Method for determining a biologically effective dose

Abstract

This disclosure relates to a method for determining bioeffective dose, wherein the method includes: detecting the boron concentration C of each voxel in the target at multiple time points. B ; Calculate C B The corresponding biological effect value (RBE) B Determine C B and RBE B The first association relationship, based on the first association relationship, determines the connection through C. B Characterized RBE B ; Calculate C B The corresponding first physical absorbed dose rate D B And other physical absorbed dose rates corresponding to dose components other than boron, and physical dose rate distribution D phy According to RBE B and D B The product of the other dose components and the product of other biological effect values ​​and other physically absorbed dose rates is used to calculate C. B The combined biological effect value (CBE); based on CBE and D phy Calculate the biologically effective dose D bio According to this disclosure, it is beneficial to determine the appropriate irradiation time for different voxels during BNCT in order to obtain better therapeutic effects.

Description

Technical Field

[0001] This invention relates to the field of tumor treatment technology, and in particular to a method for determining a biologically effective dose. Background Technology

[0002] Boron neutron capture therapy (BNCT) is an advanced binary targeted radiotherapy technique. Its basic principle is: first, a boron neutron is captured and placed in a neutron-containing plasma... 10 Boron-10 (B) drugs are injected into the patient, utilizing the specific aggregation properties of boron drugs in tumor cells, and then irradiated from outside the body using thermal or ultrathermal neutron beams.

[0003] neutron and 10 B atom undergoes a capture reaction ( 10 B (n,α) 7 Li), producing alpha particles that generate high linear energy transfer (LET) and 7 Li (lithium-7) recoil nuclei. These heavily charged particles have an extremely short range in biological tissues (about 5 to 9 μm), roughly the diameter of a cell. Therefore, almost all of their energy is deposited within the reacting cells, enabling them to efficiently kill tumor cells while causing minimal damage to surrounding normal tissues.

[0004] The core of BNCT's efficacy lies in the concentration difference of boron drugs between the tumor and surrounding normal tissue, i.e., the concentration ratio of the tumor to normal tissue (which can be denoted as T / N). Therefore, accurately assessing and utilizing the spatial distribution of boron for precise dosage calculation is a crucial step in the widespread clinical application of BNCT technology, and the accuracy of dosage calculation directly affects the success of treatment. Summary of the Invention

[0005] This invention provides a method and apparatus for determining biologically effective doses, as well as a storage medium, to address the shortcomings of related technologies.

[0006] According to a first aspect of the present invention, a method for determining a biologically effective dose is provided, comprising: detecting the boron concentration C of each voxel in a target at multiple time points. B ; Calculate the C B The corresponding biological effect value (RBE) B Determine the C B and the RBE B The first association relationship, based on the first association relationship, determines through C B Characterized RBE B ; Calculate the C B The corresponding first physical absorbed dose rate D BAnd other physical absorbed dose rates corresponding to dose components other than boron, and physical dose rate distribution D phy , wherein, the D B The other physically absorbed dose rates, the D phy Time- and voxel-related; according to the RBE B and the D B The product of the other dose components and the product of the other biological effect values ​​and the other physical absorbed dose rates is used to calculate C. B The combined biological effect value (CBE); based on the CBE and the D phy Calculate the biologically effective dose D bio .

[0007] According to a second aspect of the present invention, a bioeffective dose determination apparatus is provided, comprising: a detection module configured to detect the boron concentration C of each voxel among targets at multiple time intervals. B The processing module is configured to calculate the C. B The corresponding biological effect value (RBE) B Determine the C B and the RBE B The first association relationship, based on the first association relationship, determines through C B Characterized RBE B ; Calculate the C B The corresponding first physical absorbed dose rate D B And other physical absorbed dose rates corresponding to dose components other than boron, and physical dose rate distribution D phy , wherein, the D B The other physically absorbed dose rates, the D phy Time- and voxel-related; according to the RBE B and the D B The product of the other dose components and the product of the other biological effect values ​​and the other physically absorbed dose rates is used to calculate C. B The combined biological effect value (CBE); based on the CBE and the D phy Calculate the biologically effective dose D bio .

[0008] According to a third aspect of the present disclosure, a storage medium is provided that stores instructions that, when executed on a communication device, cause the communication device to perform the above-described method for determining biological effective doses.

[0009] According to a fourth aspect of the present disclosure, a program product is provided that, when executed by a communication device, causes the communication device to perform the biological effective dose determination method.

[0010] According to embodiments of this disclosure, the detected boron concentration is spatially and temporally related, which can characterize the boron concentration of different voxels at different times. Furthermore, the biological effect value calculated based on the boron concentration, the composite biological effect value calculated based on the biological effect value, and the bioeffective dose calculated based on the composite biological effect value are all spatially and temporally related. This allows for the determination of appropriate irradiation times for different voxels during BNCT, thereby achieving better therapeutic effects.

[0011] It should be understood that the above general description and the following detailed description are exemplary and explanatory only, and are not intended to limit the invention. Attached Figure Description

[0012] The accompanying drawings, which are incorporated in and form part of this specification, illustrate embodiments consistent with the invention and, together with the description, serve to explain the principles of the invention.

[0013] Figure 1 This is a schematic flowchart illustrating a method for determining a biologically effective dose according to embodiments of the present disclosure.

[0014] Figure 2 This is a schematic flowchart illustrating a method for detecting boron concentration according to an embodiment of the present disclosure.

[0015] Figure 3 This is a schematic flowchart illustrating a method for determining the relationship between boron concentration and time, according to an embodiment of the present disclosure.

[0016] Figure 4A This is a three-compartment pharmacokinetic model illustrated according to embodiments of the present disclosure.

[0017] Figure 4B This is another three-compartment pharmacokinetic model shown according to embodiments of this disclosure.

[0018] Figure 5 This is a schematic flowchart illustrating a method for determining the start time of treatment according to an embodiment of the present disclosure.

