Radiotherapy device and method for operating a radiotherapy device - Patents.com

Abstract

The present disclosure provides an apparatus for radiation therapy, the apparatus including at least one first radiation source configured to provide one or more very high dose rate charged particle beams, at least one second radiation source configured to provide one or more intensity modulated beams, and a controller, the controller configured to control the at least one first radiation source to generate the one or more very high dose rate charged particle beams and the at least one second radiation source to generate the one or more intensity modulated beams, such that the one or more very high dose rate charged particle beams and the one or more intensity modulated beams provide a substantially uniform total dose distribution over a target area.

Description

[Technical field]

[0001] FIELD OF THE DISCLOSURE Embodiments of the present disclosure relate to a radiotherapy device, a method for operating a radiotherapy device, and a computer readable storage medium for carrying out the method, and more particularly, to multi-beam proton therapy in cancer treatment. [Background technology]

[0002] According to the World Health Organization, cancer is the second leading cause of death worldwide after cardiovascular disease. Therefore, great efforts have been made to improve treatment methods. Radiation therapy has been used as a means of cancer treatment for over 100 years. Radiation therapy delivers ionizing radiation to tumors, damaging and ultimately killing tumor cells.

[0003] In general, there are two types of radiation therapy: internal radiation therapy, in which the radiation source is a radioactive substance inside the body, and external radiation therapy, in which the radiation source is provided by an external radiation system.

[0004] In external radiation therapy, various radiation sources can be used. For example, X-rays can be used as the radiation source, but also charged particles such as protons and electrons can be used in radiation therapy. Charged particles interact with tissues in a different way than photons, resulting in a more localized dose deposition profile in tissues depending on the incident energy. Therefore, by modulating the energy of the charged particle beam, tumors at different locations can be targeted.

[0005] The effectiveness of external radiation therapy is based on the damaging effect of, for example, charged particles on cancer cells, but the damaging effect is not limited to cancer cells. Therefore, external radiation therapy may also have a harmful effect on surrounding healthy cells, resulting in radiation toxicity. This results in a natural paradigm in which a sufficient dose is necessary to treat the tumor, while a radiation dose that is too high will have serious toxic effects on the patient.

[0006] In view of the above, a novel apparatus for radiation therapy, a method for operating an apparatus for radiation therapy, and a computer readable storage medium for carrying out the method, that overcomes at least some of the problems in the art would be beneficial. Summary of the Invention

[0007] In view of the above, a radiotherapy apparatus, a method of operating a radiotherapy apparatus, and a computer readable storage medium for carrying out the method are provided.

[0008] An object of the present disclosure is to improve the efficiency of devices for external radiation therapy. Another object of the present disclosure is to minimize toxic effects on the patient.

[0009] These objects are solved by the features of the independent claims. Preferred embodiments are defined in the dependent claims.

[0010] According to an independent aspect of the present disclosure, there is provided an apparatus for radiation therapy, in particular FLASH radiation therapy, comprising at least one first radiation source configured to provide one or more first beams, at least one second radiation source configured to provide one or more second beams, and a controller configured to control the at least one first radiation source and the at least one second radiation source.

[0011] According to some embodiments, which may be combined with other embodiments described herein, the one or more first beams and the one or more second beams are generated sequentially. For example, the one or more first beams and the one or more second beams may be pulsed beams that are intermittently generated and emitted.

[0012] The one or more first beams may include or be one or more charged particle beams, in particular the one or more charged particle beams may include or be one or more very high dose (rate) charged particle beams.

[0013] Preferably, the one or more charged particle beams are pulsed beams.

[0014] According to some embodiments, which may be combined with other embodiments described herein, the one or more ultra-high dose rate charged particle beams are one or more FLASH beams, i.e., beams for FLASH radiation therapy (FLASH-RT).

[0015] According to some embodiments, which may be combined with other embodiments described herein, the one or more ultra-high dose rate charged particle beams are modulated to provide a FLASH effect in one or more volumes of interest, such as Organs At Risk (OARs). Constraints for the FLASH effect include a minimum dose of 8 Gy, 10 Gy or 12 Gy (particularly 8 or 10 Gy / pulse) in the one or more volumes of interest, and a minimum dose rate of 30 Gy / sec, 40 Gy / sec or 50 Gy / sec in the one or more volumes of interest.

[0016] Preferably, the one or more volumes of interest, such as one or more OARs, are spatially separated from and / or adjacent to a target region, such as a planning target volume (PTV) that contains a tumor to be treated.

[0017] According to some embodiments, which may be combined with other embodiments described herein, the controller is configured to control the at least one first radiation source such that each very high dose rate charged particle beam passes through a respective volume of interest.

[0018] Preferably, the number of ultra-high dose rate charged particle beams and the number of volumes of interest are the same.

[0019] Preferably, the controller is further configured to control the at least one second radiation source such that the one or more second beams, such as one or more intensity modulated (e.g., IMPT, IMRT or VMAT) beams, do not pass through any volume of interest.

[0020] According to some embodiments, which may be combined with other embodiments described herein, the one or more charged particle beams are selected from or consist of a group including a proton beam, an electron beam, and an ion beam.

[0021] According to some embodiments, which may be combined with other embodiments described herein, the one or more first beams, in particular the one or more very high dose rate charged particle beams, are single field uniform dose (SFUD) beams.

[0022] According to some embodiments, which may be combined with other embodiments described herein, the one or more second beams may include or be one or more intensity-modulated beams.

[0023] According to some embodiments, which may be combined with other embodiments described herein, the one or more second beams, in particular the one or more intensity-modulated beams, include or are selected from the group consisting of photon beams (e.g., X-rays), proton beams, electron beams, and ion beams.

[0024] Preferably, said one or more second beams, in particular said one or more intensity modulated beams, are Intensity Modulated Proton Therapy (IMPT) beams, Intensity Modulated Radiotherapy (IMRT) beams, or Volumetric Intensity Modulated Arc Therapy (VMAT) beams.

[0025] According to some embodiments, which may be combined with other embodiments described herein, the controller is configured to control the at least one first radiation source to generate the one or more ultra-high dose rate charged particle beams and to control the at least one second radiation source to generate the one or more intensity-modulated beams, such that the one or more ultra-high dose rate charged particle beams and the one or more intensity-modulated beams provide a substantially uniform total dose distribution across the target area.

[0026] Preferably, the controller is further configured to control the at least one first radiation source to generate the one or more ultra-high dose rate charged particle beams and the at least one second radiation source to generate the one or more intensity-modulated beams, such that a first dose distribution of the one or more ultra-high dose rate charged particle beams and a second dose distribution of the one or more intensity-modulated beams combine (or complement) at a target area to provide the substantially uniform total dose distribution across a target area, e.g., substantially across an entire target area (TV).

[0027] According to some embodiments, which may be combined with other embodiments described herein, the controller is configured to control the at least one first radiation source to generate the one or more ultra-high dose rate charged particle beams, such that each ultra-high dose rate charged particle beam of the one or more ultra-high dose rate charged particle beams provides a substantially uniform first dose distribution in a corresponding first region of a target region, and to control the at least one second radiation source to generate the one or more intensity-modulated beams, such that the one or more intensity-modulated beams provide a substantially uniform second dose distribution in a second region of the target region different from the first region.

[0028] Thus, the one or more intensity-modulated beams contribute to a completely uniform coverage of the target area and prevent the formation of cold spots. In particular, the one or more intensity-modulated beams can "stitch" the first (e.g., FLASH) area or "fill in" the area of ​​the target volume that is not covered by the very high dose rate charged particle beam (e.g., FLASH beam). As a result, the one or more very high dose rate charged particle beams and the one or more intensity-modulated beams are interdependent, i.e. the one or more very high dose rate charged particle beams and the one or more intensity-modulated beams, in particular the doses and dose rates delivered by them, cannot be considered as independent of each other.

