FLASH Radiation Therapy System and Method of Use

Abstract

1. A method for delivering a field of ionizing radiation to a target tissue, the method comprising: delivering ionizing radiation; shifting the range of the ionizing radiation by passing the ionizing radiation through an adjustable range shifter so that a Bragg peak of the ionizing radiation coincides with the target tissue; and compensating the range of the ionizing radiation by passing the ionizing radiation through an adjustable range compensator so that the Bragg peak of the ionizing radiation coincides with the target tissue, thereby forming at least two fields of shifted and compensated ionizing radiation; and directing the at least two fields of shifted and compensated ionizing radiation to the target tissue to provide a uniform dose distribution across the target volume.

Description

[Technical field]

[0001] FIELD OF THE DISCLOSURE The present disclosure relates generally to systems and methods for providing radiation therapy. [Background technology]

[0002] Radiotherapy is an important treatment for both curative and palliative treatment of cancer. However, radiotherapy is limited by radiation-induced toxicity. Preclinical studies have shown that irradiation at dose rates far exceeding those currently used in clinical practice reduces radiation-induced toxicity while maintaining comparable tumor responses; this is known as the FLASH effect. The mechanism that results in reduced tissue toxicity after FLASH radiotherapy (FLASH-RT) remains unclear, and multiple hypotheses have been proposed by linking high dose rates to rapid oxygen depletion, immune responses, shortened peroxyl radical lifetime, and preservation of normal tissue stem cells.

[0003] In recent years, there has been growing interest in using proton therapy to perform FLASH-RT translational research. A transmission / shoot-through beam has been proposed for FLASH proton therapy planning. Summary of the Invention [Means for solving the problem]

[0004] In a first embodiment, a method of delivering a field of ionizing radiation to a target tissue is provided, the method comprising the steps of delivering ionizing radiation; shifting a range of the ionizing radiation by passing the ionizing radiation through an adjustable range shifter such that a Bragg peak of the ionizing radiation coincides with the target tissue; and compensating a range of the ionizing radiation by passing the ionizing radiation through an adjustable range compensator such that a Bragg peak of the ionizing radiation coincides with the target tissue, thereby forming at least two fields of shifted and compensated ionizing radiation; and directing the at least two fields of shifted and compensated ionizing radiation to the target tissue to provide a uniform dose distribution across the target volume.

[0005] A first embodiment may include administration at a dose rate of at least 40 Gy / s. A first embodiment may include administration of shifted compensated ionizing radiation that does not extend substantially proximally beyond the distal end of the target site. This embodiment may include compensated ionizing radiation comprised of protons, helium, carbon, argon, or neon. This embodiment may include compensated ionizing radiation comprised of protons.

[0006] In some embodiments, the target site is cancerous tissue. In some embodiments, the range shifter includes multiple plates that shorten the range of the ionizing radiation, and the range shifter combination is calculated by applying parameters determined using an inverse treatment plan optimization protocol, the parameters including the number and location of plates through which the ionizing radiation penetrates. In some embodiments, the range compensator contour is calculated by applying parameters determined using an inverse treatment plan optimization protocol. In some embodiments, the inverse treatment plan optimization determines ionizing radiation distribution parameters and / or determines ionizing radiation weighting parameters. In some embodiments, the shifted compensated ionizing radiation includes three, four, or five fields of shifted compensated ionizing radiation.

[0007] Further embodiments may include a system for administering at least two shifted and compensated fields of ionizing radiation to a target tissue, the system including an ionizing radiation source configured to generate a charged particle beam, a universal range shifter adjusted to shift the range of the charged particle beam such that a Bragg peak of the charged particle beam coincides with the target tissue, and a range compensator adjusted to compensate the range of the charged particle beam such that a Bragg peak of the ionizing radiation coincides with a contour of the target tissue. This embodiment may include administering the fields at a dose rate of at least 40 Gy / s. In some embodiments, the radiation fields do not extend substantially proximally beyond the distal end of the target tissue. In embodiments, the target tissue includes a neoplasm or benign tumor. In some embodiments, the range shifter includes a plurality of plates that shorten the range of the ionizing radiation, and the combination of the range shifters is calculated by applying parameters determined using an inverse treatment plan optimization protocol, the parameters including the number and location of plates through which the ionizing radiation penetrates. In some embodiments, the range compensator contour is calculated by applying parameters determined using an inverse treatment plan optimization protocol. In some embodiments, the at least two fields of shifted compensated ionizing radiation include three fields, four fields, or five fields.

[0008] Further embodiments include a system for generating at least two shifted compensated particle beam fields at a dose rate of at least 40 Gy / s, the system including an ionizing radiation source configured to generate the particle beam, a universal range shifter configured to adjustably shift the range of the particle beam, and a range compensator configured to adjustably compensate the range of the particle beam. In some embodiments, the particle beam includes protons, helium, carbon, argon, or neon.

[0009] Another embodiment includes a method of treating a target tissue, comprising the steps of diagnosing the target tissue, mapping the target tissue, developing a radiotherapy treatment plan for administering an effective amount of shifted and compensated ionizing radiation to the target tissue, shifting and compensating the ionizing radiation using a system including a source of ionizing radiation configured to generate a particle beam, a universal range shifter adjusted to shift the range of a proton / particle beam such that a Bragg peak of the particle beam coincides with the target tissue, and a range compensator adjusted to compensate the range of the particle beam such that a Bragg peak of the particle beam coincides with a contour of the target tissue, and then administering the particle beam to the target tissue. In some embodiments, the particle beam is irradiated at a dose rate of at least 40 Gy / s. In some embodiments, the target tissue includes a neoplasm or benign tumor. In some embodiments, the particle beam does not extend substantially proximally beyond a distal end of the neoplasm or benign tumor. In embodiments where the range shifter includes multiple plates that shorten the range of the ionizing radiation, the arrangement of the range shifter plates is determined by applying parameters determined using an inverse treatment plan optimization protocol, the parameters including the number and location of the plates through which the ionizing radiation passes. In some embodiments, the shape of the range compensator is calculated by applying parameters determined using an inverse treatment plan optimization protocol. In some embodiments, the at least two fields of shifted compensated ionizing radiation include three fields, four fields, or five fields. In some embodiments, the particle beam includes protons, helium, carbon, argon, or neon.

[0010] Another embodiment includes a method of adjusting a proton therapy device, the method including receiving a treatment plan designed to apply FLASH-RT to a target site, the treatment plan including a target site, a three-dimensional target shape, a number of treatment fields, and a target dose rate of at least 40 Gy / s, and modifying the energy or range of the proton therapy device using a range shifter and a range compensator, the range shifter including a plurality of plates that shorten the range of the ionizing radiation, the modifying step including using an inverse treatment planning protocol to determine parameters of the range shifter and range compensator such that a Bragg peak of the energy output of the proton therapy device coincides with the target tissue, the parameters including the number and location of plates through which the energy or range of the proton therapy device penetrates. In some embodiments, the energy output of the proton therapy device does not extend substantially in a proximal direction beyond the distal end of the cancerous tissue.

[0011] Further embodiments include a universal range shifter that includes six polycarbonate plastic plates and can generate range-shifted ionizing radiation by decreasing the range of the ionizing radiation between 0 cm and 34 cm in 1 cm increments. In some embodiments, the ionizing radiation includes protons, helium, carbon, argon, or neon. In some embodiments, the thicknesses of the six polycarbonate plastic plates are 1, 2, 3, 7, 7, and 14 cm WET.

[0012] Further embodiments include a radiation therapy treatment device that includes a universal range shifter that includes six polycarbonate plastic plates and that can generate range-shifted ionizing radiation by decreasing the range of the ionizing radiation between 0 cm and 34 cm in 1 cm increments. In some embodiments, the ionizing radiation includes protons or other ions. In one embodiment, the thicknesses of the six polycarbonate plastic plates are 1, 2, 3, 7, 7, and 14 cm WET.

[0013] Further embodiments include a method of decreasing the range of ionizing radiation between 0 cm and 34 cm in 1 cm increments, the method including passing the ionizing radiation through a universal range shifter comprising six polycarbonate plastic plates. In some embodiments, the ionizing radiation includes protons, helium, carbon, argon, or neon. In some embodiments, the six polycarbonate plastic plates have thicknesses of 1, 2, 3, 7, 7, and 14 cm WET.

[0014] Another embodiment includes a method of treating cancerous tissue comprising providing a penetrating beam of ionizing radiation having a dose rate of at least 40 Gy / s, adjusting the energy or range of the penetrating beam of ionizing radiation so that the Bragg peak of the beam coincides with a point between 3 mm and 5 mm away from an edge of the cancerous tissue, and irradiating the cancerous tissue with the penetrating beam of ionizing radiation. In one embodiment, the penetrating beam of ionizing radiation comprises protons, helium, carbon, argon, or neon. [Brief description of the drawings]

[0015] [Figure 1] 1 shows a schematic diagram of an opaque FLASH intensity-modulated particle therapy (IMPT) plan using universal range shifters (URS) and range compensators (RC). The URS and RC are placed in the beam path for illustrative purposes only, and they can be placed in various orders depending on the treatment goal. [Diagram 2] FIG. 2 shows that an example of spot distribution and weight optimization can effectively improve the plan quality and FLASH-RT dose rate distribution. [Figure 3A]FIG. 3A shows the Bragg peak plans ((b) and (e)) versus the transmission plans ((a) and (d)) using a 250 MeV proton beam for a C-shaped target in a water phantom. [Figure 3B] FIG. 3B shows the Bragg peak plans ((b) and (e)) versus the transmission plans ((a) and (d)) using a 250 MeV proton beam for a C-shaped target in a water phantom. [Figure 4A] Figure 4A shows dose comparison between the transmission and Bragg peak plans for three selected lung patients using the same beam configuration. The right and center columns represent the transmission and Bragg peak plans, respectively. [Figure 4B] Figure 4B shows dose comparisons between the transmission and Bragg peak plans for three selected lung patients using the same beam configuration. The right and center columns represent the transmission and Bragg peak plans, respectively. [Figure 5A] FIG. 5A shows a comparison of dose rates between the transmission plan (left image) and the Bragg peak plan (middle image) using the same beam configuration. [Figure 5B] FIG. 5B shows a comparison of dose rates between the transmission plan (left image) and the Bragg peak plan (middle image) using the same beam configuration. [Figure 6] Top panel of Fig. 6: 2D dose rate distribution of a single spot (1000MU / spot) of 250MeV proton beam in the central axial plane evolving in a water phantom with voids of 5, 15, and 25cm, respectively; bottom panel: spot dose rate in the central axis (the three intervals represent 20cm movement in water, void, and remaining range in water). [Figure 7]Figure 7 shows an example illustrating the optimization of beam angles. (a) and (b) are 2D dose distributions using different fields and field angles, (c) and (d) are comparisons of DVH and dose rate volume histograms (DRVH), and (e) is the V40Gy / s dose rate coverage versus OAR dose from low to high dose regions. The left lung and most of the heart are completely spared by using the beam configuration shown by (b). [Figure 8] FIG. 8 shows an exemplary range compensator (RC). [Figure 9] FIG. 9 shows dosimetric comparison between Bragg peak plans and conventional IMPT plans for 10 liver cancer patients. (a) Liver-GTV Dmean, (b) Heart D0.5cc, (c) Chest wall D2cc, and (d) CTV Dmax for SBRT, Bragg-400MU, and Bragg-800MU. "ns" indicates that the results are not statistically significant (p≧0.05). Interquartile ranges (25th-75th percentiles) are indicated by the box edges, median values ​​are represented by the horizontal lines inside the box, and highest and lowest values ​​are indicated by the two lines outside the box. Diamond markers indicate data points beyond the 25th-75th percentiles. Liver treatment plan testing demonstrated that the novel single-energy PBS delivery method can achieve similar or comparable plan quality compared to conventional multi-energy proton PBS plans. [Figure 10] Table 1, shown in FIG. 10, shows a comparison of V40Gy / s dosimetry and dose rate coverage for transmission and Bragg peak IMPT plans for all six lung cases. RTOG 0915 metrics were used for dosimetry comparison. Both dose and dose rate statistics used average values ​​for all six cases. The last row of the table represents V40Gy / s averaged over both the target and OARs. [Figure 11]Table 2, shown in Figure 11, shows how the six range shifter plates of an exemplary URS can generate 34 different combinations to "pull back" or shorten the proton range from 0 cm to 34 cm in 1 cm steps, where a "1" represents the plate being moved into the beam path to pull back the range of the proton beam, and a "0" means that the plate is not being used to pull back the range. [Figure 12] Table 3 shown in Figure 12 shows the comparison of plan quality between Bragg peak plans and traditional IMPT plans for 10 lung cancer patients. The lung treatment plan test demonstrated that the new single-energy PBS delivery method can achieve similar or equivalent plan quality compared with traditional multi-energy proton PBS plans. p1, p-value of two-tailed Student's t-test between BP-1200MU-2ms and IMPT-SBRT plans; p2, p-value of two-tailed Student's t-test between BP-300MU-0.5ms and IMPT-SBRT plans. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] FLASH-RT improves patient outcomes, but requires dedicated hardware and expertise. Furthermore, current transmission / shoot-through plans do not utilize the Bragg peak for dose delivery, resulting in unnecessary radiation exposure to normal tissue distal to the target volume. In this disclosure, "distal" refers to further along the beam path, not "anatomically" distal.