[0019] Figure 6 This is a schematic block diagram of a biological effective dose determination device according to an embodiment of the present disclosure. Detailed Implementation

[0020] Exemplary embodiments will now be described in detail, examples of which are illustrated in the accompanying drawings. When the following description relates to the drawings, unless otherwise indicated, the same numerals in different drawings denote the same or similar elements. The embodiments described in the following exemplary embodiments do not represent all embodiments consistent with the present invention. Rather, they are merely examples of apparatuses and methods consistent with some aspects of the invention as detailed in the appended claims.

[0021] In some embodiments, positron emission tomography (PET) is a powerful molecular imaging technique. It detects positron-emitting nuclides (such as...) 18 The distribution of fluorine-18 (F)-labeled tracers in the body can non-invasively and quantitatively reveal specific biochemical processes, metabolic activities, and target expression levels. Unlike CT (Computed Tomography) or MRI (Magnetic Resonance Imaging), which primarily provide anatomical information, PET reveals information at the "functional" level, which is crucial for achieving precision medicine.

[0022] In some embodiments, in the field of BNCT, the alternative PET tracer is 18 F-BPA (4-boron-L-phenylalanine).

[0023] BPA is a derivative of boronine, and its structure is similar to that of tyrosine, an amino acid required by the human body. 18 F-BPA can be rapidly and selectively taken up into tumor cells via L-amino acid transporter 1 (LAT1), which is highly expressed on the tumor cell membrane. This allows... 18 F-BPA PET images can directly and three-dimensionally visualize the actual distribution of BPA in tumors and normal tissues. Because... 18 F-BPA has almost identical biodistribution characteristics to therapeutic BPA, therefore its uptake level in PET images (usually quantified by the Standardized Uptake Value, SUV) can be used to accurately predict treatment time. 10 The concentration of B in tumors and normal tissues is an indispensable biomarker in BNCT dosimetry.

[0024] In some embodiments, the BNCT Treatment Planning System (TPS) employs a relative biological effectiveness (RBE) weighted dosing algorithm. This algorithm simplifies the total biologically effective dose to the sum of the products of the physical doses of each dose component (e.g., boron dose, nitrogen dose, hydrogen dose, photon dose, etc.) and a fixed RBE or Composite Biological Effectiveness (CBE) factor (or value).

[0025] However, in this algorithm, the boron concentration within the tumor is assumed to be uniformly distributed, or only a single concentration value is used, which is converted based on the maximum or average value of the overall tumor SUV.

[0026] In some embodiments, with the development of imaging technology, it is possible to map the spatially non-uniform boron concentration information provided by PET images onto CT images to perform three-dimensional non-uniform physical dose calculations. Furthermore, microdosimetric models such as the MK (Microdosimetric Kinetic) model and its improved SMK (Simplified Microdosimetric Kinetic) model can be introduced to obtain more radiobiologically accurate and variable RBE values ​​by calculating the line energy spectrum, thereby calculating the biologically effective dose and improving individualization and precision.

[0027] Although the BNCT dose calculation technology in the above embodiments has certain technical effects, it still has some defects and limitations.

[0028] For example, in dose calculation, whether a uniform or non-uniform model is used, it relies on boron concentration information obtained from a single static scan before treatment, ignoring the dynamic changes of boron drugs within the target (e.g., the patient), such as uptake, metabolism, and translocation. In other words, the actual boron concentration changes over time, and these changes vary among different patients, thus the optimal treatment time window varies from person to person. The aforementioned algorithms for dose calculation fail to reflect the impact of real-time changes in boron concentration during irradiation on the dose, leading to discrepancies between the calculated dose and the actual biological effect.

[0029] For example, TPS's protection of normal tissues is mainly based on anatomical delineation and uniform dose-volume constraints, and it cannot actively identify and specifically protect those tissues that also absorb nutrients due to inflammation or other reasons. 18Normal tissues affected by F-BPA, such as what are called non-target uptake areas, are potentially high-risk areas during BNCT irradiation due to the presence of boron. The aforementioned algorithms lack a method for automatically identifying these areas from images and applying protective measures.

[0030] For example, the dose assessment of the above algorithm can be static and three-dimensional, but it does not incorporate the time dimension. For instance, it does not consider the dose distribution that evolves with irradiation time and boron concentration, thus failing to provide accurate guidance for optimizing irradiation time.

[0031] Figure 1 This is a schematic flowchart illustrating a method for determining a biologically effective dose according to embodiments of the present disclosure.

[0032] In some embodiments, the bioeffective dose determination method can be performed by a medical device, such as a medical device equipped with a BNCT TPS, and the bioeffective dose determination method can be specifically performed by the BNCT TPS.

[0033] like Figure 1 As shown, the method for determining the effective biological dose may include the following steps: In step 101, the boron concentration C of each voxel in the target (e.g., within the patient, in the patient's tumor, or in the organ where the patient's tumor is located) is measured at multiple time points. B ; In step 102, the C is calculated. B The corresponding biological effect value (RBE) B Determine the C B and the RBE B The first association relationship, based on the first association relationship, determines through C B Characterized RBE B ; In step 103, the C is calculated. B The corresponding first physical absorbed dose rate D B And other physical absorbed dose rates corresponding to dose components other than boron, and physical dose rate distribution D phy , wherein, the D B The other physically absorbed dose rates, the D phy Related to time and voxels; In step 104, according to the RBE B and the D B The product of the other dose components and the product of the other biological effect values ​​and the other physically absorbed dose rates is used to calculate C. B The combined biological effect value (CBE); In step 105, according to the CBE and the Dphy Calculate the biologically effective dose D bio .

[0034] In some embodiments, the system can detect the boron concentration C of each voxel in the target at multiple time points. B Therefore, the detected C B It is related to space and time.

[0035] The information used to characterize the spatial dimension is the three-dimensional coordinates of the voxel, for example, denoted as (x, y, z); the information used to characterize the temporal dimension is time, for example, denoted as t. Based on this, C... B It can be represented using three-dimensional coordinates and one-dimensional time, for example, it can be denoted as C. B (x,y,z,t).

