model for subjects after spatially fractionated irradiation was established;

[0121] The tumor control probability model of the subject after spatial fractionation irradiation is used to iteratively optimize the tumor control probability of the subject after spatial fractionation irradiation until the optimization goal is reached, and the radiation planning scheme for spatial fractionation radiotherapy of the subject is obtained.

[0122] In addition, the logic instructions in the above-mentioned memory 830 can be implemented in the form of a software functional unit and can be stored in a computer-readable storage medium when sold or used as an independent product. Based on this understanding, the technical solution of the present invention, or the part that contributes to the prior art, or the part of the technical solution, can be embodied in the form of a software product. The computer software product is stored in a storage medium and includes several instructions for enabling a computer device (which can be a personal computer, server, or network device, etc.) to perform all or part of the steps of the method described in each embodiment of the present invention. The aforementioned storage medium includes: various media that can store program codes, such as a USB flash drive, a mobile hard disk, a read-only memory (ROM), a random access memory (RAM), a magnetic disk or an optical disk.

[0123] In another aspect, the present invention further provides a computer program product, comprising a computer program, which may be stored on a non-transitory computer-readable storage medium, and wherein when the computer program is executed by a processor, the computer is capable of performing the following steps:

[0124] Obtaining irradiation parameter data of spatially segmented target areas;

[0125] Obtain experimental data from spatially fractionated irradiation experiments on subjects in spatially fractionated target areas, determine the parameters required to calculate the volume occupied by effective immunogenic dead tumor cells, and calibrate the correction factor for the immune cell multiplication rate, where the subjects are tumor-bearing animals;

[0126] Based on the irradiation parameter data of the spatially segmented target area, the parameters required to calculate the volume occupied by effective immunogenic dead tumor cells, and the calibrated immune cell multiplication rate correction factor, a dynamic quantitative assessment model for the subject's immune cells after spatially segmented irradiation was established;

[0127] Based on the dynamic quantitative evaluation model of immune cells after spatially fractionated irradiation, a tumor control probability model for subjects after spatially fractionated irradiation was established;

[0128] The tumor control probability model of the subject after spatial fractionation irradiation is used to iteratively optimize the tumor control probability of the subject after spatial fractionation irradiation until the optimization goal is reached, and the radiation planning scheme for spatial fractionation radiotherapy of the subject is obtained.

[0129] In another aspect, the present invention further provides a non-transitory computer-readable storage medium having a computer program stored thereon, which is configured to execute the following steps when executed by a processor:

[0130] Obtaining irradiation parameter data of spatially segmented target areas;

[0131] Obtain experimental data from spatially fractionated irradiation experiments on subjects in spatially fractionated target areas, determine the parameters required to calculate the volume occupied by effective immunogenic dead tumor cells, and calibrate the correction factor for the immune cell multiplication rate, where the subjects are tumor-bearing animals;

[0132] Based on the irradiation parameter data of the spatially segmented target area, the parameters required to calculate the volume occupied by effective immunogenic dead tumor cells, and the calibrated immune cell multiplication rate correction factor, a dynamic quantitative assessment model for the subject's immune cells after spatially segmented irradiation was established;

[0133] Based on the dynamic quantitative evaluation model of immune cells after spatially fractionated irradiation, a tumor control probability model for subjects after spatially fractionated irradiation was established;

[0134] The tumor control probability model of the subject after spatial fractionation irradiation is used to iteratively optimize the tumor control probability of the subject after spatial fractionation irradiation until the optimization goal is reached, and the radiation planning scheme for spatial fractionation radiotherapy of the subject is obtained.

[0135] The device embodiments described above are merely illustrative. The units described as separate components may or may not be physically separate, and the components shown as units may or may not be physical units, i.e., they may be located in one location or distributed across multiple network units. Some or all of the modules may be selected based on actual needs to achieve the objectives of the present embodiment. Persons of ordinary skill in the art will be able to understand and implement the present invention without inventive effort.

[0136] Through the description of the above embodiments, those skilled in the art can clearly understand that each embodiment can be implemented by means of software plus a necessary general hardware platform, or of course, by hardware. Based on this understanding, the essence of the above technical solution or the part that contributes to the existing technology can be embodied in the form of a software product. The computer software product can be stored in a computer-readable storage medium, such as ROM / RAM, a magnetic disk, an optical disk, etc., and includes a number of instructions for enabling a computer device (which can be a personal computer, a server, or a network device, etc.) to execute the methods described in each embodiment or certain parts of the embodiments.