[0017] The monoenergetic pencil beam scanning (PBS) delivery method disclosed herein can achieve similar or comparable plan quality compared to conventional multi-energy proton PBS plans. By eliminating the expensive energy selection and beam focusing systems, the proton therapy cost is significantly reduced, making PBS FLASH-RT more affordable for the general public. The use of monoenergetic layered proton beams from cyclotrons for conformal conventional dose rates / FLASH-RT may be a promising solution for future proton system designs.

[0018] In contrast to conventional methods, the disclosed embodiments include commercially available equipment that has been modified with additional components to take advantage of the Bragg peak, a prominent peak on the Bragg curve, which plots the energy loss of ionizing radiation as it travels through a material. For protons, alpha rays, and other ionizing rays, this peak occurs just before the particle comes to rest. It will be appreciated that the Bragg curves for these types of particles are qualitatively different from the Bragg curves for x-rays or other types of electromagnetic radiation.

[0019] The disclosed methods and systems include a FLASH-RT tumor treatment modality that utilizes an inverse optimization algorithm-based method that requires minimal hardware modifications to adapt currently available proton and other charged heavy particle (e.g., helium, carbon, argon, and neon) systems to utilize the Bragg peak region of the proton beam to treat tumors. The Bragg peak is a prominent peak on the Bragg curve, which plots the energy loss of ionizing radiation as it travels through matter.

[0020] Bragg peaks can be identified by using a graphical representation of the energy of a particular charged particle, such as a proton, where the energy lost by the particular charged particle is inversely proportional to the square of the velocity of the charged particle, so that the graphed peak occurs just before the particle comes to a complete stop. By correlating the Bragg peaks with the target tissue, the disclosed method and system avoids "exit doses" that are delivered far beyond the target tissue, thus sparing tissue adjacent to the target area. Bragg peaks can be calculated using commercially available software.

[0021] The disclosed system includes an adjustable universal range shifter (URS) that comprises a member, such as a plastic plate, that "pull back" or reduce the energy of the ionizing radiation beam, thereby shortening the range of the beam. By providing multiple "plates" of various thicknesses at discrete distances in the beam path, the disclosed system allows a user to accurately and reproducibly shorten the range of the beam to a target depth in tissue using ionizing radiation sources that would otherwise be unsuitable for FLASH-RT, which utilizes the Bragg peaks of the particles that make up the ionizing radiation.

[0022] The disclosed system includes a range compensator (RC) with a member that further modifies the range of the ionizing radiation beam, thereby adjusting the penetration depth of the beam and delivering conformal radiation to the target tissue. For example, the disclosed RC has a three-dimensional contour for fine-tuning the range of the range-shifted ionizing radiation (an exemplary RC is shown in FIG. 8). By providing range compensators of various thicknesses in the beam direction and laterally covering the target tissue with discrete proton spots scanned to determine the optimal three-dimensional shape, the disclosed system allows users to accurately and reproducibly adapt the beam to the distal target shape using ionizing radiation sources that would otherwise not be suitable for FLASH-RT using the Bragg peaks of the particles that make up the ionizing radiation. The RC can fine-tune the ionizing radiation before, during, or after the range of the ionizing radiation is shifted.

[0023] The disclosed method includes adjusting the range of an energy beam, e.g., a proton beam, and compensating for the proton range to target a region of the target tissue, e.g., a distal region of the target tissue, or in some cases, immediately beyond the distal end of the target tissue, such that the Bragg peak of the beam coincides with the target tissue, thereby reducing or eliminating the "exit" dose of the proton beam that extends beyond the target while maintaining the efficacy of FLASH-RT. As a result of the rapid falloff of particle energy at the penetration range, reflected by the Bragg peak, a large portion of the particle energy can be confined to the target tissue.

[0024] In intensity-modulated radiation therapy (IMRT), such as intensity-modulated particle therapy (IMPT), beam intensity is varied across each treatment region (target) of a patient. Depending on the treatment modality, parameters available for intensity modulation include beam shaping (collimation), beam weighting (spot scanning), and angle of incidence (beam geometry). These degrees of freedom result in a virtually infinite number of potential treatment plans. Consistent and efficient creation and evaluation of high-quality treatment plans therefore relies on the use of computing systems.

[0025] An inverse treatment planning tool was developed to optimize IMPT using monoenergetic layers for FLASH-RT planning. Inverse treatment planning is a process by which the intensity distribution of each beam used in the treatment plan is determined such that the resulting dose distribution can best meet the criteria specified by the planner. In inverse treatment planning, the radiation oncologist defines the patient's critical organs and tumor volume, and then also determines the target dose and the respective importance coefficients. The planner then runs an optimization program to find the treatment plan that best matches all input criteria. Inverse treatment planning thus uses an optimizer to solve the inverse problem set by the planner. Range pullback values ​​and physical compensator contours can be calculated to stop the monoenergetic proton beam at the distal end of the target.

[0026] The spot maps and weights for each field were optimized to achieve sufficient dose rates using the Bragg peak of the proton beam. Both "phantom" (model) and patient treatments were planned using the disclosed methods and delivery techniques to evaluate dosimetry and dose rate characterization.

[0027] (definition)

[0028] "Administration" or "administering" refers to the step of giving (ie, administering) a therapy to a subject.

[0029] "Bragg curve" refers to a graph of the rate of energy loss, or Linear Energy Transfer (LET), of a particle as a function of distance traveled in a stopping medium. The energy loss is characterized primarily by the square of the nuclear charge, Z, and the inverse square of the projectile velocity, β. This gives the Bragg curve a shape that "peaks" just before the projectile comes to rest (thereby indicating the range at which the particle releases most of its energy).

[0030] A "Bragg peak" is a prominent peak on a Bragg curve, which plots the energy loss of ionizing radiation as it travels through a material. The Bragg peak identifies the range at which a particle loses most of its energy.

[0031] "Calculating" refers to the selection and adjustment of range shifters and / or range compensators to determine the arrangement and combination of plates to produce the desired range of ionizing radiation.

[0032] "Cancerous tissue" means any neoplasm or benign tumor.

[0033] "Field" means the area treated by a beam of ionizing radiation at a particular angle. Radiation therapy treatments can be performed using a single field or multiple fields at different angles.

[0034] "FLASH radiotherapy" or "FLASH-RT" is a radiotherapy treatment regimen that delivers hypofractionated, high-dose radiation doses using ultra-high dose rates.

[0035] "Particle radiation" refers to ionizing radiation that includes protons or other heavy particles such as helium, carbon, argon, and neon.

[0036] "Patient" means a human or non-human subject receiving medical or veterinary care.

[0037] As used herein, "plate" refers to a URS or RC component (e.g., polycarbonate plastic) that is transparent to ionizing radiation to reduce the energy of the ionizing radiation, or to shorten the penetration range, or to fine-tune the beam penetration range of the ionizing radiation.

[0038] "Range Compensator" or "RC" means hardware configured to fine-tune or shorten the range of ionizing radiation into a beam configuration suitable for administration of Bragg peak-based FLASH-RT as described herein. The range compensator fine-tunes the range of the shifted ionizing radiation to account for the three-dimensional shape of the target tissue.

[0039] "Target tissue" refers to the tissue that is to be treated, for example cancerous tissue, such as cancerous tissue including neoplastic and benign tumors.

[0040] As used herein, "tuned" means optimizing the number of spots, spot weightings, and spot locations in a process of inverse optimization to determine a spot map to arrive at an optimal plan.

[0041] "Universal Range Shifter" or "URS" means hardware configured to adjust / shorten the range of ionizing radiation to a form suitable for administration of the Bragg peak-based FLASH-RT described herein.

[0042] (Administration System)

[0043] Some embodiments disclosed herein include an administration system, such as an administration system for administering a FLASH-RT therapy. In embodiments, the disclosed system includes a source of ionizing radiation, such as a cyclotron or a synchrotron. In embodiments, the ionizing radiation source emits ionizing radiation, such as protons, helium, carbon, argon, neon, or other heavy particles.

[0044] Some disclosed embodiments further comprise a range shifter. For example, in disclosed embodiments, the range shifter may comprise a universal range shifter (URS) capable of converting ionizing radiation into fields of discrete range. In disclosed embodiments, the URS may comprise a plurality of plastic plates having various thicknesses, e.g., transparent amorphous thermoplastic plates such as polycarbonate plastic plates. In embodiments, the ranges of the separate fields may be shifted by different amounts. For example, in an embodiment using five radiation fields for treatment, the five radiation fields may include one, two, three, four, or five different range shifts, and thus may include one, two, three, four, or five different URS plate combinations.

[0045] Some disclosed system embodiments further comprise a range compensator (RC). For example, in disclosed embodiments, the RC may comprise at least one plastic plate having a profile of varying thickness, e.g., a solid, transparent, amorphous thermoplastic plate, such as a polycarbonate plastic plate. In embodiments, the plate may have a thickness of, for example, 0.5 g / cm 3 , 0.6g / cm 3 , 0.7g / cm 3 , 0.8g / cm 3 , 0.9g / cm 3 , 1.0g / cm 3 , 1.1g / cm 3 , 1.2g / cm 3 , 1.3g / cm 3 , 1.4g / cm 3 , 1.5g / cm 3 , 1.6g / cm 3 etc. In an embodiment, the RC can further refine the range of the ionizing radiation that has been range-shifted by the URS.

[0046] In an embodiment, the range of the separate fields may be modified by different RCs. For example, in an embodiment using five fields for treatment, the five fields may include one, two, three, four, or five different RCs. An exemplary RC is shown in FIG. 8, where the three-dimensional "topography" of the RC can be clearly seen.

[0047] Combined with the disclosed URS, RC, and inverse treatment planning embodiments, this enables the delivery of FLASH-RT treatments that utilize the Bragg peak using conventional proton RT devices, for example by modifying the beam range.