[0029] According to some embodiments, which may be combined with other embodiments described in this specification, the dose values ​​of the substantially uniform first dose distribution and the dose values ​​of the substantially uniform second dose distribution are substantially the same.

[0030] According to some embodiments, which may be combined with other embodiments described herein, the first region and the second region do not overlap.

[0031] According to some embodiments, which may be combined with other embodiments described herein, the target region comprises or consists of the first region and the second region.

[0032] According to some embodiments, which may be combined with other embodiments described herein, at least one interface region is provided between the first region and the second region.

[0033] According to some embodiments, which may be combined with other embodiments described herein, the target region includes or consists of the first region, the second region, and at least one interface region between the first region and the second region.

[0034] According to some embodiments, which may be combined with other embodiments described herein, the controller is further configured to control the at least one first radiation source and the at least one second radiation source to provide a substantially uniform total dose distribution across the first region and the second region, and optionally the at least one interface region.

[0035] According to further embodiments, which may be combined with other embodiments described herein, the controller is configured to control the at least one first radiation source to generate the one or more ultra-high dose rate charged particle beams and the at least one second radiation source to generate the one or more intensity-modulated beams, such that dose distributions of the one or more ultra-high dose rate charged particle beams and the one or more intensity-modulated beams spatially overlap and complement each other at the at least one interface region to provide a substantially uniform total dose distribution across the at least one interface region.

[0036] Preferably, the dose distribution of the one or more ultra-high dose rate charged particle beams and the dose distribution of the one or more intensity-modulated beams in the at least one interface region are non-uniform. For example, the vertical dose profile of the one or more ultra-high dose rate charged particle beams and the vertical dose profile of the one or more intensity-modulated beams in the at least one interface region may each have a slope. In some embodiments, the vertical dose profiles have opposite slopes, such as an upward slope and a downward slope, respectively.

[0037] According to further embodiments, which may be combined with other embodiments described herein, the controller is configured to control the at least one first radiation source to generate the one or more ultra-high dose rate charged particle beams and the at least one second radiation source to generate the one or more intensity-modulated beams, such that dose distributions of the one or more ultra-high dose rate charged particle beams and the one or more intensity-modulated beams spatially overlap and / or complement each other in the target area to provide the substantially uniform total dose distribution throughout the target area.

[0038] Thus, the one or more ultra-high dose rate charged particle beams and the one or more intensity-modulated beams contribute to a completely uniform coverage of the target area and prevent the formation of cold spots. Thus, the one or more ultra-high dose rate charged particle beams and the one or more intensity-modulated beams are interdependent, i.e. the one or more ultra-high dose rate charged particle beams and the one or more intensity-modulated beams, in particular the doses and dose rates delivered by them, cannot be considered independent of each other.

[0039] Preferably, the controller is further configured to control the at least one first radiation source to generate the one or more ultra-high dose rate charged particle beams such that a dose distribution of the one or more ultra-high dose rate charged particle beams across the target area is non-uniform, and to control the at least one second radiation source to generate the one or more intensity modulated beams such that a dose distribution of the one or more intensity modulated beams across the target area is non-uniform.

[0040] For example, the vertical dose profile of the one or more ultra-high dose rate charged particle beams and the vertical dose profile of the one or more intensity-modulated beams in the at least one interface region may each have a slope to provide a non-uniform dose distribution across the target region. In some embodiments, the vertical dose profiles have opposite slopes, such as an upward slope and a downward slope, respectively.

[0041] Preferably, the non-uniform dose distributions of the one or more ultra-high dose rate charged particle beams and the non-uniform dose distributions of the one or more intensity-modulated beams spatially overlap and / or complement each other in the target area to provide a substantially uniform total dose distribution across the target area.

[0042] Since the beams have a non-uniform dose distribution across the target area, i.e., over a large range, irradiation is stable against target motion, in particular, target motion within a large range does not affect the uniformity of the total dose distribution across the target area.

[0043] In the above example, the dose distribution of the one or more ultra-high dose rate charged particle beams and the dose distribution of the one or more intensity-modulated beams in the target region are non-uniform.For example, the vertical dose profile of the one or more ultra-high dose rate charged particle beams and the vertical dose profile of the one or more intensity-modulated beams in the at least one interface region can have a slope, respectively.In some embodiments, the vertical dose profiles have opposite slopes, such as an upslope and a downslope, respectively.

[0044] According to some embodiments, which may be combined with other embodiments described herein, the controller is further configured to control the at least one first radiation source and the at least one second radiation source to provide a substantially uniform total dose distribution substantially over a target area.

[0045] Preferably, the controller comprises: wherein the one or more intensity modulated beams complement a dose in areas of the target volume not covered by the one or more very high dose rate charged particle beams to provide a substantially uniform total dose distribution substantially throughout the entire target area. The at least one first radiation source is further configured to control the at least one first radiation source.

[0046] According to an embodiment of the present disclosure, "substantially uniform" is understood to refer to a dose distribution in a target or a specific target region, where deviations from a precisely constant dose distribution may occur. That is, "substantially uniform dose distribution" refers to a substantially uniform dose distribution in a target or a target region, and even if deviations from a precisely constant dose distribution (e.g., a reference dose, a prescribed dose, or the average / mean value of the dose accumulated in the target or target region) are, for example, up to 5%, 10%, or 15%, it is still considered to be a "substantially uniform dose distribution". This deviation may occur, for example, due to natural variations in the patient's anatomy and / or machine-related uncertainties or tolerances. However, the dose distribution in a target or a specific target region is considered to be substantially uniform.

[0047] According to some embodiments, which may be combined with other embodiments described herein, the controller is further configured to sequentially determine a dose and a dose rate for the target volume.

[0048] Preferably, the controller is configured to determine a configuration (e.g., fluence and / or intensity) of the one or more ultra-high dose rate charged particle beams based on one or more dose constraints, determine a configuration (e.g., fluence and / or intensity) of the one or more intensity-modulated beams based on a dose deposited in the target volume by the one or more ultra-high dose rate charged particle beams, and optimize the configuration (e.g., fluence and / or intensity) of the one or more ultra-high dose rate charged particle beams based on one or more dose rate constraints.

[0049] Preferably, the one or more dose constraints include one or more FLASH constraints, such as a minimum dose to be deposited in one or more volumes of interest (e.g., OARs). For example, the minimum dose may be 8 Gy or more, 10 Gy or more, or 12 Gy or more.

[0050] Preferably, the one or more dose rate constraints include one or more FLASH dose rate constraints, such as a minimum dose rate to be provided in one or more volumes of interest (e.g., OARs). For example, the minimum dose rate may be 30 Gy / s or more, 40 Gy / s or more, or 50 Gy / s or more.

[0051] In further embodiments, which may be combined with other embodiments described herein, the controller is configured to simultaneously determine a dose and a dose rate to the target volume.

[0052] Preferably, the controller is configured to determine a first influence matrix for the one or more ultra-high dose rate charged particle beams and a second influence matrix for the one or more intensity-modulated beams, combine the first influence matrix and the second influence matrix to obtain a composite matrix; and optimize the composite matrix to determine a configuration (e.g., fluence and / or intensity) of the one or more ultra-high dose rate charged particle beams and a configuration (e.g., fluence and / or intensity) of the one or more intensity-modulated beams.

[0053] Preferably, the controller is configured to perform the optimization taking into account one or more dose constraints and one or more dose rate constraints in one or more volumes of interest (eg, OARs).

[0054] Preferably, the one or more dose constraints include one or more FLASH constraints, such as a minimum dose to be deposited in one or more volumes of interest (e.g., OARs). For example, the minimum dose may be 8 Gy or more, 10 Gy or more, or 12 Gy or more.

[0055] Preferably, the one or more dose rate constraints include one or more FLASH dose rate constraints, such as a minimum dose rate to be provided in one or more volumes of interest (e.g., OARs). For example, the minimum dose rate may be 30 Gy / s or more, 40 Gy / s or more, or 50 Gy / s or more.