[0137] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or make equivalent replacements for some of the technical features therein. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the various embodiments of the present invention.

Claims

1. A method for spatially fractionated radiotherapy radiation planning, characterized in that: include: Obtain irradiation parameter data of spatially segmented target areas; Obtain experimental data from spatially fractionated irradiation experiments on subjects in spatially fractionated target areas, determine the parameters required to calculate the volume occupied by effective immunogenic dead tumor cells, and calibrate the correction factor for the immune cell multiplication rate, where the subjects are tumor-bearing animals; Based on the irradiation parameter data of the spatially segmented target area, the parameters required to calculate the volume occupied by effective immunogenic dead tumor cells, and the calibrated immune cell multiplication rate correction factor, a dynamic quantitative assessment model for the subject's immune cells after spatially segmented irradiation was established; Based on the dynamic quantitative evaluation model of immune cells after spatially fractionated irradiation, a tumor control probability model for subjects after spatially fractionated irradiation was established; The tumor control probability model of the subject after spatial fractionation irradiation is used to iteratively optimize the tumor control probability of the subject after spatial fractionation irradiation until the optimization goal is reached, and the radiation planning scheme for spatial fractionation radiotherapy of the subject is obtained.

2. The method for spatial fractionation radiotherapy planning according to claim 1, wherein: The method establishes a dynamic quantitative evaluation model for immune cells of a subject after spatially fractionated irradiation based on the irradiation parameter data of the spatially fractionated target area, the parameters required for calculating the volume occupied by effective immunogenic dead tumor cells, and the calibrated immune cell multiplication rate correction factor, including: Based on the irradiation parameter data of the spatially segmented target area, the parameters required for calculating the volume occupied by effective immunogenic dead tumor cells, and the calibrated immune cell multiplication rate correction factor, the dynamic change process of the subject's lymphocytes after spatially segmented irradiation was established, forming a dynamic quantitative evaluation model for the subject's immune cells after spatially segmented irradiation. The expression for the dynamic change process of the subject's lymphocytes after spatially segmented irradiation is: CTL n+1 =(1-λ CTL )S CTL CTL n +ρCTL n +ψ∈A n T n Where, CTL n+1 and CTL n represents the number of cytotoxic T lymphocytes in the tumor on day n+1 and day n; the first term (1-λ CTL )S CTL CTL n Describes the decrease in the number of cytotoxic T lymphocytes caused by irradiation on day n+1, and the decay constant λ of cytotoxic T lymphocytes. CTL The natural reduction process, S CTL The second term ρCTL represents the survival rate of cytotoxic T lymphocytes after cells are irradiated on day n+1. n Describes the process of activation of primitive cytotoxic T lymphocytes in tumors under natural conditions. This process is proportional to the number of cytotoxic T lymphocytes in tumors. ρ represents the first proportional coefficient, and the third term ψ∈A n T n Describes the increase in the number of cytotoxic T lymphocytes in the tumor mediated by immunogenic death of tumor cells caused by spatially fractionated irradiation, where ψ is the doubling rate, A n Represents the density of lymphocytes that trigger immunity, ∈T n Indicates the number of tumor cells immunogenic death caused by radiation, T n represents the number of tumor cells on day n, and ∈ represents the second proportional coefficient.

3. The method for spatial fractionation radiotherapy planning according to claim 2, wherein: Attenuation constant λ CTL The expression is: Where, τ CTL represents the half-life of cytotoxic T lymphocytes; The expression of the multiplication factor ψ is: Where ψ0 represents the multiplication factor corresponding to moderately immunogenic tumor cells in X-ray CONV mode, as well as represent the multiplication factor correction factors relative to X-ray, conventional irradiation dose rate, and moderately immunogenic tumor cells, respectively; The expression of the second proportional coefficient ∈ is: ∈=tanh((1-S T )V c-eff ) Where S T represents the survival fraction of tumor cells calculated according to the LQ model after irradiation, V c-eff It represents the volume of tumor cells that are effectively immunogenic and die due to radiation.