[0048] Some disclosed embodiments include inverse treatment planning for ionizing radiation. For example, in embodiments, ray tracing is used to calculate range compensation. In embodiments, the energy beam is customized to generate an intensity modulated spot map via an inverse treatment planning platform. For example, as shown in FIG. 1(a), a uniform margin of, for example, 6 mm on the CTV may be used to encompass the depth-wise spot distribution. A dose attenuation of 90% may be used as the proton range for spot map generation. (WET i The water equivalent thickness (WET) of each pencil beam proton radiography track (denoted by (x, y, z)) can be calculated by Equation 1, where rsp(x, y, z) represents the relative stopping power (rsp) of each voxel in the 3D CT image.

[0049] The integration step in Equation 1 can be calculated accurately by a ray-tracing algorithm (Siddon RL, Prism representation: A 3D ray-tracing algorithm for radiotherapy applications, Phys. Med. Biol., 1985, 10.1088 / 0031-9155 / 30 / 8 / 005 30(8), 817-824). The pullback or shortening of the range of each pencil beam is calculated by R iwhere R E0 is the range of the highest energy in water. The disclosed FLASH-RT Bragg peak treatment plan may use a multi-field configuration, e.g., a five-field beam configuration, and a multi-field-optimization (MFO) method may be used to generate the spot map.

[0050]

number

[0051] In an embodiment, a desired total range compensation per field can be achieved by using the URS and the RC. The thickness of the URS can vary, for example, from 0 cm to 34 cm, which allows treatment of tumors at any depth with the help of the RC.

[0052] In embodiments, the URS may comprise, for example, at least 1 plate, at least 2 plates, at least 3 plates, at least 4 plates, at least 5 plates, at least 6 plates, at least 7 plates, at least 8 plates, at least 9 plates, at least 10 plates, at least 11 plates, at least 12 plates, at least 13 plates, at least 14 plates, at least 15 plates, at least 16 plates, at least 17 plates, at least 18 plates, at least 19 plates, at least 20 plates, or more than 20 plates. In one example system, six plates may be used to generate a desired range depth (0 cm to 34 cm) suitable for many purposes.

[0053] In embodiments, the thickness of an individual URS plate can be, for example, 1 cm water equivalent thickness (WET), 2 cm WET, 3 cm WET, 4 cm WET, 5 cm WET, 6 cm WET, 7 cm WET, 8 cm WET, 9 cm WET, 10 cm WET, 11 cm WET, 12 cm WET, 13 cm WET, 14 cm WET, 15 cm WET, 16 cm WET, 17 cm WET, 18 cm WET, 19 cm WET, 20 cm WET, 21 cm WET, 22 cm WET, 23 cm WET, 24 cm WET, 25 cm WET, 26 cm WET, 27 cm WET, 28 cm WET, 29 cm WET, 30 cm WET, or greater than 30 cm WET.

[0054] In one embodiment, the URS comprises six polycarbonate plastic plates with thicknesses of 1, 2, 3, 7, 7, and 14 cm water equivalent, generating 35 discrete range shortening increments with a depth resolution of 1 cm. The range plate combinations for the 35 discrete range pullbacks used in the tests described in Example 1 are shown in Table 2 of FIG.

[0055] Figure 1(e) shows a schematic diagram of the six polycarbonate plastic plate URS system used in Example 1, with thicknesses of 1, 2, 3, 7, 7, and 14 cm wet, generating 35 discrete range pullbacks with 1 cm depth resolution. Each range shifter plate is driven by a stand-alone stepper motor to move "in" and "out" of the beam path, and the "in" and "out" combinations of the six plates correspond to a binary system that can generate the correct range pullbacks. The range plate combinations for 35 discrete range pullbacks are shown in Table 2 of Figure 11.

[0056] In embodiments, thicker range shifters may be placed further downstream and thinner range shifters are placed further upstream, which is a design consideration to minimize the travel distance of the scattered proton beam, reduce the spot size, and maintain a high spot peak dose rate (SPDR). The desired proton range is achieved by shifting range shifter plates "in" and "out" of the beam path. The thickness of the URS used in each beam path is determined by R in Equation 2. URS The maximum thickness of RC can be calculated using R in Equation 2. c Thus, in an embodiment, the total range pullback volume can be determined by 0 cm and R E0 The range can be between 1 cm and 2 cm, allowing for deep and superficial targets to be addressed.

[0057] Range compensation R for each proton trace under each irradiation field i can be calculated and stored, for example, by a 3D data matrix. Using the dataset, a 3D printed compensator can be easily constructed. As shown in Figure 1(e), the RCs are shown in the top right and bottom right corners.

[0058]

number

[0059] Similar to the design of compensators for scattering proton systems, the smearing method (Moyers MF, Miller DW, Bush DA, Slater JD, Methodologies and tools for proton beam design for lung tumors, Int J Radiat Oncol Biol Phys, 2001, 49(5), 1429-38) can be used to design RCs that manage range uncertainties.

[0060] In an embodiment, the minimum MU / spot or minimum treatment chamber beam current in nanoamperes (nA) required for treatment may determine the dose rate for each energy layer, and the minimum MU / spot and dose rate are further optimized to reach the FLASH dose rate threshold. An algorithm may be used to generate the optimal spot map in two steps. a. First, an initial minimum MU / spot threshold (w0) may be used for inverse optimization to generate a dense spot map with a defined spot spacing. b. Second, the distance threshold r t and the weighting factor w t Low weighted spots can be merged into new spots by applying both r and r, where r t is the ratio of the spot spacing. w t is the factor-based minimum MU / spot requirement for the FLASH dose rate. As shown in Equation 3, the weights are m The spot coordinates can be calculated based on their original coordinates and the weighting fraction using Equation 4. The final spot positions can be calculated based on the coordinate threshold r described using Equation 5. t It can be determined by applying

[0061] In some embodiments, there are at least two considerations for the application of the second step to generate the final spot map. a. First, since the minimum MU / spot determines the SPDR of a layer, a high SPDR can be achieved by merging low weighted spots. Second, similar to conventional IMPT plan optimization, low-weighted spots are important to maintain good plan quality: by merging lower-weighted spots with neighboring spots, better plan dosimetry distribution can be achieved, albeit with minimal changes in the spot distribution pattern.

[0062] It will be appreciated that other planning steps and algorithms may also be used.

[0063] In some disclosed embodiments, continuous optimization can be performed to fine-tune the spot weights and further improve target uniformity and OAR sparing. By iteratively applying the second step of spot map optimization (merging low weighted spots with neighboring spots), the dose rate can be continuously improved.

[0064] In an embodiment, the effectiveness of spot map optimization can be verified using a C-shaped target surrounding a central avoidance core structure. As shown in FIG. 2, (a) is a spot map of one field using an initial 400MU / spot threshold, (d) is a spot map after applying the spot map optimization process, (b) and (e) are comparisons of 2D dose distributions for selected slices, and (c) and (f) are comparisons of DVH and DRVH. By doing so, as can be seen from the 2D dose distributions, the low-dose region is reduced, the conformity is improved, and the DVH of the core structure is effectively shifted toward the low-dose end as a result. As shown in (f), the dose rate to the body, target, and core structure can be increased.

[0065]

number

[0066] Figure 2 shows an example of spot distribution and weight optimization, which can effectively improve the plan quality and FLASH-RT dose rate distribution. (a) and (d) are spot maps before and after the spot map optimization process, (b) and (e) are 2D dose distribution comparisons, and (c) and (f) are DVH and DRVH comparisons before and after spot map optimization. The dashed line from the DRVH indicates the 40 Gy / s threshold.

[0067] In some embodiments, multiple Coulomb scattering (MCS) between the protons and the USR and RC can significantly increase the spot divergence. Similarly, scattering effects can also result in a gradual shortening of the effective SSD of the beam. As the effective SSD shortens, the proton fluence decreases more quickly due to the larger inverse square effect, and the spot size increases more rapidly.

[0068] FIG. 6 shows the dose rate distribution of a 250 MeV single spot with 1000 monitor units (a measure of the machine output from a clinical accelerator for radiotherapy; [MU] (Monitor Units)) in a water phantom. In Example 1, 5, 15, and 25 cm gaps between the RC and the phantom surface were "mimicked" to calculate the spot dose rate at the central axis in water that changes with the gap. It was clear that the spot dose rate decreased as the gap increased, and the central axis dose rate at the Bragg peak decreased by about a factor of two between a 5 cm gap and a 25 cm gap. In the process of FLASH plan optimization, minimizing the gap often plays an important role in maintaining the proton fluence intensity and smaller penumbra, which can be important for sparing the OAR. Meanwhile, the large spot size brought about by the MCS and the large gap would significantly reduce the spot dose rate and the average dose rate of the treatment field. To achieve a higher spot dose rate, a relatively small gap is important for the Bragg peak treatment plan.

[0069] Top panel of Fig. 6: 2D dose rate distribution of a single spot (1000MU / spot) of 250MeV proton beam in the central axial plane evolving in a water phantom with voids of 5, 15, and 25cm, respectively; bottom panel: spot dose rate in the central axis (the three intervals represent 20cm movement in water, void, and remaining range in water).

[0070] Disclosed embodiments include directing ionizing radiation. In embodiments, the ionizing radiation is directed to a point or region within the target tissue plus an extended margin, for example, between the center of the target tissue and a point that is no more than 5 cm beyond the edge of the target tissue (extending outward from the center). For example, in embodiments, the ionizing radiation is directed such that the Bragg peak of the ionizing radiation coincides with a point within or near the periphery or edge of the target tissue, such as the distal end, proximal end, or lateral edge (with respect to the direction of transport of the ionizing radiation) of the target tissue.

[0071] For example, in embodiments, the ionizing radiation is directed a distance from the periphery / edge of the target tissue, such as the edge of a tumor. For example, in embodiments, the ionizing radiation is directed 1 mm from the edge of the target tissue, 2 mm from the edge of the target tissue, 3 mm from the edge of the target tissue, 4 mm from the edge of the target tissue, 5 mm from the edge of the target tissue, 6 mm from the edge of the target tissue, 7 mm from the edge of the target tissue, 8 mm from the edge of the target tissue, 9 mm from the edge of the target tissue, 10 mm from the edge of the target tissue, 11 mm from the edge of the target tissue, 12 mm from the edge of the target tissue, 13 mm from the edge of the target tissue, 14 mm from the edge of the target tissue, 15 mm from the edge of the target tissue, 16 mm from the edge of the target tissue, 17 mm from the edge of the target tissue, 18 mm from the edge of the target tissue, 19 mm from the edge of the target tissue, 20 mm from the edge of the target tissue, or more than 20 mm from the edge of the target tissue.

[0072] For example, in embodiments, ionizing radiation is directed to the periphery / margins or surroundings of a target tissue, such as the margins of a tumor. For example, in embodiments, ionizing radiation is directed to within 1 mm of the margin of the target tissue, within 2 mm of the margin of the target tissue, within 3 mm of the margin of the target tissue, within 4 mm of the margin of the target tissue, within 5 mm of the margin of the target tissue, within 6 mm of the margin of the target tissue, within 7 mm of the margin of the target tissue, within 8 mm of the margin of the target tissue, within 9 mm of the margin of the target tissue, within 10 mm of the margin of the target tissue, within 11 mm of the margin of the target tissue, within 12 mm of the margin of the target tissue, within 13 mm of the margin of the target tissue, within 14 mm of the margin of the target tissue, within 15 mm of the margin of the target tissue, within 16 mm of the margin of the target tissue, within 17 mm of the margin of the target tissue, within 18 mm of the margin of the target tissue, within 19 mm of the margin of the target tissue, within 20 mm of the margin of the target tissue, or within a distance greater than 20 mm from the margin of the target tissue.