[0056] According to another independent aspect of the present disclosure, a method of operating a radiation therapy apparatus is provided, the method including: controlling at least one first radiation source to irradiate a target region with one or more very high dose rate charged particle beams such that each very high dose rate charged particle beam of the one or more very high dose rate charged particle beams provides a substantially uniform first dose distribution in a corresponding first region of the target region; and controlling at least one second radiation source to irradiate the target region with one or more intensity modulated beams such that the one or more intensity modulated beams provide a substantially uniform second dose distribution in a second region of the target region different from the first region.

[0057] According to some embodiments, which may be combined with other embodiments described herein, the one or more intensity modulated beams complement the dose of areas of the target volume not covered by the one or more very high dose rate charged particle beams to provide a substantially uniform total dose distribution across the target area.

[0058] According to some embodiments, which may be combined with other embodiments described herein, the one or more ultra-high dose rate charged particle beams and the one or more intensity-modulated beams are pulsed beams, and the target area is sequentially irradiated by the one or more ultra-high dose rate charged particle beams and the one or more intensity-modulated beams.

[0059] According to some embodiments, which may be combined with other embodiments described herein, the method further includes sequentially determining a dose and a dose rate to the target volume.

[0060] Preferably, sequentially determining the dose and dose rate to the target volume includes: determining a configuration (e.g., fluence and / or intensity) of the one or more ultra-high dose rate charged particle beams based on one or more dose constraints; determining a configuration (e.g., fluence and / or intensity) of the one or more intensity-modulated beams based on a dose deposited in the target volume by the one or more ultra-high dose rate charged particle beams; and optimizing the configuration (e.g., fluence and / or intensity) of the one or more ultra-high dose rate charged particle beams based on one or more dose rate constraints.

[0061] Preferably, the one or more dose constraints include one or more FLASH constraints, such as a minimum dose to be deposited in one or more volumes of interest (e.g., OARs). For example, the minimum dose may be 8 Gy or more, 10 Gy or more, or 12 Gy or more.

[0062] Preferably, the one or more dose rate constraints include one or more FLASH dose rate constraints, such as a minimum dose rate to be provided in one or more volumes of interest (e.g., OARs). For example, the minimum dose rate may be 30 Gy / s or more, 40 Gy / s or more, or 50 Gy / s or more.

[0063] In further embodiments, which may be combined with other embodiments described herein, the method includes simultaneously determining the dose and dose rate of the target volume.

[0064] Preferably, simultaneously determining the dose and dose rate to the target volume includes determining a first influence matrix for the one or more ultra-high dose rate charged particle beams and a second influence matrix for the one or more intensity-modulated beams; combining the first influence matrix and the second influence matrix to obtain a composite matrix; and optimizing the composite matrix to determine a configuration (e.g., fluence and / or intensity) of the one or more ultra-high dose rate charged particle beams and a configuration (e.g., fluence and / or intensity) of the one or more intensity-modulated beams.

[0065] Preferably, the optimization is performed taking into account one or more dose constraints and one or more dose rate constraints in one or more volumes of interest (eg, OARs).

[0066] Preferably, the one or more dose constraints include one or more FLASH constraints, such as a minimum dose to be deposited in one or more volumes of interest (e.g., OARs). For example, the minimum dose may be 8 Gy or more, 10 Gy or more, or 12 Gy or more.

[0067] Preferably, the one or more dose rate constraints include one or more FLASH dose rate constraints, such as a minimum dose rate to be provided in one or more volumes of interest (e.g., OARs). For example, the minimum dose rate may be 30 Gy / s or more, 40 Gy / s or more, or 50 Gy / s or more.

[0068] The embodiments are also directed to apparatus aspects for carrying out the disclosed methods, including method aspects for carrying out each described apparatus aspect. The method aspects may be performed by hardware components, a computer programmed by appropriate software, any combination of the two, or in any other manner. Additionally, the embodiments according to the present disclosure are also directed to methods of operating the described apparatus. The present disclosure includes method aspects for carrying out any function of said apparatus.

[0069] According to another independent aspect of the present disclosure, a machine-readable storage medium is provided, the machine-readable storage medium including instructions executable by one or more processors for performing a method of operating a radiation therapy device according to an embodiment of the present disclosure.

[0070] According to another independent aspect of the present disclosure, a machine-readable storage medium is provided that includes instructions stored thereon that, when executed, cause one or more processors to control at least one first radiation source to irradiate a target area with one or more very high dose rate charged particle beams and control at least one second radiation source to irradiate the target area with one or more intensity modulated beams.

[0071] Preferably, controlling the at least one first radiation source and controlling the at least one second radiation source are performed such that the one or more very high dose rate charged particle beams and the one or more intensity modulated beams provide a substantially uniform total dose distribution over the target area.

[0072] The machine-readable storage media (e.g., non-transitory) may include, for example, optical media such as CD-ROMs and digital video disks (DVDs), and semiconductor memory devices such as electrically programmable read-only memories (EPROMs) and electrically erasable programmable read-only memories (EEPROMs). The machine-readable media may be used to securely hold computer program instructions or code embodied in one or more modules and written in any desired computer programming language. For example, such computer program code, when instructions are executed by one or more processors, may perform one or more of the methods described herein.

[0073] According to another independent aspect of the present disclosure, a radiotherapy device is provided, the device including one or more processors and a memory (e.g., a machine-readable medium as described above) coupled to the one or more processors and including instructions executable by the one or more processors to perform a method of operating a radiotherapy device according to an embodiment of the present disclosure.

[0074] So that the above-mentioned features of the present disclosure can be understood in detail, a more particular description of the present disclosure briefly summarized above can be had by reference to embodiments, the accompanying drawings of which relate to embodiments of the present disclosure and which are described below. [Brief description of the drawings]

[0075] [Figure 1] The X-ray dose distribution is shown on the left, and the proton dose distribution is shown on the right. [Diagram 2] 1 shows the target volume used in radiation therapy. [Figure 3A] Dose distributions of two SFUD proton beams covering the target volume are shown. [Figure 3B] Dose distributions of two IMPT proton beams covering the target volume are shown. [Figure 4] Full IMPT irradiation of the target and adapted batch-based irradiation of the target are shown. [Diagram 5] 1 illustrates a stitching geometry according to an embodiment of the present disclosure. [Figure 6] 13 illustrates a vertical dose profile for providing a stitching geometry according to an embodiment of the present disclosure. [Figure 7] 1 illustrates various stitching geometries according to embodiments of the present disclosure. [Figure 8] 1 illustrates a radiation therapy device according to an embodiment of the present disclosure. [Figure 9] 1 illustrates a target volume irradiated using a radiation therapy device according to an embodiment of the present disclosure. [Figure 10] 1 shows the workflow of a FLASH treatment plan where dose and dose rate are sequentially optimized. [Figure 11] 1 shows the workflow of FLASH treatment planning when dose and dose rate are simultaneously optimized. [Figure 12] 1 shows a flowchart of a method of operating a radiation therapy device according to an embodiment of the present disclosure. [Figure 13]13 illustrates dose distributions provided by IMRT and SFUD beams covering a target volume according to a further embodiment of the present disclosure. [Figure 14] FIG. 14 shows the total dose of the IMRT and SFUD beams. [Figure 15] 14 shows the vertical dose profiles of the IMRT and SFUD beams of FIG. 13. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0076] Reference will now be made in detail to various embodiments of the present disclosure, one or more examples of which are illustrated in the figures. In the following description of the drawings, like reference numerals refer to like components. Generally, only the differences with respect to individual embodiments will be described. Each example is provided to illustrate the present disclosure, and not to limit it. Furthermore, features illustrated or described as part of one embodiment may be used in other embodiments or in combination with other embodiments to produce yet another embodiment. It is intended that this specification include such modifications and variations.