[0036] Based on this, this application is based on C B Calculate RBE B For example, the first association can be represented by a function denoted as RBE. B =f(C B ), through C B Characterized RBE B In this case, RBE B It is also related to space and time.

[0037] In some embodiments, the dosage components other than boron may include at least one of the following: Nitrogen, hydrogen, photons.

[0038] For example, other physically absorbed dose rates are determined based on clinical consensus values; and / or, the corresponding D for each time period. B The other physical absorbed dose rates were determined based on simulation.

[0039] For example, the physical absorbed dose rate of nitrogen is denoted as D. N The biological effect value corresponding to nitrogen is denoted as RBE. N For example, the physical absorbed dose rate of hydrogen is denoted as D. H The biological effect value corresponding to hydrogen is denoted as RBE. H For example, the physical absorbed dose rate corresponding to a photon is denoted as D. γ The biological effect value corresponding to a photon is denoted as RBE. γ .

[0040] Because of D B Other physical absorbed dose rates are time- and voxel-dependent; therefore, D B It can be written as D B (x,y,z,t), D N It can be written as D N(x,y,z,t), D H It can be written as D H (x,y,z,t), D γ It can be written as D γ (x,y,z,t), For example, D B Other physical absorbed dose rates determined based on simulations may include: the physical absorbed dose rates of each dose component (e.g., boron, nitrogen, hydrogen, photons) of a voxel at time t, obtained from Monte Carlo treatment planning system simulations, thereby obtaining D. B (x,y,z,t),D N (x,y,z,t),D H (x,y,z,t),D γ (x,y,z,t), these dose rates depend on the neutron beam characteristics and the patient's anatomy, and are known quantities during the treatment planning optimization process.

[0041] For example, RBE H RBE N RBE γ These are the fixed RBE values ​​for hydrogen, nitrogen, and photon dose components, which can be clinically consensus values ​​or, in the calculation process of this application, can be treated as known quantities.

[0042] In some embodiments, due to the RBE used to calculate CBE B D B (x,y,z,t),D N (x,y,z,t),D H (x,y,z,t),D γ (x, y, z, t) are all quantities related to space and time; therefore, the calculated CBE is also a quantity related to space and time. And D... phy This is the total physical absorbed dose rate at time t for voxels, and therefore, it is also a spatially and temporally related quantity. Based on this, and using CBE and D... phy Calculated D bio That is, quantities related to space and time.

[0043] As can be seen, according to the embodiments of this disclosure, the detected boron concentration is spatially and temporally related, which can characterize the boron concentration of different voxels at different times. Furthermore, the biological effect value calculated based on the boron concentration, the composite biological effect value calculated based on the biological effect value, and the bioeffective dose calculated based on the composite biological effect value are all spatially and temporally related. This allows for the determination of the appropriate irradiation time for different voxels during BNCT, in order to obtain better therapeutic effects.

[0044] The following examples illustrate the detection of C in this disclosure. B The process is illustrated by example.

[0045] Figure 2 This is a schematic flowchart illustrating a method for detecting boron concentration according to an embodiment of the present disclosure.

[0046] like Figure 2 As shown, the boron concentration C of each voxel in the detection target at multiple time points. B ,include: In step S201, a positron emission tomography (PET) tracer is injected into the target; In step S202, the normalized uptake value of the tracer within each voxel in the three-dimensional PET image of the target is acquired at multiple times. The normalized uptake value of the tracer within the first voxel in the three-dimensional PET image of the target acquired at the first time is used to determine the C0 of the first voxel at the first time. B .

[0047] It should be noted that when the operation of injecting the PET tracer into the target is performed by the above system, the method may include S201; however, when the operation of injecting the PET tracer into the target is performed manually, the method may not include S201.

[0048] In some embodiments, the tracer for PET includes 18 F-BPA, but not limited to 18 F-BPA can also be used as a tracer, and other boron-containing substances can also be used. The following examples mainly use 18F-BPA as a tracer for PET to illustrate the technical solution of this disclosure. 18 The uptake level of F-BPA in PET images, for example, using the standardized uptake value (SUV), can be used to accurately predict boron (e.g., during treatment). 10 B) Concentration in tumors and normal tissues.

[0049] For example, when injecting into the target 18 After F-BPA, three-dimensional PET images of the target can be acquired at multiple time points. 18 The standardized uptake value of F-BPA per voxel. The number of time periods included in the multiple time periods is not limited in this disclosure; for example, it can be 10 time periods or 100 time periods, and can be set as needed.

[0050] For example, there are n time points, where n is an integer greater than 1. For instance, the n time points are denoted as t1 to tn. For each voxel in the target, the n time points can be detected separately. 18 Standardized intake values ​​corresponding to F-BPA.

[0051] For example, for the first voxel in the target (referring to a specific voxel, not a particular voxel), the time at which it is acquired can be determined (e.g., denoted as ti, where i is an integer greater than 1 and less than or equal to n). 18 The standardized uptake value corresponding to F-BPA, as the first voxel's C at the first moment. B Based on this, t1 to tn 18 The standardized uptake value corresponding to F-BPA can be used as the C value of the first voxel at each time point from t1 to tn. B .

[0052] In some embodiments, a CT scan of the target can be performed first to obtain high-resolution anatomical images, which are then used to perform attenuation correction on the PET images and to provide three-dimensional anatomical coordinates for constructing a non-uniform human model (e.g., a three-dimensional PET image).

[0053] In some embodiments, dynamic PET scan acquisition can be continuously recorded. 18 The complete dynamic process of F-BPA uptake, distribution and clearance in vivo was obtained to obtain the time-activity curve (TAC) of boron concentration for each voxel.

[0054] It should be noted that the boron concentration obtained in this embodiment is the boron concentration of voxels at multiple time points. It is necessary to fit the collected boron concentration with time to obtain the TAC curve, so as to characterize the relationship between the boron concentration in voxels and time. The implementation method of fitting will be described in subsequent embodiments.