[0073] In embodiments, the ionizing radiation is directed toward the center of the tumor or within a distance on either side of the center. For example, in embodiments, the ionizing radiation is directed within 1 mm of the center of the target tissue, within 2 mm of the center of the target tissue, within 3 mm of the center of the target tissue, within 4 mm of the center of the target tissue, within 5 mm of the center of the target tissue, within 6 mm of the center of the target tissue, within 7 mm of the center of the target tissue, within 8 mm of the center of the target tissue, within 9 mm of the center of the target tissue, within 10 mm of the center of the target tissue, within 11 mm of the center of the target tissue, within 12 mm of the center of the target tissue, within 13 mm of the center of the target tissue, within 14 mm of the center of the target tissue, within 15 mm of the center of the target tissue, within 16 mm of the center of the target tissue, within 17 mm of the center of the target tissue, within 18 mm of the center of the target tissue, within 19 mm of the center of the target tissue, within 20 mm of the center of the target tissue, or within a distance of more than 20 mm from the center of the target tissue.

[0074] In a further embodiment, the ionizing radiation is directed to a point between an edge of the target tissue and the three-dimensional center of the target tissue.

[0075] The disclosed embodiments may produce field dose rates of, for example, at least 40 Gy / s or more. For example, in embodiments, the dose rates may be at least 40 Gy / s, at least 42 Gy / s, at least 44 Gy / s, at least 46 Gy / s, at least 48 Gy / s, at least 50 Gy / s, at least 52 Gy / s, at least 56 Gy / s, at least 58 Gy / s, at least 60 Gy / s, at least 62 Gy / s, at least 64 Gy / s, at least 66 Gy / s, at least 68 Gy / s, at least 70 Gy / s, at least 72 Gy / s, at least 74 Gy / s, at least 76 Gy / s, at least 78 Gy / s, at least 80 Gy / s, at least 82 Gy / s, at least 84 Gy / s, at least 86 Gy / s, at least at least 88 Gy / s, at least 90 Gy / s, at least 92 Gy / s, at least 94 Gy / s, at least 96 Gy / s, at least 98 Gy / s, at least 100 Gy / s, at least 102 Gy / s, at least 104 Gy / s, at least 106 Gy / s, at least 108 Gy / s, at least 110 Gy / s, at least 112 Gy / s, at least 114 Gy / s, at least 116 Gy / s, at least 118 Gy / s, at least 120 Gy / s, at least 122 Gy / s, at least 124 Gy / s, at least 126 Gy / s, at least 128 Gy / s, at least 130 Gy / s, at least 132 Gy / s, or more.

[0076] The disclosed embodiments further include computer readable instructions for determining the use of range shifters and range compensators. For example, in the disclosed embodiments, the computer readable instructions may include instructions for calculating the number, thickness, and placement of URS and RC based on the properties of the unshifted and uncompensated ionizing radiation, the target treatment depth, and the three-dimensional shape of the target.

[0077] (How to use)

[0078] The methods disclosed herein may include generating shifted and compensated ionizing radiation from an initial ionizing radiation source. For example, in embodiments, the initial ionizing radiation source may include protons, alpha rays, carbon ions, other ion rays, and combinations thereof. In embodiments, the methods include the use of a cyclotron or synchrotron to generate the ionizing radiation, which is then subject to a range shifter and range compensation.

[0079] In an embodiment, the range shifting includes the use of multiple plastic plates of different thicknesses, e.g., clear amorphous thermoplastic plates such as polycarbonate plastic plates, to reduce the range of the initial ionizing radiation to the desired range. For example, in an embodiment, an inverse treatment planning tool is used to determine the number, position, and thickness of individual URS plates required to reduce the range of the initial ionizing radiation to the desired range.

[0080] In embodiments, range compensation includes the use of at least one amorphous thermoplastic contour, such as a polycarbonate plastic contour, to adjust the range of the initial ionizing radiation to a desired depth. For example, in embodiments, an inverse treatment planning tool is used to determine the contour thickness of the RC plate required to adjust the range of the initial ionizing radiation to a desired depth and fit the distal end of the target. In embodiments, the range-shifted and compensated ionizing radiation field may be further used to treat the target tissue, e.g., cancerous tissue. For example, the disclosed method of use includes: a. diagnosing cancerous tissue; b. mapping the cancerous tissue; c. developing a radiation therapy treatment plan for administering an effective amount of ionizing radiation to the cancerous tissue; d. administering range-shifted and compensated ionizing radiation to the cancerous tissue; may include.

[0081] In embodiments, the disclosed methods may include diagnosing cancerous tissue, for example, by using clinical tests, imaging tests, biopsies, etc. For example, high or low levels of certain substances in the body may be indicative of cancer. Thus, clinical tests of blood, urine, or other bodily fluids or cells may measure these substances and assist physicians in making a diagnosis. In embodiments, the clinical tests include testing blood or tissue samples for tumor markers. Tumor markers are substances produced by cancer cells or by other cells of the body in response to cancer. Although most tumor markers are produced by normal cells and cancer cells, they are generally produced at much higher levels by cancer cells.

[0082] The disclosed method may further include the use of imaging tests to identify cancerous tissue. For example, imaging tests visualize areas within the body that aid in identifying cancerous tissue. The disclosed method including imaging tests may include, for example, CT scans, in which an X-ray machine connected to a computer takes a series of images of internal organs from different angles. These images are used to create a detailed three-dimensional image of the inside of the body.

[0083] Further methods include the use of magnetic resonance imaging (MRI), which uses powerful magnets and radio waves to produce cross-sectional images of the body, which can show the differences between healthy and unhealthy tissue.

[0084] Further disclosed methods may include nuclear scanning, which uses radioactive materials to image inside the body. This type of scan is sometimes called a radionuclide scan.

[0085] Further disclosed treatment methods may include a bone scan, a type of nuclear scan used to identify bone abnormalities.

[0086] Further disclosed methods may include a positron emission tomography (PET) scan. A PET scan is an imaging test that allows doctors to check for disease inside the body. This scan uses special dyes that contain radioactive tracers. These tracers are swallowed, inhaled, or injected into a vein in the patient's arm, depending on which part of the body is being examined.

[0087] Additional diagnostic methods suitable for use in the disclosed embodiments may include ultrasound. Ultrasonography uses high-energy sound waves that "bounce" off tissue inside the body. A computer uses these echoes to create a picture of an area inside the body.

[0088] In embodiments, multiple diagnostic methods may be used to identify potential therapeutic areas, hi embodiments, the therapeutic area comprises a tumor, e.g., a malignant tumor.

[0089] Once the diagnosis is complete, the treatment area can be mapped and a treatment plan can be developed, e.g., after the target tissue is three-dimensionally mapped, the appropriate URS, RC, dose, and beam angle are determined.

[0090] A treatment regimen can then be applied as the administration of appropriate doses of range-shifted and compensated ionizing radiation. For example, the disclosed methods can include a treatment dose of, for example, at least 1.8 Gy / fraction or more. For example, in embodiments, the dose can be at least 1.8 Gy / fraction, at least 2 Gy / fraction, at least 3 Gy / fraction, at least 4 Gy / fraction, at least 5 Gy / fraction, at least 6 Gy / fraction, at least 8 Gy / fraction, at least 10 Gy / fraction, at least 12 Gy / fraction, at least 14 Gy / fraction, at least 16 Gy / fraction, at least 18 Gy / fraction, at least 20 Gy / fraction, at least 22 Gy / fraction, at least 24 Gy / fraction, at least 26 Gy / fraction, at least 28 Gy / fraction, at least 30 Gy / fraction, at least 32 Gy / fraction, at least 36 Gy / fraction, at least 38 Gy / fraction, at least 39 Gy / fraction, at least 40 Gy / fraction, at least 42 Gy / fraction, at least 46 Gy / fraction, at least 48 Gy / fraction, at least 48 Gy / fraction, at least 50 Gy / fraction, at least 52 Gy / fraction, at least 56 Gy / fraction, at least 58 Gy / fraction, at least 59 Gy / fraction, at least 60 Gy / fraction, at least 61 Gy / fraction, at least 62 Gy / fraction, at least 64 Gy / fraction, at least 65 Gy / fraction, at least 66 Gy / fraction, at least 68 Gy / fraction, at least 70 Gy / fraction, at least 72 Gy / at least 34 Gy / fraction, at least 36 Gy / fraction, at least 38 Gy / fraction, at least 40 Gy / fraction, at least 42 Gy / fraction, at least 44 Gy / fraction, at least 46 Gy / fraction, at least 48 Gy / fraction, at least 50 Gy / fraction, at least 52 Gy / fraction, at least 54 Gy / fraction, at least 56 Gy / fraction, at least 58 Gy / fraction, at least 60 Gy / fraction, at least 62 Gy / fraction, at least 64 Gy / fraction, at least 66 Gy / fraction, at least 68 Gy / fraction, at least 70 Gy / fraction, or more than 70 Gy / fraction.

[0091] In embodiments, the fraction dose is, for example, 1.8 Gy / fraction or more. For example, in embodiments, the dose is 1.8 Gy / fraction, 2 Gy / fraction, 3 Gy / fraction, 4 Gy / fraction, 5 Gy / fraction, 6 Gy / fraction, 8 Gy / fraction, 10 Gy / fraction, 12 Gy / fraction, 14 Gy / fraction, 16 Gy / fraction, 18 Gy / fraction, 20 Gy / fraction, 22 Gy / fraction, 24 Gy / fraction, 26 Gy / fraction, 28 Gy / fraction, 30 Gy / fraction, 32 Gy / fraction, 36 Gy / fraction, 38 Gy / fraction, 39 Gy / fraction, 40 Gy / fraction, 41 Gy / fraction, 42 Gy / fraction, 43 Gy / fraction, 44 Gy / fraction, 45 Gy / fraction, 46 Gy / fraction, 47 Gy / fraction, 48 Gy / fraction, 49 Gy / fraction, 50 Gy / fraction, 51 Gy / fraction, 52 Gy / fraction, 53 Gy / fraction, 54 Gy / fraction, 55 Gy / fraction, 56 Gy / fraction, 57 Gy / fraction, 58 Gy / fraction, 59 Gy / fraction, 60 Gy / fraction, 61 Gy / fraction, 62 Gy / fraction, 63 Gy / fraction, 64 Gy / fraction, 65 Gy / fraction, 66 Gy / fraction, 67 Gy / fraction, 68 Gy / fraction, 69 Gy / fraction, 70 Gy / fraction, 72 Gy / fra 34Gy / fraction, 36Gy / fraction, 38Gy / fraction, 40Gy / fraction, 42Gy / fraction, 44Gy / fraction, 46Gy / fraction, 48Gy / fraction, 50Gy / fraction, 52Gy / fraction, 54Gy / fraction, 56Gy / fraction, 58Gy / fraction, 60Gy / fraction, 62Gy / fraction, 64Gy / fraction, 66Gy / fraction, 68Gy / fraction, 70Gy / fraction, etc.

[0092] In embodiments, the fraction dose is 1.8 Gy / fraction or less, 2 Gy / fraction or less, 3 Gy / fraction or less, 4 Gy / fraction or less, 5 Gy / fraction or less, 6 Gy / fraction or less, 8 Gy / fraction or less, 10 Gy / fraction or less, 12 Gy / fraction or less, 14 Gy / fraction or less, 16 Gy / fraction or less, 18 Gy / fraction or less, 20 Gy / fraction or less, 22 Gy / fraction or less, 24 Gy / fraction or less, 26 Gy / fraction or less, 28 Gy / fraction or less, 30 Gy / fraction or less, 32 Gy / fraction or less, 50Gy / fraction or less, 52Gy / fraction or less, 54Gy / fraction or less, 56Gy / fraction or less, 58Gy / fraction or less, 60Gy / fraction or less, 62Gy / fraction or less, 64Gy / fraction or less, 66Gy / fraction or less, 68Gy / fraction or less, 70Gy / fraction or less, etc.