[0077] Radiation therapy has been used as a means of cancer treatment for over 100 years. It involves the application of ionizing radiation to tumors, damaging and ultimately killing tumor cells. Different radiation sources can be used for external radiation therapy. For example, X-rays can be used as the radiation source, but also charged particles such as protons and electrons can be used for radiation therapy. Charged particles interact with tissues in a different way than photons, resulting in a more localized dose deposition profile in the tissue depending on the incident energy. This is illustrated in Figure 1, where the dose distribution of X-rays is shown on the left and the dose distribution of protons on the right. Thus, by adjusting the energy of the charged particle beam, tumors can be targeted at different locations.

[0078] In the following description, the concept of dose is used. Dose is defined as the energy (joule) irradiated per unit mass (kilogram) and is expressed in units of gray (Gy). The gray is used as a unit of radiation dose that measures the energy deposited by ionizing radiation per unit mass of irradiated material, and is used to measure the administered dose of ionizing radiation therapy. In many cases, treatment is performed based on the total dose to be irradiated to the tumor site (sometimes referring to the maximum dose that can be irradiated to the surrounding healthy sites).

[0079] Figure 2 shows a volume of interest used in radiation therapy. For example, when images of the patient's anatomy are available, volumes of interest are defined that are relevant to the treatment, in particular the Organs At Risk (OAR).

[0080] The volume of interest may include or be the target volume TV, which is usually represented by four main volumes: gross tumor volume (GTV), clinical target volume (CTV), internal tumor volume (ITV), and planning target volume (PTV).

[0081] The gross tumor volume (GTV) refers to the volume identified by a physician looking at an algorithm analyzing volumetric images or CT data, etc.

[0082] The clinical target volume (CTV) consists of the GTV plus an extra margin, which is defined based on the probability level that the surrounding tissue is still considered malignant.

[0083] The internal tumor volume (ITV) consists of the CTV plus an additional margin to account for physiological variations in the CTV (eg, size and shape).

[0084] The planning target volume (PTV) is a critical volume in radiation therapy planning. Additional margins around the CTV that define the PTV allow for dose delivery uncertainties; these margins ensure that the correct dose is delivered to the CTV, regardless of possible variations (whether due to natural variations in the patient's anatomy or machine-related uncertainties) to which radiation therapy is susceptible.

[0085] In addition to the target volume TV, other volumes of interest may be identified, such as at least one organ at risk (OAR). These volumes may include healthy organs that are sensitive to radiation and therefore should be taken into account in the treatment plan. In these regions, the radiation dose should be minimized or only to a certain value. Additional margins may also be defined around the OAR to allow for uncertainties during the procedure.

[0086] When determining the volume of interest, a plan is made to achieve a balance between achieving the desired dose in the target volume (TV=PTV) and minimizing the dose to which the specified OARs are exposed.

[0087] External beam radiation therapy

[0088] Generally, two types of radiation may be used in external radiation therapy: electromagnetic radiation (e.g., X-rays) and charged particles (e.g., protons, ions, electrons). The charged particles interact with tissue in a different manner than electromagnetic radiation. As shown in Figure 1, photons exhibit a dose deposition profile that changes very slowly in tissue, whereas the dose deposition profile of protons exhibits a rapid increase in dose deposition at a particular depth point or depth region, thereby resulting in a maximum accumulated dose at that depth point (single Bragg peak) or depth region (diffuse Bragg peak, SOBP). As a result, different radiation involvements are directly linked to different clinical outcomes.

[0089] FLASH radiotherapy

[0090] FLASH radiotherapy (FLASH-RT) is a subtype of external radiation therapy that uses ultra-high dose-rate charged particle beams. FLASH radiotherapy is associated with reduced radiation-induced toxic effects while maintaining a similar response to tumor tissue.

[0091] FLASH-RT uses ultrafast delivery with dose rates several orders of magnitude higher than those used in conventional radiotherapy (e.g., 35-100 Gy / sec compared to 1-4 Gy / min). Thus, FLASH-RT does not pose any problems related to organ movement, since the time the tissue is irradiated is short, typically less than 0.1 seconds. Furthermore, several studies have shown that the high dose rate can reduce the toxicity induced directly by radiation in normal tissues, while maintaining an equally effective response in tumor tissues. This is the so-called "FLASH effect".

[0092] One of the best-known hypotheses to explain the FLASH effect is based on oxygen depletion. Oxygen is a molecule considered a radiosensitizer, which, due to its large electron affinity, contributes to converting radiation-induced damage that can still be repaired by cellular mechanisms into permanent damage in DNA. According to the oxygen depletion hypothesis, when tissues are irradiated with very high doses of radiation, such as in FLASH-RT, oxygen is removed from the cells much faster than it can return to the cells by diffusion processes in healthy tissue, creating a state of intracellular hypoxia, thereby eliminating the radiosensitizing effect of oxygen. Furthermore, the lack of oxygen in the cells reduces the formation of reactive oxygen species during the irradiation process, weakening their potential toxic effects on cells.

[0093] However, the oxygen depletion hypothesis alone cannot explain the FLASH effect, and further research is currently being conducted to elucidate the mechanisms that cause or contribute to the FLASH effect.

[0094] FLASH-RT uses a beam of charged particles to irradiate the tumor, which can be protons, electrons, or ions.

[0095] The type of charged particle used in radiation therapy can be selected based on various factors such as the type of tumor, its location within the patient's body, accessibility of the procedure, etc. For example, the energy range of electron beams commonly used in radiation therapy can only irradiate superficial regions, whereas protons or ions can be used to treat tumors located deeper within the patient's body.

[0096] The charged particles may be provided by a particle accelerator, which uses electromagnetic fields to steer the charged particles to a desired energy and maintain them in a well-defined charged particle beam. For example, a linear accelerator, cyclotron, or synchrotron may be used to generate proton and / or ion beams for FLASH-RT.

[0097] In one preferred embodiment, the particle accelerator is configured to generate a SOBP (Spread-Out Bragg Peak) FLASH dose, which can be generated by varying the energy of a charged particle beam, using different energies with appropriate weighting to generate a flat and uniform SOBP.

[0098] Charged Particle Irradiation Technology

[0099] The shape of the charged particle beam can be adjusted before it is delivered to the tumor. Beam shaping can be achieved by any suitable means, such as a "nozzle" placed at the exit of the radiation source. There are two main charged particle irradiation techniques that can be used: Passive Scattering (PS) and Pencil Beam Scanning (PBS) (or simply Pencil Beam).

[0100] In Passive Scattering (PS), at least one scattering device may be arranged to spread the charged particle beam laterally, and a range modulation device configured to modulate the charged particle beam longitudinally may be arranged after the at least one scattering device.

[0101] Pencil Beam Scanning (PBS) uses a magnetic field to deflect a charged particle beam with the Lorentz force and scan the charged particle beam over a specific area. PBS allows for more flexible beam shaping than PS, reducing unnecessary radiation exposure to surrounding non-cancerous cells. In addition, it does not require a physical scattering device like PS, allowing for more efficient proton irradiation.

[0102] PBS is particularly useful for FLASH-RT, however the disclosure is not so limited and PBS may be used with other radiation therapy techniques. Similarly, techniques other than PBS may be used with FLASH-RT.

[0103] Radiation Optimization Techniques: SFUD and IMPT

[0104] The intensity of the charged particle beams is individually modulated to obtain the desired total dose distribution of the charged particle beam in the target or target volume. In particular, when using pencil protons, two optimization methods are considered: Single Field Uniform Dose (SFUD) and Intensity Modulated Proton Therapy (IMPT).

[0105] In the SFUD process, each individual proton beam is optimized to achieve an essentially uniform dose for that particular proton beam across at least a portion of the target or target volume having a tumor therein. It is noted that multiple proton beams are often used for more specific target irradiation. In this case, each proton beam of the two or more proton beams is optimized to achieve an essentially uniform distribution.