[0055] In some embodiments, the target can be injected via intravenous bolus injection or constant-rate infusion. 18 For F-BPA, the injection start signal must be synchronized with the dynamic PET scan start signal (i.e., the signal used to detect boron concentration).

[0056] Then, continuous data acquisition can be performed on boron concentration. The time range of the acquired data can be divided into multiple time periods (e.g., every two time periods serve as the start and end points of a time period), ultimately resulting in a three-dimensional PET image set arranged in a time series, with each frame representing a corresponding time period. 18 F-BPA distribution values, for example, represent the distribution over a time period. 18 The average distribution of F-BPA.

[0057] In some embodiments, dynamically acquired data can be reconstructed into transverse images using iterative reconstruction algorithms or deep learning algorithms. During the reconstruction process, images acquired by CT scans are subjected to attenuation correction, scattering, and random coincidence correction to obtain quantitatively normalized uptake value (SUV) images.

[0058] In addition, since the target may move during long-term scanning, rigid or non-rigid registration algorithms can be used to register PET images from all time frames to a common reference space to eliminate artifacts caused by patient movement and ensure that each voxel describes the same physical location at different time points.

[0059] In some embodiments, on registered CT or PET images (e.g., 3D PET images), automatic or semi-automatic segmentation algorithms can delineate the tumor target volume (GTV) and key normal tissues and organs.

[0060] Furthermore, the embodiments of this disclosure do not calculate the average TAC for the entire ROI (Region of Interest) region (e.g., a specific organ or region within a target) in a 3D PET image, but rather calculate the time-activity curve (TAC) of boron concentration independently for each voxel in the PET image. That is, for each voxel in a 3D PET image, its TAC is a sequence of SUV values ​​that change over time.

[0061] Figure 3 This is a schematic flowchart illustrating a method for determining the relationship between boron concentration and time, according to an embodiment of the present disclosure.

[0062] As can be seen from the foregoing embodiments, this disclosure allows for the detection of C at multiple time points for each voxel. B This allows us to obtain three-dimensional PET images corresponding to multiple time points (e.g., dozens of time points), and the C values ​​within voxels in the three-dimensional PET images. B Changes over time.

[0063] To accurately determine C in voxels B The correlation with time (e.g., denoted as the second correlation) can be used to fit boron concentration to time. However, this is only based on C corresponding to multiple time periods. B Determining the second association only guarantees the C corresponding to the detection (or acquisition) time. B It is relatively accurate, but it is difficult to guarantee the corresponding C between adjacent detection times. B This is also accurate, and the present disclosure further proposes the following embodiments.

[0064] like Figure 3As shown, the method for determining the effective biological dose also includes the following steps: In step S301, the boron concentration in the first voxel of the target is determined as a function of time in the tumor compartment of the multiple compartments according to a multi-compartment pharmacokinetic model, wherein the parameters in the function include the exchange rate between the tumor compartment and other compartments, and the volume of the tumor compartment in the target. In step S302, based on C detected at multiple times within the first voxel B The function is fitted, and the fitted function is used as the C within the first voxel. B The second correlation with time, wherein the RBE within the first voxel B C in B Based on the second association relationship representation.

[0065] In some embodiments, the multi-compartment pharmacokinetic model may include a two-compartment pharmacokinetic model or a three-compartment pharmacokinetic model, and may also include pharmacokinetic models with more than one compartment; this disclosure is not limited thereto. The following mainly uses a three-compartment pharmacokinetic model as an example to illustrate the technical solution of this disclosure.

[0066] In some embodiments, based on the blood perfusion status of the target tumor in the tissue, two three-compartment pharmacokinetic models can be established, for example, as follows: Figure 4A and Figure 4B As shown.

[0067] For example, the three compartments in a three-compartment pharmacokinetic model can include a central compartment, a peripheral compartment, and a specific compartment. The central compartment corresponds to plasma and highly perfused tissues, the peripheral compartment corresponds to low-perfused tissues and the intact blood-brain barrier region, and the specific compartment corresponds to the tumor.

[0068] Figure 4A This is a three-compartment pharmacokinetic model illustrated according to embodiments of the present disclosure.

[0069] When the tumor is located in a low-perfusion tissue within the target area, such as a glioma in the brain, a three-compartment pharmacokinetic model can be used as follows: Figure 4A As shown, in this situation, the exchange of substances between the specific chamber (tumor) and the central chamber is restricted. 18 F-BPA uptake relies primarily on the active transport mechanism of tumor cells, rather than the effect of blood perfusion.

[0070] For example, C in the central chamber B The relationship with time can be characterized as The volume of the central chamber within the target (e.g., the patient's body) is characterized as .

[0071] For example, in the surrounding room C B The relationship with time can be characterized as The volume of the central chamber within the target (e.g., the patient's body) is characterized as .

[0072] For example, C in the special chamber B The relationship with time can be characterized as The volume of the central chamber within the target (e.g., the patient's body) is characterized as .

[0073] For example, K1 represents 18 The exchange rate of F-BPA from the central chamber to the peripheral chambers, K2 represents... 18 The exchange rate of F-BPA from the peripheral chamber to the central chamber, K3 represents... 18 The exchange rate of F-BPA from the specific chamber to the surrounding chamber, K4 represents... 18 The exchange rate of F-BPA from the peripheral chamber to the specific chamber, K5 represents... 18 The overall rate of F-BPA, including processes such as absorption, metabolism, and excretion, express 18 F-BPA injection intensity varies with time.

[0074] For example, a system of equations can be constructed based on the following formulas 1, 2, and 3 to characterize , and The relationship between them: Formula 1: ; Formula 2: ; Formula 3: .

[0075] Figure 4B This is another three-compartment pharmacokinetic model shown according to embodiments of this disclosure.

[0076] When the tumor is located in a highly perfused tissue, such as the liver or kidney, a three-compartment pharmacokinetic model can be used as follows: Figure 4B As shown, in this situation, the exchange of substances between the specific chamber (tumor) and the central chamber is faster. 18 F-BPA can rapidly enter tumor cells and accumulate therein. Figure 4B The model shown is relative to Figure 4A The model shown can more accurately predict different types of tumors. 18 The enrichment of F-BPA provides an optimization basis for individualized treatment of BNCT.