[0093] In embodiments, the range-shifted and compensated ionizing radiation is administered in multiple fields. For example, in embodiments, 2, 3, 4, 5, 6, 7, 8, 9, etc. fields are administered. In embodiments, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, etc. fields are administered. In embodiments, 2 or less, 3 or less, 4 or less, 5 or less, 6 or less, 7 or less, 8 or less, 9 or less, 10 or less, 11 or less, 12 or less, 13 or less, 14 or less, 15 or less, etc. fields are administered.

[0094] In an embodiment, the angles at which the range-shifted and compensated fields of ionizing radiation are administered to the target tissue are equal between the fields. For example, in an embodiment in which five fields are administered, the angles at which the fields are administered may vary at 72 degree intervals. The angles between the fields may be appropriately determined to meet clinical requirements.

[0095] The frequency of use of the disclosed methods may be determined based on the nature and location of the particular area being treated, although in some cases, repeat treatments in the future may be desirable to achieve optimal results.

[0096] All disclosed methods and procedures described in this disclosure may be realized using one or more computer programs or components. These components may be provided as a series of computer instructions on any conventional computer-readable or machine-readable medium, including volatile and non-volatile memories such as RAM, ROM, flash memory, magnetic or optical disks, optical memory, or other storage media. The instructions may be provided as software or firmware and may be implemented in whole or in part in hardware components such as ASICs, FPGAs, DSPs, or any other similar devices. The instructions may be configured to be executed by one or more processors, which, when executing the series of computer instructions, perform or facilitate the execution of all or part of the disclosed methods and procedures.

[0097] (Example) The following non-limiting examples are provided for illustrative purposes only to facilitate a more complete understanding of representative embodiments, and should not be construed as limiting any of the embodiments described herein.

[0098] Example 1 (Lung tumor treatment) By using the highest monoenergetic beam of the cyclotron or synchrotron, the Bragg peak plan achieved sufficient beam current for the FLASH dose rate, while the multi-field inverse optimization treatment plan with a range pullback device (URS) in the beam path enabled the treatment plan to eliminate the exit dose beyond the target. An inverse algorithm that achieves uniform dose distribution by MFO has been developed based on the matRad platform (Wieser HP, Cisternas E, Wahl N, et al., Development of the opensource dose calculation and optimization toolkit matRad, Med Phys, 2017, 44, 2556-2568), and once the treatment plan satisfied the target coverage and OAR constraints, the ray tracing method created range compensators for each field. As shown in Fig. 1(e), the 5-field IMPT plan used the universal range shifter (URS) and range compensator (RC) for lung cancer FLASH-RT, and the proton range was adjusted to fit the distal end of the target.

[0099] The three-dimensional dose rate was quantified by the dose averaged dose rate (DADR) (Water S, Safai S, Schippers JM, et al., Towards FLASH proton therapy: the impact of treatment planning and machine characteristics on achievable dose rates, Acta Oncologica, 2019, 58:10, 1463-1469, https: / / doi:10.1080 / 0284186X.2019.1627416). It will be understood that other approaches may also be used. The center of the PBS spot had the greatest dose rate, and the dose rate decreased radially from the center of the spot to the side. Here, we adopted the definition of spot peak dose rate (SPDR) first proposed by van Marlen et al. for the FLASH planning study, which defines the maximum dose rate in the central axis (van Marlen P, Dahele M, Folkerts M, et al., Bringing FLASH to the Clinic: Treatment Planning Considerations for Ultrahigh Dose-Rate Proton Beams, Int J Radiation Oncol Biol Pys, 2020, 106(3), 621-629, https: / / doi.org / 10.1016 / j.ijrobp.2019.11.011). An in-house 3D PBS dose rate calculation tool was developed in MATLAB that uses a pencil beam convolution superposition algorithm with non-uniformity correction, Gaussian spot profile (σ=3.5mm), and modeled spot delivery time structure to calculate the dose rate. The dose rate volume histogram (DRVH) method was also used to quantify the dose coverage of the target and OARs. At the same time, the dose rate coverage index V, which represents the proportion of the volume receiving a dose rate of 40 Gy / s or more for the target and OARs, was used to quantitatively evaluate the FLASH dose rate. 40Gy / s was defined.

[0100] Figure 1. Schematic of an opaque FLASH IMPT plan using a universal range shifter (URS) and range compensator (RC). The URS and RC are placed in the beam path for illustrative purposes only. (a) Example phantom using a 6 mm distal margin to determine the proton stopping position. The dots represent the positions where the protons stop, and the integrated water equivalent thickness (WET) distance from the body contour was calculated to determine the range pullback and compensator contour. (b) Dose distribution using a monoenergetic layer based on the spot map in (a). (c) Beam-eye view of 2D range compensation calculated by ray tracing method. (d) 1D range compensation at the central axis. (e) Five-field beam arrangement for lung treatment plan, with the top and bottom corners showing one of the 5-RC in two different views.

[0101] 2.1 Inverse treatment planning to realize IMPT treatment plans

[0102] 2.1.1 Ray tracing to calculate range compensation

[0103] The monoenergetic beam was customized to generate an intensity modulated spot map via an inverse treatment planning platform. A uniform margin of 6 mm on the CTV was used to encompass the depthwise spot distribution as shown in Figure 1(a). 90% of the dose attenuation was used as the proton range for spot map generation. (WET i The water equivalent thickness (WET) of each pencil beam proton radiography track (denoted by (x,y,z)) was calculated by Eq. 1, where rsp(x,y,z) represents the relative stopping power (rsp) of each voxel in the 3D CT image. The integration step in Eq. 1 was calculated accurately by a ray tracing algorithm. The range pullback of each pencil beam was calculated by R i where R E0is the range of the highest energy in water. All FLASH-RT Bragg peak plans used a five-field beam configuration and the MFO method was used to generate the spot maps.

[0104]

number

[0105] 2.1.2 Universal Range Shifter (URS) and Range Compensator (RC)

[0106] Total range compensation for each radiation field was achieved by using the URS and RC. The thickness of the URS varied from 0 cm to 34 cm, which allows the treatment of tumors at any depth with the help of the RC.

[0107] The URS consists of six polycarbonate plastic plates with thicknesses of 1, 2, 3, 7, 7, and 14 cm wet to generate 35 discrete range pullbacks with 1 cm depth resolution. Each range shifter plate is driven by a stand-alone stepper motor to move "in" and "out" of the beam path, and the "in" and "out" combinations of the six plates correspond to a binary system that can generate the correct range pullbacks. The range plate combinations for the 35 discrete range pullbacks are shown in Table 2 of Figure 11.

[0108] Figure 1(e) shows a schematic of the URS system, with thicker range shifters located further downstream. Thinner range shifters are further upstream, which is a design consideration to minimize the travel distance of the scattered protons, reduce the spot size, and maintain a high SPDR. The desired proton range is achieved by shifting range shifter plates "in" or "out" of the beam path. The thickness of the URS used in each beam path is determined by R in Equation 2. URS The maximum thickness of RC was calculated using R in Eq. c Therefore, the total range pullback volume is determined by 0 cm and RE0 cm, covering targets from the deepest to the most superficial. i is calculated and stored by a 3D data matrix. The dataset can be used to construct a suitable 3D printed compensator. As shown in Figure 1(e), RC is shown in the top right and bottom right corners.

[0109]

number

[0110] The smearing method (Moyers MF, Miller DW, Bush DA, Slater JD, Methodologies and tools for proton beam design for lung tumors, Int J Radiat Oncol Biol Phys, 2001, 49(5), 1429-38) was used to design the RC to manage the range uncertainty as well as to design the compensator for the scattering proton system. Robust planning is important to achieve the clinical intent for the target and OAR. Large uncertainties due to setup and operation can lead to wide range uncertainties. In applying the smearing method, 3.5% CT Hounsfield unit (HU) for the relative stopping conversion uncertainty and 3 mm setup error were used.

[0111] 2.2 Spot map optimization to improve plan quality and dose rate

[0112] Then, the minimum MU / spot or the minimum treatment chamber beam current in nanoamperes (nA) determines the dose rate for each energy layer, and the minimum MU / spot and dose rate need to be further optimized to reach the FLASH dose rate threshold. An in-house algorithm was developed to generate an optimal spot map through two steps: first, an initial minimum MU / spot threshold (w0) is used for inverse optimization to generate a dense spot map with a defined spot spacing; second, a distance threshold r t and the weighting factor w t By applying both and, the low weighted spots are merged into a new spot, where r t is the ratio of the spot spacing. w t is the factor-based minimum MU / spot requirement for the FLASH dose rate. As shown in Equation 3, the weights are m and the spot coordinates are calculated based on their original coordinates and the weighting fraction using Equation 4. The final spot positions are calculated based on the coordinate threshold r described using Equation 5. t In general, there are two considerations for the application of the second step to generate the final spot map. First, the minimum MU / spot determines the SPDR of the layer, so a high SPDR can be achieved by merging low-weighted spots. Second, similar to conventional IMPT plan optimization, low-weighted spots contribute significantly to maintaining a good plan quality. By merging lower-weighted spots with neighboring spots, a better plan dosimetry distribution can be achieved, albeit with minimal changes in the spot distribution pattern.

[0113] Continuous optimization was performed to fine-tune the spot weights and further improve the target uniformity and OAR sparing. The dose rate was continuously improved by iteratively applying the second step of spot map optimization. The effectiveness of the spot map optimization was verified using a C-shaped target surrounding a central avoided core structure. As shown in Figure 2, (a) is the spot map of one field using the initial 400MU / spot threshold, (d) is the spot map after applying the spot map optimization step, (b) and (e) are the comparison of the 2D dose distributions for selected slices, and (c) and (f) are the comparison of the DVH and DRVH. As can be seen from the 2D dose distributions, it was clear that the low-dose region was reduced and the conformance was improved, resulting in a substantial shift of the DVH of the core structure towards the low-dose end. As shown in (f), the dose rate to the body, target, and core structure was increased.

[0114]

number

[0115] Figure 2 shows an example of spot distribution and weight optimization, which can effectively improve the plan quality and FLASH-RT dose rate distribution. (a) and (d) are spot maps before and after the spot map optimization process, (b) and (e) are 2D dose distribution comparisons, and (c) and (f) are DVH and DRVH comparisons before and after spot map optimization. The dashed line from the DRVH indicates the 40 Gy / s threshold.

[0116] 2.3 Spot dose rate development in range shifter, air, and phantom

[0117] The MCS between the protons and the USR and RC can significantly expand the spot divergence. Similarly, scattering effects can also result in a gradual shortening of the effective SSD of the beam. As the effective SSD shortens, the proton fluence decreases more quickly due to the larger inverse square effect, and the spot size increases more rapidly. Figure 6 shows the dose rate distribution of a 250 MeV single spot with 1000 MU in a water phantom. To calculate the spot dose rate at the central axis in water that changes with the gap, 5, 15, and 25 cm gaps between the RC and the phantom surface were mimicked. It was evident that the spot dose rate decreased as the gap increased, and the central axis dose rate at the Bragg peak decreased by about a factor of two between the 5 cm gap and the 25 cm gap. During the FLASH plan optimization, minimizing the gap played an important role in maintaining the proton fluence intensity and smaller penumbra, which is important for the sparing of the OAR. On the other hand, the large spot size provided by MCS and the large air gap would significantly reduce the spot dose rate and the average dose rate in the treatment field. To achieve a higher spot dose rate, a relatively small air gap is important for Bragg peak treatment planning.

[0118] Figure 6. Top: 2D dose rate distributions of a single spot (1000MU / spot) of 250MeV protons in the central axial plane evolving in a water phantom with voids of 5, 15, and 25cm, respectively; bottom: spot dose rate in the central axis (the three intervals represent 20cm travel in water, void, and remaining range in water).