[0106] For example, FIG. 3A shows the dose distribution for two proton beams covering a target volume (indicated by the larger circle in the center of each dose map). The smaller circle indicates the OAR. FIG. 3A(a) shows a first proton beam (gantry angle 90°) with an essentially uniform dose distribution, FIG. 3A(b) shows a second proton beam (gantry angle 270°) with an essentially uniform dose distribution, and FIG. 3A(c) shows both proton beams covering the target volume and delivering a total dose of, for example, 14 Gy to the tumor site.

[0107] In IMPT, each proton beam does not need to have a uniform dose distribution as in the SFUD approach. In other words, in IMPT, each proton beam can have a non-uniform dose distribution in at least a portion of the target or target volume. However, the weights of the individual proton beams can be optimized such that the overall dose distribution in at least a portion of the target or target volume is essentially uniform, regardless of the dose distribution of the individual proton beams.

[0108] FIG. 3B shows the dose distribution of two intensity-modulated proton beams covering the target volume (indicated by the larger circle in the center of each dose map). The smaller circle indicates the OAR. FIG. 3B(a) shows a first proton beam (gantry angle 90°) with a non-uniform or modulated dose distribution, FIG. 3B(b) shows a second proton beam (gantry angle 270°) with a non-uniform or modulated dose distribution, and FIG. 3A(c) shows that both proton beams cover the target volume and deliver a total dose of, for example, 14 Gy to the tumor site.

[0109] Compared to SFUD, IMPT allows for more flexible beam modulation since each pencil proton beam is individually optimized, resulting in IMPT being able to protect more critical structures that may be in the beam path, such as OARs, without significantly affecting the treatment dose at the tumor.

[0110] Multibeam FLASH radiotherapy: geometry

[0111] In multifield IMPT, overlapping areas of different beams are not an issue because the contribution from each beam is modulated so that the total dose delivered to the target is equal to the therapeutic dose. However, in FLASH radiotherapy, there is a minimum dose and dose rate that must be deposited in critical healthy structures to be protected by the FLASH effect. Thus, if all beams penetrate healthy structures, each beam delivers at least the same minimum dose to the target. As a result, areas where the three beams overlap at the target will result in a larger excess dose.

[0112] As shown in Fig. 4(a), if 10 Gy is considered as the minimum dose for the FLASH effect, the total dose will be at least 30 Gy = 3 × 10 Gy when three beams are irradiated under FLASH conditions. This total dose exceeds the total dose that can be delivered to tissues at a given irradiation rate, as it may cause significant toxic effects. Therefore, this geometry needs to be modified to achieve the FLASH minimum dose while avoiding extreme toxic effects to the patient.

[0113] One solution is to adapt the patch-based geometry of the target area, where each beam is responsible for irradiating a specific patch of the target, as shown in Fig. 4(b). In the adapted patch-based geometry, each beam is irradiated with 10 Gy per pulse, but there are no overlapping areas, which prevents over-irradiation of the target area.

[0114] Beams for the adapted patch-based geometry can be generated, for example, using a 3D range modulator such as the 3D range modulator described in Weber et al. (FLASH radiotherapy with carbon ion beams. Med Phys. 2021;00:1-19. https: / / doi.org / 10.1002 / mp.15135).

[0115] However, the adapted patch-based geometry creates only a limited number of patches that match the total number of beams, and does not create coincidence lines between the patches. Therefore, the adapted patch-based target irradiation only partially covers the tumor, which impairs effective control. To address this problem, the inventors have developed a novel geometry for irradiating the tumor. Hereinafter, this novel geometry is called "stitching geometry".

[0116] FIG. 5 illustrates a stitching geometry according to an embodiment of the present disclosure.

[0117] According to an embodiment of the present disclosure, the stitching geometry is obtained by generating one or more ultra-high dose rate charged particle beams (e.g., SFUD FLASH proton beams), such that each ultra-high dose rate charged particle beam provides a substantially uniform first dose distribution in a corresponding first region of a target region; generating one or more intensity modulated beams (e.g., IMPT beams), such that one or more intensity modulated beams provide a substantially uniform second dose distribution in a second region of the target region that is different from the first region; and irradiating the one or more ultra-high dose rate charged particle beams and the one or more intensity modulated beams to provide a substantially uniform total dose distribution across the first region and the second region.

[0118] Therefore, the ultra-high dose rate charged particle beam can be modulated to obtain the FLASH effect at the OAR while avoiding overdose scenarios.

[0119] In some embodiments, the ultra-high dose rate charged particle beam can be a scattered beam generated using a ridge filter. Thus, when irradiating a tumor, each FLASH beam can be considered as a scattered beam that irradiates the area of ​​the tumor. The FLASH beam must deposit a minimum dose and dose rate in the organ to be protected.

[0120] In addition to the initial FLASH illumination of the adapted patch geometry, for example in FIG. 4(b), one or more intensity-modulated beams are used to illuminate the remaining volume of the target area. For this purpose, an optimized stitching geometry is used to integrate the different illumination areas. In particular, the one or more intensity-modulated beams provide a completely uniform coverage of the target and prevent the formation of cold spots. That is, the one or more intensity-modulated beams "stitch" the FLASH area.

[0121] In the exemplary stitching geometry of Figure 5, a single OAR is considered, and thus a single SFUD / FLASH region is considered. The target region TV (e.g., the PTV shown in Figure 2) is divided into a single SFUD / FLASH region, an interface region, and an IMPT region.

[0122] In particular, the SFUD / FLASH region is first covered with a uniform dose distribution. The beam may be directed toward an OAR that is close to the target and should be avoided. The uniform dose distribution may be modeled based on the distal end of the target, so that the shape of the SFUD / FLASH region is idealized as a "projection" of the OAR onto the target. As a result, the OAR can be completely covered with the FLASH beam while avoiding the appearance of edges on the beam that are more difficult to modulate.

[0123] The IMPT region is the volume of the target region TV that is irradiated only by the IMPT beam.

[0124] The interface region between the SFUD / FLASH region and the IMPT region is the coincidence line of the two exposures and is subject to dose fluctuations, which may cause hot spots in this region, and therefore the dose delivered to this region by the IMPT beam needs to be carefully evaluated.

[0125] In addition to the target, one or more (e.g., spherical) OARs may be located around the target. Since the OARs should be spared by the FLASH effect, each FLASH beam penetrates a corresponding OAR. As a result, the number of FLASH beams considered for a given treatment plan corresponds to the number of OARs located around the target. In the example shown in FIG. 5, since only one OAR is located around the target, only one FLASH beam is used in the treatment.

[0126] Figure 6 shows a vertical dose profile to result in the stitching geometry of Figure 5 according to an embodiment of the present disclosure. In the example of Figure 6, a FLASH minimum dose of 10 Gy was considered. The dashed horizontal line at 15 Gy represents the treatment dose prescription.

[0127] As can be seen, the FLASH radiation provides a FLASH minimum dose of 10 Gy in the OAR and provides a substantially uniform dose distribution in a first region of the target. The IMPT radiation does not contribute to the dose deposited in the OAR, but provides a substantially uniform dose distribution in a second region of the target that is different from said first region. In particular, the IMPT radiation locally "fills up" the dose previously provided by the FLASH radiation. In short, the FLASH radiation and the IMPT radiation provide a substantially uniform total dose distribution in the target region.

[0128] FIG. 7 illustrates various stitching geometries according to embodiments of the present disclosure.

[0129] Fig. 7(a) shows a stitching geometry with one OAR at the target and one corresponding FLASH beam. Fig. 7(b) shows a stitching geometry with two OARs at the target and two corresponding FLASH beams. Fig. 7(c) shows a stitching geometry with three OARs at the target and three corresponding FLASH beams. Fig. 7(d) shows a stitching geometry with four OARs at the target and four corresponding FLASH beams.

[0130] In these figures, the central sphere is the target volume to be irradiated. The target volume is divided into different regions of stitching geometry, namely, SFUD / FLASH region (red), interface region (purple), and IMPT region (pink). Furthermore, different spherical OARs are placed in the same orientation as the SFUD / FLASH region (yellow).