[0077] For example, C in the central chamberB The relationship with time can be characterized as The volume of the central chamber within the target (e.g., the patient's body) is characterized as .

[0078] For example, in the surrounding room C B The relationship with time can be characterized as The volume of the central chamber within the target (e.g., the patient's body) is characterized as .

[0079] For example, C in the special chamber B The relationship with time can be characterized as The volume of the central chamber within the target (e.g., the patient's body) is characterized as .

[0080] For example, K1 represents 18 The exchange rate of F-BPA from the central chamber to the peripheral chambers, K2 represents... 18 The exchange rate of F-BPA from the peripheral chamber to the central chamber, K3 represents... 18 The exchange rate of F-BPA from the specific chamber to the surrounding chamber, K4 represents... 18 The exchange rate of F-BPA from the peripheral chamber to the specific chamber, K5 represents... 18 The overall rate of F-BPA, including processes such as absorption, metabolism, and excretion, express 18 F-BPA injection intensity varies with time.

[0081] For example, a system of equations can be constructed based on the following formulas 1, 2, and 3 to characterize , and The relationship between them: Formula 4: ; Formula 5: ; Formula 6: .

[0082] exist Figure 4A and Figure 4B In the illustrated embodiment, f represents the boron element in 18 The mass fraction percentage in F-BPA. In the above formula, besides... , and All other parameters can be treated as known parameters. Therefore, a system of equations can be constructed based on formulas 1, 2, and 3, or based on formulas 4, 5, and 6, to solve the problem. , and The solution obtained It can characterize C in tumor compartments B Time-varying functions.

[0083] Furthermore, for the first voxel (any voxel, not a specific voxel), C can be corresponding to multiple detected times. B Based on this, Perform a fitting operation, and use the fitted function as the C in the first voxel. B The relationship with time, for example, is called a second relationship.

[0084] C was detected at multiple times B It can relatively accurately characterize C at each of multiple times. B ,and This allows for a relatively accurate characterization of C within the time intervals between the aforementioned multiple times. B The correlation with time, therefore, C based on multiple time detections B By fitting the function, the resulting fitted function can relatively accurately characterize C at each time point across multiple time periods. B and C within the time intervals between multiple times B The relationship with time, that is, accurately characterizing C within a continuous time range (including the above-mentioned multiple times). B The relationship with time.

[0085] Furthermore, in determining C B and RBE B When the first association is defined, for example, the first association is represented by the function RBE. B =f (C B C can be characterized based on the second association relationship. B Since the second correlation is C in the first voxel B The correlation with time allows us to substitute the second correlation into the first correlation to determine the RBE in the first voxel. B The correlation with time allows for the determination of the RBE within each voxel. B The relationship with time.

[0086] The following examples illustrate the process of calculating biologically effective doses.

[0087] In some embodiments, since the CBE factor is not constant, it is essentially a heavy charged particle (e.g., α and β) generated during the BNCT process. 7The relative biological effect (RBE) of radiation (Li) is reflected in macroscopic dose calculations. RBE primarily depends on the linear energy transfer (LET) of radiation and the dose. Therefore, when calculating the total bioeffective dose, the CBE factor should no longer be a fixed value, but rather a time-dependent dynamic value.

[0088] In order to establish CBE and C B The functional relationship between them can be calculated using the MK model, SMK model, or other biological effect models, for a specific voxel, through simulation calculations on multiple C... B In this case, the RBE factor of the boron dose component generated by the BNCT radiation field (e.g., including a neutron beam) at the voxel location. During this process, a specific biological endpoint can be set as needed, such as a survival fraction (SF) of 10%.

[0089] The total CBE factor (or value) obtained in a voxel is the weighted average of the REB for all dose components, such as boron, and other dose components (e.g., hydrogen, nitrogen, photons). Therefore, for example, it can be calculated based on the RBE. B and D B The product of the other dose components and the product of other biological effect values ​​and other physically absorbed dose rates is used to calculate C. B The combined biological effect value (CBE).

[0090] For example, for a voxel at position (x, y, z), the CBE can be calculated based on the following formula: ; Among them, RBE B Characterized as .

[0091] For details on how to determine other dose components, other biological effect values, and other physical absorbed dose rates, please refer to the previous examples; they will not be repeated here.

[0092] Therefore, in determining C B (that is, in the formula) Based on this, a CBE map can be obtained in four-dimensional (three spatial dimensions and one temporal dimension), which can characterize the change of CBE over time in each voxel. For example, this CBE map can be represented in a computer as a function or a high-dimensional data array, which can return a definite CBE value for any given four coordinates (x, y, z, t).

[0093] Based on this, the correlation between CBE and time is established. Therefore, for any given future irradiation (e.g., neutron beam irradiation) start time (e.g., denoted as ts), the correlation between CBE and time can predict the start time from ts (e.g., denoted as ts). 18 F-BPA is used as ts (other times can also be chosen as ts) and the duration is T (e.g., T is a known quantity) within a time range, where each voxel in the target corresponds to the CBE at each time.

[0094] In some embodiments, the method based on the CBE and the D phy Calculate the biologically effective dose D bio ,include: The CBE and the D phy Substituting into the first function, where the first function is used to evaluate the CBE and the D phy The product is integrated, with the lower bound of the first function being the start time of neutron beam irradiation and the upper bound being the end time of neutron beam irradiation, the end time being related to the start time.

[0095] For example, the first function can be represented by the following formula 7: Formula 7: ; Where ts is the start time of neutron beam irradiation, and ts+T is the end time of neutron beam irradiation, where T is a known quantity.

[0096] In some embodiments, neutron source parameters can be determined, such as neutron energy spectrum, neutron source intensity, neutron beam irradiation duration, and irradiation direction and range.

[0097] For each candidate time ts, the Monte Carlo dose engine can be invoked to simulate the irradiation process starting from ts, based on the neutron source-related parameters and the geometric model of the target (e.g., the patient) in the above embodiments, and calculate the physical dose rate distribution D over time. phy (x,y,z,t).