[0119] 3.3 Feasibility study using both phantom and patient images

[0120] A rectangular water "phantom" with a C-shaped target was used for planning to investigate the dosimetric quality and dose rate distribution for both transmission and Bragg-peak plans. Concurrently, six consecutive lung cancer patients previously treated with proton SBRT at our institution were replanned and received both transmission and Bragg-peak FLASH plans to assess dose and dose rate distribution. The planning goal of using Bragg-peak FLASH-RT was to achieve comparable V for the critical OARs. 40Gy / s The goal was to achieve dose rate coverage yet significantly improve OAR sparing while using OAR dose constraints from the original clinical treatment parameters. Marlen et al. reported a FLASH transmission study using 8–12 non-coplanar beams for lung cancer planning. The reason for using more fields is to reduce the normal lung dose and improve target conformance. To perform a “fair” dosimetric comparison, the study used a 5-field plan with equal angular spacing (72 degrees) for both the transmission and Bragg peak plans. The phantom plans used a prescription of 50 Gy per fraction, and the patient plans used a standard treatment prescription of 34 Gy per fraction. The minimum MU to maintain the FLASH dose rate for the transmission and Bragg peak plans were 400 MU / spot and 1200 MU / spot, respectively. The DADR method is used for 3D dose rate quantification, and the DRVH is investigated for both the phantom and patient plans.

[0121] 3. Results

[0122] 3.1 Bragg Peak FLASH-RT Planning Using a Phantom

[0123] The phantom plan used five fields with even angular spacing of 72 degrees, and the distance between the core and the C-shaped target was about 1.5 cm. Figures 3A(a) and 3A(b) are two-dimensional dose distributions for the selected slices. Due to the absence of exit dose in the Bragg-peak method, the Bragg-peak plan resulted in lower dose scatter haze and integral dose than the transmission plan. The target coverage and uniformity were nearly the same, but the dose leakage to the body and core structures was much less. As shown in Figure 3A(c), there was a large gap between the two FLASH delivery methods in the DVHs of the body and core, indicating that the Bragg-peak plan significantly reduced the dose leakage from low to moderate levels. Figures 3B(d) and 3B(e) are DADR dose rate distributions for the same image slices, and Figure 3B(f) is a comparison of the DRVHs. It was clear that the transmission plan tended to produce a higher dose rate distribution compared to the Bragg-peak plan. However, the Bragg peak can be reached by increasing the minimum MU / spot (1200MU / spot) and through dose rate optimization to reach the FLASH-RT threshold of 40Gy / s. As shown in Figure 3B(f), after applying the spot map optimization, the V 40Gy / s The coverage was as high as 95%. Phantom dosimetry and dose rate comparisons showed that the Bragg-peak plan could achieve much better sparing of OARs compared to the transmission plan, despite achieving similar target coverage. At the same time, the FLASH-RT dose rate could be successfully maintained by the Bragg-peak plan.

[0124] 3A and 3B. Bragg peak plan ((b) and (e)) versus transmission plan ((a) and (d)) using a 250 MeV proton beam to a C-shaped target in a water phantom: (a) and (b) are 2D dose distributions for selected slices, (c) is the DVH comparison between them, (d) and (e) are 2D dose rate distributions, and (f) is the DRVH comparison. The dashed line from the DRVH indicates the 40 Gy / s threshold.

[0125] 3.2 Lung hypofractionation plan testing

[0126] The 2D dose distributions for the three selected cases are shown in Figure 4A(a) and Figure 4A(b). As can be seen from the dose color wash, the Bragg Peak plans were superior in the low-dose and medium-dose regions. The scattered dose haze and integral dose were significantly less in the dose distributions of the Bragg Peak plans for all three cases. The three DVHs (Figure 4B(c)) also showed significant dose-volume reduction for the lung-GTV, esophagus, spinal cord, and heart when using the Bragg Peak method for FLASH plans. Table 1 in Figure 10 summarizes the dosimetric parameters based on the RTOG0915 protocol for both the transmission IMPT plans and the Bragg Peak IMPT plans for all six lung patients (RTOG0915. https: / / www.nrgoncology.org / Clinical-Trials / Protocol / rtog-0915?filter=rtog-0915). D2% represents the high-dose area of ​​the target and the dose uniformity. Bragg-peak plans yielded slightly worse uniformity than transmission plans (110.6% vs. 112.2% of the prescribed dose) due to an increase in the minimum MU / spot. However, most OAR dosimetric metrics were better with the Bragg-peak plans. For example, for the lung-GTV, the mean volume for V7Gy decreased from 724.9cc to 492.6cc, corresponding to a maximum 32% volume reduction (p=0.001); the mean volume for V7.4Gy decreased from 672.8cc to 468.7cc, corresponding to a 30% reduction in irradiated volume (p=0.002). Furthermore, doses to the esophagus, heart, and spinal cord are sensitive to target location and beam placement, but some of these OARs may be completely spared with the Bragg-peak plans if there is no beam penetrating or directed at them. Given the large statistical error and heterogeneity of the tumor site in this initial cohort, these differences were not statistically significant (p>0.05).

[0127] 5A and 5B are comparisons of 2D dose rate distributions and DRVH for three selected lung cancer patients. The left column shows the dose rate distributions for the transmission plan, showing that the dose rate of protons decays with depth as it penetrates tissue, and for each single field, the exit dose rate is much lower than the entrance dose rate. The middle column shows the dose rate distributions for the Bragg Peak plan, including the bands of high dose rates and valleys of low dose rates observed in each field. As is known, the degrees of freedom for plan optimization include spot maps, spot weights, number of spots and fields, minimum MU / spot, etc. Using 400MU / spot and 1200MU / spot for the transmission plan and the Bragg Peak plan, the increase of the minimum MU / spot would make it more difficult to achieve good uniformity and sparing of OARs for the Bragg Peak plan. All parameters except energy and number of fields are optimized to meet the required dosimetry objectives via inverse optimization. Here, the highly modulated fluence acts as a compensation for the reduced flexibility with increasing MU / spot in maintaining higher 3D dose rates. The inverse algorithm plays a key role in achieving uniform dose distribution through the non-uniform dose fluence of the MFO method. 40Gy / s The dose rate coverage is summarized in Table 1 of Figure 10. All targets were almost 100%, V 40Gy / s and the average V of all OARs for both the transmittance and Bragg peak plans. 40Gy / s Coverage was at least >91.0±3.8% (spinal cord for Bragg Peak plans). Overall, comparison of dose distributions, DVH, and dosimetrics indicates that Bragg Peak plans significantly improved sparing of the lungs, spinal cord, heart, and esophagus, and in contrast, these plans maintained the FLASH dose rate.

[0128] Table 1 in Figure 10. V for transmittance IMPT plans and Bragg peak IMPT plans for all six lung cases 40Gy / sComparison of dosimetry and dose rate coverage for the 10 ... 40Gy / s Represents.

[0129] Figures 4A and 4B. Dose comparison between transmission and Bragg peak plans for three selected lung patients using the same beam configuration. The right and center columns represent the transmission and Bragg peak plans, respectively. Figures 4A(a) and 4(b) are the 2D dose distributions of selected slices, and Figure 4B(c) is the DVH comparison between the two types of plans.

[0130] Figures 5A and 5B. Comparison of dose rates between the transmission plan (left image) and the Bragg peak plan (middle image) using the same beam configuration. Figures 5A(a) and 5A(b) are 2D dose rate distributions of selected slices, and Figure 5B(c) is a comparison of DRVH between the two plans. The dashed line indicates the 40 Gy / s threshold.

[0131] 4. Discussion

[0132] Although the definition of MU varies among proton vendors, the universal quantification of dose rate is to use the beam current in the treatment room. However, in treatment planning, MU is used as the base unit for calculating the planned dose. To accurately describe the dose rate, the correlation between the beam current and the number of protons per MU needs to be determined, for example, by Monte Carlo simulation or experimental methods. The ability of treatment planning systems (TPSs) to optimize spot weights can vary from TPS to TPS. Different optimizers and dose calculation engines can result in different plan quality and dose rate distributions. Therefore, the treatment planning strategy, DVH, and DRVH distributions need to be extensively studied for these commercially available TPSs to be available for clinical use. Due to the inherent nature of dose rate attenuation as the PBS spot penetrates the URS, RC, air gap, and patient tissue, the 3D dose rate distribution of the OAR is a function of the proton range pullback and the minimum MU / spot. A larger proton range pullback is required to treat shallow targets, and correspondingly, a larger minimum MU / spot is desirable for plan optimization to maintain FLASH dose rates for irradiation to the OARs.

[0133] Plan optimization involving multiple parameters with more degrees of freedom will certainly increase the flexibility and the possibility of achieving better plan quality. Variable minimum MU / spot, number of beams, and beam angle are important parameters that should generally be considered during the treatment plan optimization process. As shown in Fig. 7, (a) uses four posterior oblique beam configurations, which are closer to the traditional beam angles compared to the beam configuration in (b). The contralateral lung is completely spared with nearly zero dose, and the dose to the esophagus and heart is also significantly reduced (DVH in Fig. 7(c)). The V for CTV and OAR 40Gy / s(Fig. 7(d)) ​​The coverage is similar. This case comparison shows that the Bragg Peak plan has a great potential to further reduce the OAR dose by optimizing the number of fields and the beam angles. The robustness of the plan is very important to achieve the clinically intended dose to the target and OARs. A smearing method is used to account for the setup and range uncertainties from CT HU to stopping power conversion uncertainties. Motion uncertainties can also affect the treatment of the target. Although dose interaction effects may not be an issue for each field since each field is delivered in less than 1 second, target motion still needs to be addressed between fields and fractions. 4D CT is needed to delineate the moving target, considering the amplitude and area of ​​motion. On the other hand, average images can help to make the treatment plan more robust. Strategies to mitigate motion (DIBH, gating, etc.) may also be needed to reduce the target margin and achieve robust treatment.

[0134] In the Bragg Peak project, even when the minimum MU / spot was increased to 1200 MU / spot, V 40Gy / s The coverage was slightly worse. We analyzed where the low dose rate regions were located. To quantitatively evaluate the dose rate statistical distribution versus the OAR dose, we define eight dose regions with 5 Gy dose intervals from 0 Gy to 40 Gy. As shown in Figure 7(e), there are eight dose regions from 0-5 Gy to 35-40 Gy. Most of the volumes receiving less than 96% FLASH dose rate coverage had a dose less than 15 Gy. As the OAR dose increases, the dose rate increases accordingly. Tests have shown that the FLASH sparing effect may be correlated with a combination of dose, dose rate, and total delivery time. Because tests have shown that the FLASH effect may be dose dependent, V 40Gy / s We hypothesize that this low-dose region with minor loss of coverage is likely to be insignificant and clinically inconsequential.

[0135] Figure 7. (a)-(d) Examples illustrating the optimization of beam angles. (a) and (b) are 2D dose distributions using different fields and field angles, (c) and (d) are comparisons of DVH and DRVH, and (e) is the V versus OAR dose from low to high dose regions. 40Gy / s Dose rate coverage. The left lung and most of the heart are completely spared using the beam configuration shown by (b).

[0136] 5. Conclusion

[0137] The dedicated designed URS and RS accomplished the mission of pulling back the proton range from the target in the distal to proximal direction. This novel method does not require major upgrades of the cyclotron / synchrotron or beamline to meet the FLASH-RT dose rate threshold using Bragg-peak. The URS is an effective tool to pull back the proton range. With the help of the RC, the proton range can be further adjusted to fit the contour of the distal target and achieve a conformal dose distribution. The exit dose can be eliminated by the Bragg-peak FLASH plan, which allows much better OAR sparing than the transmission FLASH plan. An effective inverse optimizer by taking full advantage of the planning degrees of freedom, e.g., beam, angle, spot map, spot weighting, is another key element to achieve high-quality IMPT plans with sufficient 3D dose rates for FLASH-RT. An efficient dose rate optimization algorithm and an accurate dose calculation engine are essential to make the Bragg-peak FLASH-RT clinically feasible. We have presented initial cohort planning analyses showing that using Bragg peaks, similar target coverage and uniformity can be maintained, but OAR sparing is significantly improved, compared to transmission planning. This initial proof-of-concept study demonstrated a novel method that combines range pullback and powerful inverse optimization to achieve FLASH dose rates using currently available machine parameters.