[0131] The exemplary stitching geometries in Fig. 7 were implemented in the matRad open source dose calculation tool in a box-shaped water phantom, considering a computed tomography (CT) grid with a resolution of 0 mm in the x, y and z directions, respectively. All SFUD / FLASH beams were delivered with a treatment couch angle of 0°, and only the antipodal gantry angle was considered. The four stitch-based geometries implemented in matRad and the respective gantry angles are shown separately in Fig. 7.

[0132] Radiation therapy equipment

[0133] Fig. 8 shows an apparatus for radiation therapy according to an embodiment of the present disclosure, in particular a FLASH radiation therapy apparatus 800. Fig. 9 shows a target volume TV irradiated using the radiation therapy apparatus 800 of Fig. 8.

[0134] The apparatus 800 includes at least one first radiation source 810 configured to provide or emit one or more ultra-high dose rate charged particle beams 812 and at least one second radiation source 820 configured to provide or emit one or more intensity-modulated beams 822.

[0135] The at least one first radiation source 810 is a charged particle source configured to emit the one or more very high dose rate charged particle beams 812. The one or more very high dose rate charged particle beams 812 may be Single Field Uniform Dose (SFUD) beams. In some embodiments, the charged particles are protons, ions, or electrons. In one preferred embodiment, the charged particles are protons.

[0136] The at least one second radiation source 820 is configured to provide one or more intensity-modulated beams 822, which may be photon beams (e.g., X-rays), proton beams, electron beams, or ion beams. In one preferred embodiment, the one or more intensity-modulated beams 822 are proton beams. In particular, the one or more intensity-modulated beams 822 may be intensity-modulated proton therapy (IMPT) beams.

[0137] The apparatus 800 further includes a controller 830 configured to control the at least one first radiation source 810 and the at least one second radiation source 820 .

[0138] In Fig. 9, the target region TV (e.g., planning target volume, PTV) is shown diagrammatically. The spherical shape of the target region TV is for simplification, and the target region TV, especially the PTV, may have any other shape depending on the situation in radiation therapy.

[0139] As an example, two volumes of interest are shown adjacent to the target area TV and spatially separated from the target area TV. The two volumes of interest include a first organ at risk OAR1 and a second organ at risk OAR2. The spherical shape of the volumes of interest is for simplicity, and the volumes of interest, especially the organs at risk, may have other shapes, for example depending on the physiology of the patient. It should be further understood that said volumes of interest may be one or more than two.

[0140] The controller 830 may be configured to control the at least one first radiation source 810 to generate the one or more ultra-high dose rate charged particle beams 812 such that each ultra-high dose rate charged particle beam of the one or more ultra-high dose rate charged particle beams 812 provides a substantially uniform first dose distribution in a corresponding first region of a target region TV (e.g., a planning target volume, PTV).

[0141] In the example of Fig. 9, the first very high dose rate charged particle beam 812a provides a substantially uniform first dose distribution in a corresponding first region R1a of the target region TV, and the second very high dose rate charged particle beam 812b provides a substantially uniform first dose distribution in another corresponding first region R1b of the target region TV.

[0142] When multiple ultra-high dose rate charged particle beams are used in radiation therapy, a corresponding number of first regions can be defined. In other words, the number of ultra-high dose rate charged particle beams and the number of first regions can be the same. The first regions can be separate from each other, i.e., the first regions can not overlap.

[0143] The controller 830 may be configured to control the at least one first radiation source 810 such that each very high dose rate charged particle beam passes through a respective volume of interest. In a preferred embodiment, the number of very high dose rate charged particle beams, and thus the number of first regions, may be selected to correspond to the number of volumes of interest determined, for example, by a medical professional, such as a physician, or by an algorithm.

[0144] 9, the first very-high-dose-rate charged particle beam 812a passes through a first risk organ OAR1, and the second very-high-dose-rate charged particle beam 812b passes through a second risk organ OAR2, thereby providing a protective effect, particularly a FLASH effect, in the first risk organ OAR1 and the second risk organ OAR2.

[0145] In particular, one or more ultra-high dose rate charged particle beams 812 provide a dose high enough to minimize toxic effects in one or more volumes of interest, such as Organs At Risk, during radiation therapy. In some embodiments, the one or more ultra-high dose rate charged particle beams 812 may provide a dose high enough to produce a FLASH effect in the one or more volumes of interest. Thus, in some embodiments, the one or more ultra-high dose rate charged particle beams 812 may be referred to as a "FLASH beam." Constraints on the FLASH effect may include a minimum dose of 10 Gy in the one or more volumes of interest, and a minimum dose rate of 40 Gy / s in the one or more volumes of interest.

[0146] The controller 830 may be configured to control at least one second radiation source 820 to generate one or more intensity-modulated beams 822, such as IMPT beams, so that the one or more intensity-modulated beams 822 provide a substantially uniform second dose distribution in a second region R2 of the target region TV that is different from the first region.

[0147] Thus, the one or more intensity-modulated beams 822 provide complete uniform coverage of the target volume TV and prevent the formation of cold spots. In particular, the one or more intensity-modulated beams 822 can "stitch together" a first (e.g., FLASH) area or "make up" areas of the target volume TV that are not covered by the very high dose rate charged particle beam (e.g., FLASH beam).

[0148] The interface region IR is located between the first and second regions, is the coincidence line between the two irradiations, and may be subject to dose variations. These variations may cause the occurrence of hot spots in this region. Therefore, the dose delivered to this region by the one or more intensity-modulated beams 822 should be carefully evaluated.

[0149] The number of intensity-modulated beams 822 can be selected such that the areas of the target volume TV that are not covered by the very high dose rate charged particle beam are well, preferably completely, covered. In the example of Fig. 9, three intensity-modulated beams 822a, 822b and 822c are shown. However, one, two or more than three intensity-modulated beams can be used.

[0150] When multiple intensity-modulated beams are used, these beams may be adapted to jointly cover the entire second region R2. In particular, the second region R2 may have multiple sub-regions, each of the multiple intensity-modulated beams being adapted to irradiate a respective sub-region. Thus, the number of sub-regions of the second region R2 may correspond to the number of intensity-modulated beams. Since the beams are intensity-modulated, the sub-regions of the second region R2 may at least partially overlap, so that the doses provided by the multiple intensity-modulated beams complement each other to provide a substantially uniform second dose distribution throughout the second region R2.

[0151] Preferably, the controller 830 is further configured to control the at least one second radiation source 820 such that the one or more intensity-modulated beams 822 do not pass through a volume of interest, such as an OAR, so that a volume of interest can be protected.

[0152] In some embodiments, the one or more ultra-high dose rate charged particle beams 812 and the one or more intensity-modulated beams 822 are generated sequentially. For example, the one or more ultra-high dose rate charged particle beams 812 and the one or more intensity-modulated beams 822 can be pulsed beams that are intermittently generated and emitted.

[0153] According to some embodiments, which may be combined with other embodiments herein, the controller 830 is further configured to control the at least one first radiation source 810 and the at least one second radiation source 820 to provide a substantially uniform total dose distribution across the first region and the second region, such that the same dose may be provided to the first region and the second region.

[0154] Dose and dose rate calculations

[0155] The one or more ultra-high dose rate charged particle beams and the one or more intensity modulated beams are interdependent, i.e., the one or more ultra-high dose rate charged particle beams and the one or more intensity modulated beams, in particular the doses and dose rates provided by them, cannot be considered independent of each other. Therefore, a process for determining the dose and dose rate for a given target volume is required.

[0156] Two exemplary processes for determining the dose and dose rate for a treatment are described below with respect to Figures 10 and 11. However, the disclosure is not limited thereto and other processes capable of providing a substantially uniform dose distribution at a target such as the PTV may be used.

[0157] FIG. 10 shows the workflow of FLASH treatment planning where dose and dose rate are sequentially optimized.