[0098] Therefore, for a voxel located at position (x,y,z), a suitable ts can be selected to obtain the D required for treatment. bio (This can correspond to the prescribed dose of irradiation), and thus D bio Treatment should be administered in order to achieve the desired therapeutic effect.

[0099] It should be noted that regarding D bio The calculation method for D is not limited to Formula 7 above; it can also be obtained based on other calculation methods. bio For example, D can be calculated based on the following formula 8. bio : ; D does not need to be applied in this process. phy So, in the previous embodiments, the method used to determine D... phy The operation can be omitted. The following examples mainly calculate D based on Formula 7. bio The technical solution of this disclosure will be illustrated by example.

[0100] The above embodiments mainly consider the treatment process targeting the uptake area. However, in the actual treatment process of BNCT, 18 F-BPA is taken up not only by the targeted uptake region but also by the non-targeted uptake region. Furthermore, the neutron beam irradiates not only the targeted uptake region but also the non-targeted uptake region. The irradiation of the non-targeted uptake region by the neutron beam will cause unnecessary damage to the cells in the non-targeted uptake region.

[0101] Therefore, based on any of the embodiments described above, this disclosure further proposes embodiments that distinguish between targeted uptake regions and non-targeted uptake regions, as well as optimizations to the calculation process in the embodiments described above, taking into account non-targeted uptake regions. Several embodiments are described below as examples.

[0102] In some embodiments, targeted and non-targeted uptake areas can be determined in a three-dimensional PET image of the target.

[0103] For example, in a three-dimensional PET image of a target, voxels with a standardized uptake value greater than (or equal to) a first threshold are identified as belonging to the non-targeted uptake region.

[0104] In some embodiments, the non-targeted uptake region appears on a 3D PET image as being located inside normal tissue or organ, but... 18 The uptake intensity of F-BPA (e.g., SUV) is significantly higher than the average background uptake level of the organ.

[0105] The non-targeted uptake area identified accordingly may differ from the organ at risk (OAR) identified in the treatment planning system (TPS). For example, it could be a non-targeted uptake area within normal tissue caused by inflammation, infection, or postoperative repair. 18 For areas with relatively high F-BPA uptake intensity (e.g., above the average background uptake level of the organ), dose constraints should also be set for these non-targeted uptake areas to avoid causing excessive damage to the non-targeted uptake areas during BNCT treatment.

[0106] In some embodiments, after precise registration with CT has been completed 18In F-BPA PET static images (such as 3D PET images, typically peak or plateau images at specific time points after injection), the PET images are calibrated using standardized uptake values ​​(SUVs) to ensure the accuracy of quantitative analysis.

[0107] Normal tissues and organs (such as skin, mucous membranes, salivary glands, etc.) are automatically or semi-automatically delineated to form an initial mask, which is used to distinguish normal tissues and organs from tumor areas.

[0108] Furthermore, an SUV threshold (e.g., called the first threshold) can be set for each normal tissue or organ, and all voxels in that organ with SUV values ​​greater than (or equal to) the first threshold can be automatically extracted and identified as non-targeted uptake areas.

[0109] Based on the dose constraints set for the OAR, even stricter dose constraints can be set for the non-target uptake area. Accordingly, it can be ensured that during BNCT treatment, when determining the intensity distribution of the neutron beam, the irradiation of the non-target uptake area can be effectively reduced or avoided, thereby preventing excessive damage to the non-target uptake area.

[0110] Figure 5 This is a schematic flowchart illustrating a method for determining the start time of treatment according to an embodiment of the present disclosure.

[0111] like Figure 5 As shown, the method for determining the effective biological dose also includes the following steps: In step S501, when the first number of candidate times are determined as the lower bound of the integration of the first function, the first function outputs a first result for voxels in the targeted uptake region and a second result for voxels in the non-targeted uptake region. In step S502, a candidate time when the first result and the second result satisfy the constraint condition is determined as the start time to be applied, wherein the constraint condition includes the first result being greater than (or equal to) a second threshold and the second result being less than (or equal to) a third threshold.

[0112] In some embodiments, non-targeted regions are also ingested. 18 F-BPA, therefore, D is calculated based on the first function mentioned above (e.g., Formula 7). bio During the process, the first result corresponding to ts can be obtained for voxels in the targeted uptake area, and the second result corresponding to ts can be obtained for voxels in the non-targeted uptake area.

[0113] On the one hand, in order to ensure the therapeutic effect on the targeted uptake area, the first result needs to be relatively large, for example, greater than (or equal to) the second threshold; on the other hand, in order to avoid causing excessive damage to cells in the non-targeted uptake area, the second result needs to be relatively small, for example, less than (or equal to) the third threshold.

[0114] Therefore, constraints can be set such that the first result is greater than (or equal to) a second threshold, and the second result is less than (or equal to) a third threshold. Based on these constraints, appropriate first and second results can be determined. This ensures therapeutic efficacy in the targeted uptake region while avoiding excessive damage to cells in non-targeted uptake regions.

[0115] It should be noted that the thresholds (such as the second threshold and the third threshold) in the above constraints can be determined based on dose-volume constraints, and the specific determination method is not limited in this disclosure.

[0116] In some embodiments, determining the candidate time when the first result and the second result satisfy the constraint condition as the neutron beam irradiation start time for the therapeutic application includes: If the candidate time when the first result and the second result satisfy the constraint conditions includes a second number of candidate times, the candidate time corresponding to the quality of the treatment plan is determined from the second number of candidate times as the start time to be applied, wherein the quality of the treatment plan is positively correlated with the first result and negatively correlated with the second result.

[0117] In some embodiments, the way the foregoing embodiments determine the first and second results based on constraints may result in multiple (e.g., a second number) ts that satisfy the constraints. In this case, it is necessary to select an optimal ts from these ts so that the combined effect of the therapeutic effect on the targeted uptake region and the damage to the non-targeted uptake region is optimal.