4. The method for spatial fractionation radiotherapy planning according to claim 3, wherein: The volume of effectively immunogenic dead tumor cells caused by radiation V c-eff The expression is: Where, represents the volume of tumor cell immunogenic death in the i-th Vertex, and the parameter a is determined based on the experimental data of the subject undergoing spatially segmented irradiation experiment in the spatially segmented target area.

5. The method for spatial fractionation radiotherapy planning according to claim 4, wherein: Density of lymphocytes that trigger immunity A n The expression of the change process is: A n+1 =(1-∈)A n S i Where A n+1 and A n S represents the density of lymphocytes that trigger immunity on day n+1 and day n. i represents the survival fraction of the i-th type of cells calculated by the LQ model, and 1-∈ represents the proportion of unactivated cytotoxic T lymphocytes.

6. The method for spatial fractionation radiotherapy planning according to claim 5, characterized in that: The method of establishing a tumor control probability model for a subject after spatially fractionated irradiation based on a dynamic quantitative evaluation model of immune cells of the subject after spatially fractionated irradiation includes: Based on the dynamic quantitative evaluation model of immune cells in subjects after spatially fractionated irradiation, expressions for surviving tumor cells and cells destined to die were established to form a tumor control probability model for subjects after spatially fractionated irradiation. The expression for surviving tumor cells is: Where, T n+1 and T n represents the number of surviving tumor cells on day n+1 and day n, μ represents the proliferation rate of tumor cells, μ = ln2 / τ pot , τ pot represents the tumor doubling time, S T represents the survival fraction of tumor cells calculated according to the LQ model after spatially fractionated irradiation, Z n represents the contribution of immune response to tumor cell death; The expression for cells destined to die is: Where D n+1 and D n represents the cells destined to die on day n+1 and day n, λ D represents the decay / clearance constant of cells destined to die, (1-λ D )D n It represents the result of the natural decay of cells destined to die. Indicates tumor cell death directly caused by spatially fractionated irradiation, Indicates tumor cell death caused by immune response.

7. The method for spatial fractionation radiotherapy planning according to claim 6, wherein: Contribution of immune response to tumor cell death b There are two types of sources, represented as: WITH b =Z p,n +Z s,n Where Z p,n Indicates primary anti-tumor immune response, Z s,n represents secondary immune response / memory effect, w represents the number of CTL n The tumor cell killing rate of cytotoxic T lymphocytes, Describe the immunosuppressive effect, 1+p n Describes the effect of PD1-PDL1 immunotherapy on tumor control, γ represents the sensitivity coefficient, c i Describes the effect of CTLA4 immunotherapy on tumor control, r represents the normalization factor, Z p,i represents the contribution of primary anti-tumor immune response to tumor cell death on day i.

8. A spatially fractionated radiotherapy radiation planning system, characterized in that: include: The irradiation parameter data acquisition module is used to: acquire irradiation parameter data of the spatially segmented target area; An experimental data acquisition module is used to: obtain experimental data of a spatially segmented irradiation experiment performed on a subject in a spatially segmented target area, determine the parameters required for calculating the volume occupied by effective immunogenic dead tumor cells, and calibrate the correction factor for the immune cell multiplication rate, wherein the subject is a tumor-bearing animal; The module for establishing a dynamic quantitative evaluation model for immune cells is used to establish a dynamic quantitative evaluation model for immune cells in subjects after spatially fractionated irradiation based on the irradiation parameter data of the spatially fractionated target area, the parameters required for calculating the volume occupied by effective immunogenic dead tumor cells, and the calibrated immune cell multiplication rate correction factor. A tumor control probability model building module is used to: build a tumor control probability model for a subject after spatially fractionated irradiation based on a dynamic quantitative evaluation model of immune cells in the subject after spatially fractionated irradiation; The tumor control probability iterative optimization module is used to iteratively optimize the tumor control probability of the subject after spatial fractionation irradiation using the tumor control probability model of the subject after spatial fractionation irradiation until the optimization target is reached, thereby obtaining a radiation planning scheme for spatial fractionation radiotherapy of the subject.

9. An electronic device comprising a memory, a processor, and a computer program stored in the memory and executable on the processor, wherein: When the processor executes the program, the spatially fractionated radiotherapy radiation planning method according to any one of claims 1 to 7 is implemented.

10. A non-transitory computer-readable storage medium having a computer program stored thereon, characterized in that: When the computer program is executed by a processor, the spatially fractionated radiotherapy radiation planning method according to any one of claims 1 to 7 is implemented.

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