[0158] First, the target volume is segmented for stitching. An example of a segmented target volume is shown in Figure 2. Then, two steps are performed sequentially: dose optimization and dose rate optimization.

[0159] Dose optimization

[0160] The fluence of the various FLASH beams is first optimized based only on the imposed dose constraints. Thus, the focus is on achieving the total treatment dose and verifying the minimum FLASH dose in the healthy structures to be protected (OARs). In this optimization strategy, no dose target is predefined for the entire PTV. Instead, different dose targets are defined for different regions of the stitching geometry during planning.

[0161] First, the dose deposited by the FLASH beams is examined. In the exemplary stitching geometry, these beams always pass through the OAR to be protected by the FLASH effect before irradiating the target area. As a result, the optimization of these beams is focused on achieving a minimum dose, for example 10 Gy, in the area to be protected. Each FLASH beam irradiates only the FLASH area, which is part of the target. Therefore, it is only this area that has a dose target assigned for this radiation. This dose target assignment is determined by trial and error until the resulting dose distribution meets the required minimum dose in the FLASH area.

[0162] The dose delivered by the intensity modulated beam is then optimized with the aim of providing the missing dose for the entire treatment prescription. Therefore, the dose originally delivered by the FLASH beam must be taken into account. The intensity modulated beam is delivered to each region of the PTV, which receives more or less dose depending on whether the region was previously irradiated by the FLASH beam. Therefore, a separate dose target must be defined for each irradiated region of the stitching geometry. As with the FLASH irradiation, different combinations of dose targets are tested until a suitable uniform dose accumulation is obtained.

[0163] At the end of such dose optimization, an optimal set of fluences and intensities can be determined for both the FLASH beam and the intensity modulated beam.

[0164] Dose rate optimization

[0165] The intensities of the FLASH beams are optimized with a focus on achieving the minimum FLASH dose rate at the OARs. Since this dose rate constraint only affects the FLASH beams, the optimization of the intensities of these beams must be done more carefully.

[0166] Prior to optimizing the intensity of the FLASH beams, each FLASH beam can be collapsed into a single scattered pencil beam. This step does not change the dose deposition of the beam, but considering a monoenergetic scattered beam for the FLASH exposure also reduces the inherent variability associated with the dose average dose rate.

[0167] Since each FLASH beam is a single pencil beam, the minimum intensity at which this beam must be delivered to deposit a minimum of 40 Gy / s in the OAR can be calculated from the following formula:

[0168]

number

[0169] In the formula, I beam a is the calculated intensity for beam a, and d' ia is the influence matrix calculated after collapsing the same beam, where i considers the voxel for which the OAR is defined.

[0170] If no constraints are set on the dose rate at which a particular beam must be delivered, this beam is assumed to be delivered at a default intensity. Thus, the intensity of the intensity-modulated beam is automatically set to a constant value. In one example, this value is 2·10 10 It can be set to protons / second, which is the maximum beam intensity that can be generated at the Heidelberg Ion Beam Therapy Center (HIT) facility.

[0171] FIG. 11 shows the workflow of FLASH treatment planning when dose and dose rate are optimized simultaneously.

[0172] First, the target volume is segmented for stitching. An example of a segmented target volume is shown in Figure 2. Then, two steps are performed simultaneously: dose optimization and dose rate optimization.

[0173] First, the geometries of the FLASH beam and the intensity modulated beam are generated as a function of the treatment plan parameters, and both dose impact matrices are calculated in parallel. The generated FLASH impact matrix is ​​then sequentially adjusted to a collapsed form to simulate the scattered beam.

[0174] Finally, both the collapsed FLASH influence matrix and the influence matrix generated for the intensity modulated irradiation are combined into a total dij that is given as input to the optimizer. The generated influence matrix has a total of n+m columns, where the first n columns represent the n FLASH beams included in the treatment, and the next m columns represent all beams other than the FLASH beam.

[0175] In this optimization strategy, only the treatment dose is defined as the target dose in the PTV, which differs from sequential dose and dose rate optimization, where different target doses exist in different regions depending on the type of irradiation. The beam fluence and intensity are optimized with the goal of minimizing an objective function that considers both dose and dose rate constraints. Two examples of this joint optimization strategy are shown below.

[0176] 1. Partial optimization with separate optimization of FLASH and non-FLASH beams. In this embodiment, the fluence and intensity of the FLASH beam are optimized first, focusing on achieving a minimum dose and average dose rate of 10 Gy and 40 Gy / s at the OAR, respectively. Once this first optimization step is completed, the optimized variables are used as input for the optimization of the intensity-modulated beam. In this way, the dose already accumulated after FLASH exposure is also taken into account in the fluence optimization of the intensity-modulated beam, avoiding over-dose scenarios.

[0177] 2. Full pencil beam optimization where both the FLASH fluence and intensity and the intensity modulated beam fluence and intensity are optimized simultaneously. This represents a more automated optimization approach where both the required FLASH conditions and the full treatment prescription are optimized within the same cycle.

[0178] 12 shows a flow chart of a method 1200 of operating an apparatus for radiation therapy according to an embodiment of the present disclosure. The apparatus may be the apparatus described with respect to FIGS.

[0179] The method 1200 includes, in block 1210, controlling at least one first radiation source to irradiate a target area with one or more ultra-high dose rate charged particle beams such that each ultra-high dose rate charged particle beam of the one or more ultra-high dose rate charged particle beams provides a substantially uniform first dose distribution in a corresponding first region of the target area; and, in block 1220, controlling at least one second radiation source to irradiate the target area with one or more intensity-modulated beams such that the one or more intensity-modulated beams provide a substantially uniform second dose distribution in a second region of the target area different from the first region.

[0180] The one or more intensity-modulated beams compensate for dose in areas of the target volume that are not (completely) covered by the one or more very high dose rate charged particle beams to provide a substantially uniform total dose distribution over the target area.

[0181] In some embodiments, the method 1200 further includes sequentially determining a dose and dose rate to the target volume by: determining a configuration (e.g., fluence and / or intensity) of the one or more ultra-high dose rate charged particle beams based on one or more dose constraints; determining a configuration (e.g., fluence and / or intensity) of the one or more intensity-modulated beams based on a dose deposited in the target volume by the one or more ultra-high dose rate charged particle beams; and optimizing the configuration (e.g., fluence and / or intensity) of the one or more ultra-high dose rate charged particle beams based on one or more dose rate constraints.

[0182] In a further embodiment, the method 1200 further includes simultaneously determining a dose and a dose rate for the target volume by: determining a first influence matrix for the one or more very high dose rate charged particle beams and a second influence matrix for the one or more intensity modulated beams; combining the first influence matrix and the second influence matrix to obtain a composite matrix; and optimizing the composite matrix to determine a configuration (e.g., fluence and / or intensity) of the one or more very high dose rate charged particle beams and a configuration (e.g., fluence and / or intensity) of the one or more intensity modulated beams. The optimization may be performed taking into account one or more dose constraints and one or more dose rate constraints in one or more volumes of interest (e.g., OARs).

[0183] The one or more dose constraints may include one or more FLASH constraints, such as a minimum dose to be deposited in one or more volumes of interest (e.g., OARs). For example, the minimum dose is 8 Gy, 10 Gy, or 12 Gy. Additionally or alternatively, the one or more dose rate constraints may include one or more FLASH dose rate constraints, such as a minimum dose rate provided to one or more volumes of interest (e.g., OARs). For example, the minimum dose rate may be 40 Gy / s.

[0184] According to the embodiments described herein, the method of operating a radiation therapy device may be implemented by computer programs, software, computer software products, and interrelated controllers, which may have a CPU, memory, a user interface, and input and output means for communicating with corresponding components of the radiation therapy device.

[0185] Figure 13 shows dose distributions resulting from IMRT and SFUD beams covering a target volume according to further embodiments of the present disclosure. Figure 14 shows the total dose of the IMRT and SFUD beams of Figure 13. Figure 15 shows the vertical dose profile of the IMRT and SFUD beams of Figure 13.