[0118] For example, treatment plan quality can be constructed that is positively correlated with the first outcome and negatively correlated with the second outcome. For instance, denoted as Z for treatment plan quality, X for the first outcome, and Y for the second outcome, treatment plan quality can be represented based on the following formula 9: Formula 9: Z = aX - bY; where a and b are positive numbers.

[0119] Based on this, the X and Y corresponding to the second number of ts can be substituted into Formula 9 to obtain the second number of Z. Then, each Z can be compared to determine the ts corresponding to the largest Z as the starting time for application. Subsequently, during BNCT treatment, irradiation can be performed using the starting time for application as the treatment start time, which helps to ensure the best overall effect of treatment on the targeted uptake area and damage to the non-targeted uptake area.

[0120] It should be noted that the relationship between the quality of the treatment plan and the first and second outcomes is not limited to Formula 9, but can also be represented by other formulas, and this disclosure does not limit this.

[0121] The embodiments of this disclosure, through integration 18 F-BPA positron emission tomography (PET) technology combined with boron neutron capture therapy (BNCT) dose calculation enables precise mapping of the spatial distribution of boron concentration and individualized dose assessment, thereby significantly improving the accuracy and safety of treatment planning.

[0122] The embodiments of this disclosure, through dynamic 18 F-BPA detection can obtain a complete data chain of boron concentration evolution over time and space, and by constructing a voxel-level pharmacokinetic model, it can predict the precise boron concentration at any point in the body at any time from the start of drug injection to the end of treatment.

[0123] The embodiments of this disclosure abandon the simplified model of fixed CBE factor and construct a four-dimensional spatiotemporal biological effect map, coupling the voxel-level dynamic boron concentration with the variable CBE factor calculated by the biological effect model.

[0124] In the embodiments of this disclosure, addressing the problem in related technologies that cannot effectively distinguish and protect normal tissues that undergo "non-targeted uptake" due to inflammation or other reasons, the present invention employs a method based on... 18 The automatic recognition algorithm of F-BPA PET images intelligently delineates the "non-target uptake area" with abnormally high SUV values ​​and applies a more stringent independent dose constraint to it in the treatment planning system (TPS) than to the normal organ in which it is located.

[0125] In embodiments of this disclosure, the aforementioned dynamic model (e.g., the correlation between boron concentration and CBE factor) and dose constraints (e.g., constraint conditions) are integrated into a closed-loop optimization framework. The optimization algorithm automatically simulates the treatment process at different irradiation start times ts, evaluates the plan quality based on the objective function, and automatically determines the optimal irradiation time window for a specific patient.

[0126] In summary, this disclosure will... 18F-BPA functional imaging information is deeply integrated into the entire chain of BNCT dose calculation, creating a new dosimetry system that is precise, dynamic, intelligent and quantifiable.

[0127] Corresponding to the biological effective dose determination method described in the foregoing embodiments, this disclosure also proposes embodiments of a biological effective dose determination device.

[0128] Figure 6 This is a schematic block diagram of a biological effective dose determination device according to an embodiment of the present disclosure.

[0129] In some embodiments, the bioeffective dose determination device may be partially or wholly incorporated into the BNCT treatment planning system.

[0130] like Figure 6 As shown, the biological effective dose determination device may include: a detection module 601, a processing module 602, and an injection module 603.

[0131] It should be noted that when the operation of injecting the PET tracer into the target is performed by the above-described device, the device may include the injection module 603; however, when the operation of injecting the PET tracer into the target is performed manually, the device may not include the injection module 603.

[0132] In some embodiments, the detection module is configured to detect the boron concentration C of each voxel in the target at multiple time points. B The processing module is configured to calculate the C. B The corresponding biological effect value (RBE) B Determine the C B and the RBE B The first association relationship, based on the first association relationship, determines through C B Characterized RBE B ; Calculate the C B The corresponding first physical absorbed dose rate D B And other physical absorbed dose rates corresponding to dose components other than boron, and physical dose rate distribution D phy , wherein, the D B The other physically absorbed dose rates, the D phy Time- and voxel-related; according to the RBE B and the D B The product of the other dose components and the product of the other biological effect values ​​and the other physically absorbed dose rates is used to calculate C. B The combined biological effect value (CBE); based on the CBE and the D phy Calculate the biologically effective dose D bio .

[0133] In some embodiments, the processing module is further configured to determine, based on a multi-compartment pharmacokinetic model, the boron concentration in a first voxel within the target as a function of time variations in a multi-compartment tumor compartment, wherein parameters in the function include, based on the exchange rate between the tumor compartment and other compartments in the plurality of compartments, and the volume of the tumor compartment within the target; based on C detected at multiple times within the first voxel. B The function is fitted, and the fitted function is used as the C within the first voxel. B The second correlation with time, wherein the RBE within the first voxel B C in B Based on the second association relationship representation.

[0134] In some embodiments, the other dosage components include at least one of the following: nitrogen, hydrogen, and photons.

[0135] In some embodiments, the other physically absorbed dose rates are determined based on clinical consensus values; and / or, the D corresponding to each time period. B The other physical absorbed dose rates were determined based on simulation.

[0136] In some embodiments, the injection module is configured to inject a positron emission tomography (PET) tracer into the target; the detection module is configured to acquire, at multiple times, the normalized uptake value of the tracer within each voxel in a three-dimensional PET image of the target, wherein the normalized uptake value of the tracer within a first voxel in a three-dimensional PET image of the target acquired at a first time is used to determine the Ci of the first voxel at the first time. B .

[0137] In some embodiments, the processing module is configured to process the CBE and the D phy Substituting into the first function, where the first function is used to evaluate the CBE and the D phy The product is integrated, with the lower bound of the first function being the start time of neutron beam irradiation and the upper bound being the end time of neutron beam irradiation, the end time being related to the start time.

[0138] In some embodiments, the processing module is further configured to determine the targeted uptake area and the non-targeted uptake area in the three-dimensional PET image of the target.