[0138] Example 2 (Lung tumor treatment) A 26 year old male was diagnosed with a lung tumor. The cancerous tissue was imaged, mapped, and a treatment plan was developed. Using an inverse treatment plan optimization protocol, an optimal URS plate combination was established to match the range of the shifted and compensated ionizing radiation to the distal end of the target tissue with the following parameters:

[0139] [Table 1]

[0140] FLASH-RT treatment was then delivered to the cancerous tissue in five radiation fields spaced at an angle of 72°.

[0141] Example 3 (Treatment of liver tumors) A 46 year old woman was diagnosed with a liver tumor. The cancerous tissue was imaged, mapped, and a treatment plan was developed. Using an inverse treatment plan optimization protocol, an optimal URS plate combination was established to match the Bragg peak of the shifted and compensated ionizing radiation to the distal end of the target tissue with the following parameters:

[0142] [Table 2]

[0143] FLASH-RT treatment was then delivered to the cancerous tissue in six radiation fields spaced at 60° angles.

[0144] Example 4 (Brain tumor treatment) A 41 year old male was diagnosed with a brain tumor. The cancerous tissue was imaged, mapped, and a treatment plan was developed. Using an inverse treatment plan optimization protocol, an optimal URS plate combination was established to match the Bragg peak of the shifted and compensated ionizing radiation to the distal end of the target tissue with the following parameters:

[0145] [Table 3]

[0146] FLASH-RT treatment was then delivered to the cancerous tissue in four radiation fields spaced at 90° angles.

[0147] Example 5 (Brain tumor treatment) A 21 year old male was diagnosed with a brain tumor. The cancerous tissue was imaged, mapped, and a treatment plan was developed. Using an inverse treatment plan optimization protocol, an optimal URS plate combination was established to match the Bragg peak of the shifted and compensated ionizing radiation to the distal end of the target tissue with the following parameters:

[0148] [Table 4]

[0149] FLASH-RT treatment was then delivered to the cancerous tissue in eight radiation fields spaced at 45° angles.

[0150] Example 6 (Treatment of liver tumors) A 56-year-old woman was diagnosed with a liver tumor. The cancerous tissue was imaged, mapped, and a treatment plan was developed. Using an inverse treatment plan optimization protocol, an optimal URS plate combination was established to match the Bragg peak of the shifted and compensated ionizing radiation to the distal end of the target tissue with the following parameters:

[0151] [Table 5]

[0152] FLASH-RT treatment was then delivered to the cancer tissue in three radiation fields spaced at an angle of 120°.

[0153] Example 7 (Treatment of esophageal tumors) A 51-year-old man was diagnosed with an esophageal tumor. The cancerous tissue was imaged, mapped, and a treatment plan was developed. Using an inverse treatment plan optimization protocol, an optimal URS plate combination was established to match the Bragg peak of the shifted and compensated ionizing radiation to the distal end of the target tissue with the following parameters:

[0154] [Table 6]

[0155] FLASH-RT treatment was then delivered to the cancerous tissue in five radiation fields spaced at an angle of 72°.

[0156] Finally, although aspects of the present specification have been emphasized by reference to specific embodiments, it should be understood that those skilled in the art will readily appreciate that these disclosed embodiments are merely illustrative of the principles of the subject matter disclosed herein. Therefore, it should be understood that the disclosed subject matter is in no way limited to the specific methodology, protocols, and / or reagents, etc. described herein. Thus, various modifications or alterations to the disclosed subject matter, or alternative configurations of the disclosed subject matter, may be made in accordance with the teachings herein without departing from the spirit of the specification. Finally, the terms used herein are for the purpose of describing particular embodiments only, and are not intended to limit the scope of the present disclosure, which is defined solely by the claims. Thus, the embodiments of the present disclosure are not limited to the exact embodiments shown and described.

[0157] Certain embodiments are described herein, including the best mode known to the inventors for carrying out the methods and apparatus described herein. Of course, variations of these described embodiments will become apparent to those of ordinary skill in the art upon reading the above description. Accordingly, this disclosure includes all modifications and equivalents of the subject matter recited in the claims appended hereto to the extent permitted by applicable law. Moreover, any combination of the above-described embodiments in all possible variations thereof is encompassed by this disclosure unless otherwise stated herein or clearly contradicted by context.

[0158] Groupings of alternative embodiments, elements, or steps in the present disclosure should not be construed as limitations. Each group member may be referenced and claimed individually or in any combination with other group members disclosed herein. It is contemplated that one or more members of a group may be included in or deleted from a group for reasons of convenience and / or patentability. When such inclusion or deletion is made, the specification will be deemed to include the group as modified and thus satisfy the written description requirement of all Markush groups used in the appended claims.

[0159] Unless otherwise indicated, all numbers expressing features, items, quantities, parameters, properties, periods, etc. used in the specification and claims should be understood in all instances as being modified by the term "about". As used herein, the term "about" means that the feature, item, quantity, parameter, property, or period so modified encompasses a range of plus or minus 10 percent above or below the value of the stated feature, item, quantity, parameter, property, or period. Thus, unless otherwise indicated, the numerical parameters set forth in the specification and appended claims are approximations that may vary. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical indication should be construed in light of at least the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and values ​​setting forth the broad scope of the present disclosure are approximations, the numerical ranges and values ​​set forth in the specific examples are reported as precisely as possible. However, any numerical range or value inherently contains certain errors necessarily resulting from the standard deviation in the testing measurements of each of these numerical ranges or values. The recitation of numerical ranges of values ​​herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, and unless otherwise stated herein, each separate value in a numerical range is incorporated herein as if it were individually set forth herein.

[0160] As used in the context of describing the present disclosure (particularly in the context of the claims), the terms "a," "an," "the," and similar referents should be construed to encompass both the singular and the plural, unless otherwise stated herein or otherwise clearly contradicted by context. All methods described herein may be performed in any suitable order, unless otherwise stated herein or otherwise clearly contradicted by context. The use of any examples or exemplary language (e.g., "etc.") provided herein is intended only to better clarify the disclosure and does not impose limitations on the scope of the claims, as otherwise described. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the embodiments disclosed herein.

[0161] Specific embodiments disclosed herein may be further limited in the claims by using the phrases "consisting of" or "consisting essentially of." When used in a claim, whether as originally filed or added by amendment, the transition term "consisting of" excludes any component, step, or ingredient not recited in the claim. The transition term "consisting essentially of" limits the scope of the claim to those materials or steps recited and those materials or steps that do not materially affect the basic and novel characteristic(s). The embodiments of the disclosure thus claimed are inherently or explicitly described and enabled herein.

[0162] Disclosed Embodiments (Embodiment 1) 1. A method for delivering a field of ionizing radiation to a target tissue, comprising: providing ionizing radiation; shifting the range of the ionizing radiation by passing the ionizing radiation through an adjustable range shifter so that a Bragg peak of the ionizing radiation coincides with the target tissue; compensating the range of the ionizing radiation by passing the ionizing radiation through an adjustable range compensator such that a Bragg peak of the ionizing radiation coincides with the target tissue; forming at least two fields of shifted compensated ionizing radiation by directing at least two fields of the shifted and compensated ionizing radiation to the target tissue to provide a uniform dose distribution across a target volume; Including, method.

[0163] (Embodiment 2) The at least two fields of the shifted and compensated ionizing radiation are directed at a dose rate of at least 40 Gy / s. 2. The method of embodiment 1.

[0164] (Embodiment 3) the at least two fields of the shifted and compensated ionizing radiation do not extend substantially in a proximal direction beyond a distal end of the target site. 3. The method according to embodiment 1 or 2.

[0165] (Embodiment 4) the at least two fields of shifted compensated ionizing radiation include protons, helium, carbon, argon, or neon; 4. The method according to any one of embodiments 1 to 3.

[0166] (Embodiment 5) the at least two fields of the shifted compensated ionizing radiation include protons; 5. The method according to any one of embodiments 1 to 4.

[0167] (Embodiment 6) The target site comprises cancer tissue; 6. The method according to any one of embodiments 1 to 5.

[0168] (Embodiment 7) the range shifter comprises a plurality of plates for shortening the range of the ionizing radiation, and the combination of the range shifters is calculated by applying parameters determined using an inverse treatment plan optimization protocol, the parameters including the number and positions of the plates through which the ionizing radiation passes; 7. The method according to any one of embodiments 1 to 6.

[0169] (Embodiment 8) the range compensator contour is calculated by applying parameters determined using an inverse treatment plan optimization protocol; 8. The method according to any one of embodiments 1 to 7.

[0170] (Embodiment 9) the inverse treatment plan optimization determines the distribution parameters of the ionizing radiation. 9. The method of embodiment 8.

[0171] (Embodiment 10) The inverse treatment plan optimization determines the weighting parameters of the ionizing radiation. The method according to embodiment 8 or 9.

[0172] (Embodiment 11) the at least two fields of the shifted compensated ionizing radiation include three fields of the shifted compensated ionizing radiation; 11. The method according to any one of embodiments 1 to 10.

[0173] (Embodiment 12) the at least two fields of the shifted compensated ionizing radiation include four fields of the shifted compensated ionizing radiation; 12. The method according to any one of embodiments 1 to 11.

[0174] (Embodiment 13) the at least two fields of the shifted compensated ionizing radiation include five fields of the shifted compensated ionizing radiation; 13. The method according to any one of embodiments 1 to 12.

[0175] (Embodiment 14) 1. A system for administering at least two fields of shifted and compensated ionizing radiation to a target tissue, comprising: an ionizing radiation source configured to generate a beam of charged particles; a universal range shifter adapted to shift the range of the charged particle beam so that the Bragg peak of the charged particle beam coincides with the target tissue; a range compensator adjusted to compensate the range of the charged particle beam so that the Bragg peak of the ionizing radiation coincides with the contour of the target tissue; Equipped with system.

[0176] (Embodiment 15) The at least two radiation fields are irradiated at a dose rate of at least 40 Gy / s; 15. The system of embodiment 14.

[0177] (Embodiment 16) the at least two radiation fields do not extend substantially proximally beyond the distal end of the target tissue; 16. The system of embodiment 14 or 15.

[0178] (Embodiment 17) The target tissue comprises a neoplasm or a benign tumor. A system described in any one of embodiments 14 to 16.

[0179] (Embodiment 18) the range shifter comprises a plurality of plates for shortening the range of the ionizing radiation, and the combination of the range shifters is calculated by applying parameters determined using an inverse treatment plan optimization protocol, the parameters including the number and positions of the plates through which the ionizing radiation passes; A system described in any one of embodiments 14 to 17.

[0180] (Embodiment 19) the range compensator contour is calculated by applying parameters determined using an inverse treatment plan optimization protocol; A system described in any one of embodiments 14 to 18.

[0181] (Embodiment 20) The at least two fields of shifted compensated ionizing radiation include three fields. A system described in any one of embodiments 14 to 19.

[0182] (Embodiment 21) The at least two fields of shifted compensated ionizing radiation include four fields. A system described in any one of embodiments 14 to 29.

[0183] (Embodiment 22) The at least two fields of the shifted and compensated ionizing radiation include five fields. A system described in any one of embodiments 14 to 21.

[0184] (Embodiment 23) 1. A system for generating at least two shifted and compensated particle beam fields at a dose rate of at least 40 Gy / s, comprising: a source of ionizing radiation configured to generate a particle beam; a universal range shifter configured to adjustably shift the range of the particle beam; a range compensator configured to adjustably compensate for the range of the particle beam; Equipped with system.