[0186] In the examples of Figures 13-15, the dose distribution of the one or more ultra-high dose rate charged particle beams (IMRT; Figure 13(a)) and the dose distribution of the one or more intensity modulated beams (SFUD; Figure 13(b)) spatially overlap and complement each other in a target region to provide a substantially uniform total dose distribution across the target region.

[0187] In particular, the dose distribution of one or more ultra-high dose rate charged particle beams across the target area is non-uniform and the dose distribution of one or more intensity-modulated beams across the target area is non-uniform, together providing a substantially uniform total dose distribution across the target area.

[0188] For example, as shown in Figure 15, the vertical dose profile of the one or more ultra-high dose rate charged particle beams and the vertical dose profile of the one or more intensity modulated beams at the at least one interface region may each have a slope to provide a non-uniform dose distribution across the target region. In some embodiments, the vertical dose profiles each have opposite slopes, such as an upslope and a downslope.

[0189] Thus, the one or more ultra-high dose rate charged particle beams and the one or more intensity modulated beams provide a completely uniform coverage of the target area and prevent the formation of cold spots. Furthermore, the beams have a non-uniform dose distribution, i.e., a wide dose range, over the target area, so that the irradiation is stable against target movement. In particular, a significant range of target movement does not affect the uniformity of the total dose distribution over the target area.

[0190] While the forgoing is directed to embodiments of the present disclosure, other and further embodiments of the present disclosure may be devised without departing from the basic scope thereof, which scope is determined by the following claims.

Claims

1. A radiation therapy device (800), comprising: at least one first radiation source (810) configured to provide one or more ultra-high dose rate charged particle beams (812); at least one second radiation source (820) configured to provide one or more intensity-modulated beams (822); A controller (830), controlling the at least one first radiation source (810) to generate the one or more ultra-high dose rate charged particle beams (812) and the at least one second radiation source (820) to generate the one or more intensity-modulated beams (822) such that the one or more ultra-high dose rate charged particle beams (812) and the one or more intensity-modulated beams (822) provide a substantially uniform total dose distribution over a target region (TV); and a controller configured to:

2. The controller (830) 2. The apparatus (800) of claim 1, further configured to control the at least one first radiation source (810) to generate the one or more ultra-high dose rate charged particle beams (812) and to control the at least one second radiation source (820) to generate the one or more intensity-modulated beams (822), such that a first dose distribution of the one or more ultra-high dose rate charged particle beams (812) and a second dose distribution of the one or more intensity-modulated beams (822) combine at the target region (TV) to provide the substantially uniform total dose distribution across the target region (TV).

3. The apparatus (800) of claim 2, configured to provide the substantially uniform total dose distribution across substantially the entire target region (TV).

4. The controller (830) controlling the at least one first radiation source (810) to generate the one or more ultra-high dose rate charged particle beams (812) such that each ultra-high dose rate charged particle beam of the one or more ultra-high dose rate charged particle beams (812) provides a substantially uniform first dose distribution in a corresponding first region (R1a, R1b) of the target region (TV); and 3. The apparatus (800) of claim 1 or 2, further configured to control the at least one second radiation source (820) to generate the one or more intensity-modulated beams (822) so that the one or more intensity-modulated beams (822) provide a substantially uniform second dose distribution in a second region (R2) of the target region (TV) that is different from the first regions (R1a, R1b).

5. The apparatus (800) of claim 4, wherein the first regions (R1a, R1b) and the second region (R2) do not overlap.

6. The target region (TV) comprises the first region (R1a, R1b), the second region (R2), and at least one interface region (IR) between the first region (R1a, R1b) and the second region (R2); 5. The apparatus (800) of claim 4.

7. The controller (830):

7. The apparatus (800) of claim 6, further configured to control the at least one first radiation source (810) to generate the one or more ultra-high dose rate charged particle beams (812) and to control the at least one second radiation source (820) to generate the one or more intensity-modulated beams (822), such that dose distributions of the one or more ultra-high dose rate charged particle beams (812) and the one or more intensity-modulated beams (822) spatially overlap and complement each other at the at least one interface region (IR) to provide the substantially uniform total dose distribution across the at least one interface region (IR).

8. The controller (830) 3. The apparatus (800) of claim 1 or 2, further configured to control the at least one first radiation source (810) to generate the one or more ultra-high dose rate charged particle beams (812) and to control the at least one second radiation source (820) to generate the one or more intensity-modulated beams (822), such that dose distributions of the one or more ultra-high dose rate charged particle beams (812) and the one or more intensity-modulated beams (822) spatially overlap and complement each other in the target region (TV) to provide the substantially uniform total dose distribution over the target region (TV).

9. the controller is further configured to control the at least one first radiation source (810) to generate the one or more ultra-high dose rate charged particle beams (812) such that the dose distribution of the one or more ultra-high dose rate charged particle beams (812) across the target region (TV) is non-uniform, and to control the at least one second radiation source (820) to generate the one or more intensity-modulated beams (822) such that the dose distribution of the one or more intensity-modulated beams (822) across the target region (TV) is non-uniform; 9. The apparatus (800) of claim 8, wherein the non-uniform dose distribution of the one or more ultra-high dose rate charged particle beams (812) and the non-uniform dose distribution of the one or more intensity-modulated beams (822) are complementary in the target region (TV) to provide the substantially uniform total dose distribution across the target region (TV).

10. the one or more ultra-high dose rate charged particle beams (812) are one or more FLASH beams; the one or more ultra-high dose rate charged particle beams (812) are one or more single field uniform dose (SFUD) beams; and / or 3. The apparatus (800) of claim 1 or 2, wherein the one or more ultra-high dose rate charged particle beams (812) are modulated to provide a minimum dose of 8 Gy, 10 Gy, or 12 Gy to one or more volumes of interest and to provide a minimum dose rate of 30 Gy / s, 40 Gy / s, or 50 Gy / s to the one or more volumes of interest (OAR1, OAR2).

11. The apparatus (800) of claim 10, wherein the one or more volumes of interest (OAR1, OAR2) are spatially separated from the target region (TV).

12. The apparatus (800) of claim 1 or 2, wherein the one or more ultra-high dose rate charged particle beams (812) are selected from the group consisting of a proton beam, an electron beam, and an ion beam.

13. The apparatus (800) of claim 1 or 2, wherein the one or more intensity-modulated beams (822) are selected from the group consisting of photon beams, proton beams, electron beams, and ion beams.

14. The apparatus (800) of claim 1 or 2, wherein the one or more intensity-modulated beams (822) are intensity-modulated proton therapy (IMPT) beams.

15. The apparatus (800) of claim 1 or 2, wherein the one or more ultra-high dose rate charged particle beams (812) and the one or more intensity-modulated beams (822) are pulsed beams that are intermittently generated and provided to the target region (TV).

16. The controller (830) controlling said at least one first radiation source (810) so that each ultra-high dose rate charged particle beam passes through a respective volume of interest (OAR1, OAR2); and / or The apparatus (800) of claim 1 or 2, configured to control the at least one second radiation source (820) so that the one or more intensity-modulated beams (822) do not pass through a volume of interest (OAR1, OAR2).

17. A machine-readable storage medium having stored thereon computer-executable instructions that, when executed, cause one or more processors to: controlling at least one first radiation source to irradiate the target area with one or more ultra-high dose rate charged particle beams (1210); and controlling at least one second radiation source to irradiate (1220) the target area with one or more intensity-modulated beams (822); wherein controlling the at least one first radiation source and controlling the at least one second radiation source are performed such that the one or more ultra-high dose rate charged particle beams (812) and the one or more intensity-modulated beams (822) provide a substantially uniform total dose distribution across the target region (TV).

18. 20. The machine-readable storage medium of claim 17 having stored thereon computer-executable instructions that, when executed, cause the one or more processors to perform the functions of the apparatus (800) of claim 1 or 2.

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