[0139] In some embodiments, the non-targeted uptake region is determined by identifying voxels in a three-dimensional PET image of the target whose standardized uptake value is greater than a first threshold as belonging to the non-targeted uptake region.

[0140] In some embodiments, the processing module is further configured to determine, when a first number of candidate times are respectively used as the lower bound of the integral of the first function, a first result output by the first function for voxels in the targeted uptake region and a second result output by the first function for voxels in the non-targeted uptake region; and to determine the candidate time when the first result and the second result satisfy a constraint condition as the start time to be applied, wherein the constraint condition includes the first result being greater than a second threshold and the second result being less than a third threshold.

[0141] In some embodiments, the processing module is configured to determine, if the candidate time when the first result and the second result satisfy the constraint conditions includes a second number of candidate times, a candidate time corresponding to the quality of the treatment plan as the start time to be applied from the second number of candidate times, wherein the quality of the treatment plan is positively correlated with the first result and negatively correlated with the second result.

[0142] Embodiments of this disclosure also provide a storage medium storing instructions that, when executed on a communication device, cause the communication device to perform the biological effective dose determination method described in any of the above embodiments.

[0143] Embodiments of this disclosure also provide a program product that, when executed by a communication device, causes the communication device to perform the biological effective dose determination method described in any of the above embodiments.

[0144] Regarding the apparatus in the above embodiments, the specific manner in which each module performs its operation has been described in detail in the embodiments related to the method, and will not be elaborated upon here.

[0145] For the device embodiments, since they basically correspond to the method embodiments, the relevant parts can be referred to in the description of the method embodiments. 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, that is, they may be located in one place or distributed across multiple network units. Some or all of the modules can be selected to achieve the purpose of the present invention according to actual needs. Those skilled in the art can understand and implement this without creative effort.

[0146] Other embodiments of the invention will readily occur to those skilled in the art upon consideration of the specification and practice of the disclosure herein. The invention is intended to cover any variations, uses, or adaptations of the invention that follow the general principles of the invention and include common knowledge or customary techniques in the art not disclosed herein. The specification and examples are to be considered exemplary only, and the true scope and spirit of the invention are indicated by the following claims.

[0147] It should be understood that the present invention is not limited to the precise structure described above and shown in the accompanying drawings, and various modifications and changes can be made without departing from its scope. The scope of the invention is limited only by the appended claims.

Claims

1. A method for determining a biologically effective dose, characterized in that, include: The boron concentration C of each voxel in the detection target at multiple time points. B ; Calculate the C B The corresponding biological effect value (RBE) B Determine the C B and the RBE B The first association relationship, based on the first association relationship, determines through C B Characterized RBE B ; Calculate the C B The corresponding first physical absorbed dose rate D B And other physical absorbed dose rates corresponding to dose components other than boron, and physical dose rate distribution D phy , wherein, the D B The other physically absorbed dose rates, the D phy Related to time and voxels; According to the RBE B and the D B The product of the other dose components and the product of the other biological effect values ​​and the other physical absorbed dose rates is used to calculate C. B The combined biological effect value (CBE); According to the CBE and the D phy Calculate the biologically effective dose D bio .

2. The method according to claim 1, characterized in that, The method further includes: The boron concentration in the first voxel of the target is determined according to a multi-compartment pharmacokinetic model as a function of time in the tumor compartment of the multi-compartment, wherein the parameters in the function include the exchange rate between the tumor compartment and other compartments, and the volume of the tumor compartment in the target. Based on C detected at multiple times within the first voxel B The function is fitted, and the fitted function is used as the C within the first voxel. B The second correlation with time, wherein the RBE within the first voxel B C in B Based on the second association relationship representation.

3. The method according to claim 1, characterized in that, The other dosage components include at least one of the following: Nitrogen, hydrogen, photons.

4. The method according to claim 3, characterized in that, The other physically absorbed dose rates are determined based on clinical consensus values; and / or, the D corresponding to each time period. B The other physical absorbed dose rates were determined based on simulation.

5. The method according to any one of claims 1 to 4, characterized in that, The boron concentration C of each voxel in the detection target at multiple time points B ,include: Injecting tracers from positron emission tomography (PET) into the target; The tracer's standardized uptake value within each voxel is obtained in three-dimensional PET images of the target acquired at multiple time points. Specifically, the standardized uptake value of the tracer within a first voxel in the three-dimensional PET image of the target acquired at the first time point is used to determine the C0 value of the first voxel at the first time point. B .

6. The method according to any one of claims 1 to 4, characterized in that, The terms based on the CBE and the D phy Calculate the biologically effective dose D bio ,include: The CBE and the D phy Substituting into the first function, where the first function is used to evaluate the CBE and the D phy The product is integrated, with the lower bound of the first function being the start time of neutron beam irradiation and the upper bound being the end time of neutron beam irradiation, the end time being related to the start time.

7. The method according to claim 6, characterized in that, The method further includes: Identify the targeted uptake area and non-targeted uptake area in the 3D PET image of the target.

8. The method according to claim 7, characterized in that, The non-targeted uptake region is determined based on the following method: In the three-dimensional PET image of the target, voxels with standardized uptake values ​​greater than a first threshold are identified as belonging to the non-targeted uptake region.

9. The method according to claim 7, characterized in that, The method further includes: When a first number of candidate times are determined as the lower bound of the integral of the first function, the first function outputs a first result for voxels in the targeted uptake region and a second result for voxels in the non-targeted uptake region. The candidate time when the first result and the second result satisfy the constraint condition is determined as the start time to be applied, wherein the constraint condition includes the first result being greater than a second threshold and the second result being less than a third threshold.

10. The method according to claim 9, characterized in that, The step of determining the candidate time when the first result and the second result satisfy the constraint conditions as the neutron beam irradiation start time for the therapeutic application includes: If the candidate time when the first result and the second result satisfy the constraint conditions includes a second number of candidate times, the candidate time corresponding to the quality of the treatment plan is determined from the second number of candidate times as the start time to be applied, wherein the quality of the treatment plan is positively correlated with the first result and negatively correlated with the second result.

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