[0185] (Embodiment 24) The particle beam includes protons, helium, carbon, argon, or neon. 24. The system of embodiment 23.

[0186] (Embodiment 25) 1. A method of treating a target tissue, comprising: diagnosing the target tissue; mapping the target tissue; developing a radiation therapy treatment plan for administering an effective amount of the shifted and compensated ionizing radiation to said target tissue; a source of ionizing radiation configured to generate a particle beam; a universal range shifter adapted to shift the range of the proton / particle beam so that the Bragg peak of the particle beam coincides with the target tissue; a range compensator adjusted to compensate the range of the particle beam so that the Bragg peak of the particle beam coincides with the contour of the target tissue; Shifting and compensating for ionizing radiation using a system comprising: administering the particle beam to the target tissue; Including, method.

[0187] (Embodiment 26) The particle beam is irradiated at a dose rate of at least 40 Gy / s. 26. The method of embodiment 25.

[0188] (Embodiment 27) The target tissue comprises a neoplasm or a benign tumor. 26. The method of embodiment 25.

[0189] (Embodiment 28) the particle beam does not extend substantially proximally beyond the distal end of the neoplasm or benign tumor; 27. The method of embodiment 26.

[0190] (Embodiment 29) the range shifter comprises a plurality of plates for shortening the range of the ionizing radiation, and the arrangement of the range shifter plates is determined by applying parameters calculated using an inverse treatment plan optimization protocol, the parameters including the number and positions of the plates through which the ionizing radiation passes; 29. The method according to any one of embodiments 25 to 28.

[0191] (Embodiment 30) the shape of the range compensator is calculated by applying parameters determined using an inverse treatment planning optimization protocol. 30. The method of any one of embodiments 25 to 29.

[0192] (Embodiment 31) The at least two fields of shifted compensated ionizing radiation include three fields. The method according to any one of embodiments 25 to 30.

[0193] (Embodiment 32) The at least two fields of shifted compensated ionizing radiation include four fields. 32. The method according to any one of embodiments 25 to 31.

[0194] (Embodiment 33) The at least two fields of the shifted and compensated ionizing radiation include five fields. 33. The method according to any one of embodiments 25 to 32.

[0195] (Embodiment 34) The particle beam includes protons, helium, carbon, argon, or neon. The method according to any one of embodiments 25 to 33.

[0196] (Embodiment 35) 1. A method for calibrating a proton therapy device, comprising: receiving a treatment plan designed to apply FLASH-RT to a target region, the treatment plan including a target region, a three-dimensional target shape, a number of treatment fields, and a target dose rate of at least 40 Gy / s; changing the energy or range of the proton therapy device using a range shifter and a range compensator, the range shifter comprising a plurality of plates that shorten the range of the ionizing radiation; Including, The step of modifying includes determining range shifter and range compensator parameters using an inverse treatment planning protocol such that the Bragg peak of the energy output of the proton therapy device coincides with a target tissue, the parameters including the number and position of the plates through which the energy or range of the proton therapy device penetrates. method.

[0197] (Embodiment 36) the energy output of the proton therapy device does not extend substantially proximally beyond the distal end of the cancerous tissue; 36. The method of embodiment 35.

[0198] (Embodiment 37) Equipped with six polycarbonate plastic plates, it can generate range-shifted ionizing radiation by shortening the range of ionizing radiation between 0cm and 34cm in 1cm increments. Universal range shifter.

[0199] (Embodiment 38) The ionizing radiation includes protons, helium, carbon, argon, or neon. 38. A universal range shifter as described in embodiment 37.

[0200] (Embodiment 39) The ionizing radiation includes protons. 39. A universal range shifter as described in embodiment 38.

[0201] (Embodiment 40) The thicknesses of the six polycarbonate plastic plates are 1, 2, 3, 7, 7, and 14 cm in WET (water equivalent thickness). 38. A universal range shifter as described in embodiment 37.

[0202] (Embodiment 41) a universal range shifter, the universal range shifter comprising six polycarbonate plastic plates, capable of shortening the range of ionizing radiation between 0 cm and 34 cm in 1 cm increments to produce range-shifted ionizing radiation; Radiation therapy treatment equipment.

[0203] (Embodiment 42) The ionizing radiation includes protons or other ions. A radiation therapy treatment device as described in embodiment 41.

[0204] (Embodiment 43) The ionizing radiation includes protons. A radiation therapy treatment device as described in embodiment 42.

[0205] (Embodiment 44) The thicknesses of the six polycarbonate plastic plates are 1, 2, 3, 7, 7, and 14 cm when wet. A radiation therapy treatment device as described in embodiment 43.

[0206] (Embodiment 45) 1. A method for reducing the range of ionizing radiation between 1 cm and 34 cm in 1 cm increments, comprising the steps of passing said ionizing radiation through a universal range shifter comprising six polycarbonate plastic plates; method.

[0207] (Embodiment 46) The ionizing radiation includes protons, helium, carbon, argon, or neon. 46. ​​The method of embodiment 45.

[0208] (Embodiment 47) The ionizing radiation includes protons. 46. ​​The method of embodiment 45.

[0209] (Embodiment 48) The thicknesses of the six polycarbonate plastic plates are 1, 2, 3, 7, 7, and 14 cm when wet. 48. The method of embodiment 47.

[0210] (Embodiment 49) 1. A method of treating cancerous tissue, comprising: providing a penetrating beam of ionizing radiation having a dose rate of at least 40 Gy / s; adjusting the energy or range of the transmitted beam of ionizing radiation so that the Bragg peak of the beam coincides with a point between 3 mm and 5 mm away from an edge of the cancerous tissue; irradiating the cancerous tissue with the penetrating beam of ionizing radiation; Including, method.

[0211] (Embodiment 50) the ionizing radiation transmission beam comprises protons, helium, carbon, argon, or neon; 50. The method of embodiment 49.

[0212] (Embodiment 51) The ionizing radiation includes protons. The method of embodiment 50.

Claims

1. 1. A system for delivering at least two fields of ionizing radiation to a target tissue, comprising: an ionizing radiation supply unit that supplies ionizing radiation; shifting the range of the ionizing radiation by passing the ionizing radiation through an adjustable range shifter so that a Bragg peak of the ionizing radiation coincides with the target tissue; compensating for the range of the ionizing radiation by passing each field of the ionizing radiation through a separate range compensator, each range compensator having a three-dimensional topography that conforms the ionizing radiation to a shape of the target tissue; a radiation field forming unit for forming at least two radiation fields of shifted and compensated ionizing radiation by a field directing section for directing at least two fields of the shifted and compensated ionizing radiation to the target tissue to provide a uniform dose distribution across a target volume; Equipped with system.

2. The at least two fields of the shifted and compensated ionizing radiation are directed at a dose rate of at least 40 Gy / s. The system of claim 1 .

3. the at least two fields of the shifted and compensated ionizing radiation do not extend substantially in a proximal direction beyond a distal end of the target tissue.

3. A system according to claim 1 or 2.

4. the at least two fields of shifted and compensated ionizing radiation include protons, helium, carbon, argon, or neon; 3. A system according to claim 1 or 2.

5. the at least two fields of the shifted compensated ionizing radiation include protons; 3. A system according to claim 1 or 2.

6. The target tissue includes cancer tissue.

3. A system according to claim 1 or 2.

7. the range shifter comprises a plurality of plates for shortening the range of the ionizing radiation, and the combination of the range shifters is calculated by applying parameters determined using an inverse treatment plan optimization protocol, the parameters including the number and positions of the plates through which the ionizing radiation passes; 3. A system according to claim 1 or 2.

8. the range compensator contour is calculated by applying parameters determined using an inverse treatment plan optimization protocol; 3. A system according to claim 1 or 2.

9. the inverse treatment planning optimization protocol determines distribution parameters of the ionizing radiation. The system of claim 8.

10. the inverse treatment planning optimization protocol determines weighting parameters for the ionizing radiation. The system of claim 8.

11. the at least two fields of the shifted compensated ionizing radiation include three, four, or five fields of the shifted compensated ionizing radiation.

3. A system according to claim 1 or 2.

12. 1. A system for administration of at least two fields of shifted and compensated ionizing radiation to a target tissue, comprising: an ionizing radiation source configured to generate a beam of charged particles; a universal range shifter adapted to shift the range of the charged particle beam so that the Bragg peak of the charged particle beam coincides with the target tissue; at least two range compensators adjusted to compensate the range of the charged particle beam so that the Bragg peak of the ionizing radiation coincides with a contour of the target tissue, each of the range compensators having an optimal three-dimensional shape that conforms the charged particle beam to a shape of the target tissue; Equipped with system.

13. The at least two radiation fields are irradiated at a dose rate of at least 40 Gy / s; The system of claim 12.

14. the at least two radiation fields do not extend substantially proximally beyond the distal end of the target tissue; 14. A system according to claim 12 or 13.

15. The target tissue comprises a neoplasm or a benign tumor.

14. A system according to claim 12 or 13.

16. the universal range shifter comprises a plurality of plates for shortening the range of the ionizing radiation, the universal range shifter combination being calculated by applying parameters determined using an inverse treatment plan optimization protocol, the parameters including the number and positions of the plates through which the ionizing radiation passes; 14. A system according to claim 12 or 13.

17. the range compensator contour is calculated by applying parameters determined using an inverse treatment plan optimization protocol; 14. A system according to claim 12 or 13.

18. The at least two fields of shifted compensated ionizing radiation include three, four, or five fields.

14. A system according to claim 12 or 13.

19. 1. A system for generating at least two shifted and compensated particle beam fields at a dose rate of at least 40 Gy / s, comprising: a source of ionizing radiation configured to generate a particle beam; a universal range shifter configured to adjustably shift the range of the particle beam; at least two range compensators configured to adjustably compensate the range of the particle beam, each range compensator having an optimal three-dimensional shape that conforms the particle beam to a shape of a target; Equipped with system.

20. The particle beam includes protons, helium, carbon, argon, or neon.

20. The system of claim 19.

21. 1. A method for calibrating a proton therapy device, comprising: receiving a treatment plan designed to apply FLASH-RT to a target region, the treatment plan including a target region, a three-dimensional target shape, a number of treatment fields, and a target dose rate of at least 40 Gy / s; changing the energy or range of the proton therapy device using a range shifter and a range compensator, the range shifter comprising a number of plates that shorten the range of ionizing radiation, and the range compensator comprising an optimal three-dimensional shape that conforms the ionizing radiation to the shape of a target; Including, The step of modifying includes determining parameters of a range shifter and a range compensator using an inverse treatment planning protocol such that a Bragg peak of an energy output of the proton beam therapy device coincides with a target tissue, the parameters including the number and position of the plates through which the energy or range of the proton beam therapy device penetrates. method.

22. the energy output of the proton therapy device does not extend substantially proximally beyond the distal end of the target tissue; 22. The method of claim 21.

23. It is equipped with six polycarbonate plastic plates, and can generate range-shifted ionizing radiation by shortening the range of the ionizing radiation between 0 cm and 34 cm in 1 cm increments. Universal range shifter.

24. The ionizing radiation includes protons, helium, carbon, argon, or neon.

24. The universal range shifter of claim 23.

25. The ionizing radiation includes protons.

25. The universal range shifter of claim 24.

26. The thicknesses of the six polycarbonate plastic plates are 1, 2, 3, 7, 7, and 14 cm WET (water equivalent thickness); 24. The universal range shifter of claim 23.

27. a universal range shifter, the universal range shifter comprising six polycarbonate plastic plates, capable of shortening the range of ionizing radiation between 0 cm and 34 cm in 1 cm increments to produce range-shifted ionizing radiation; Radiation therapy treatment equipment.

28. The ionizing radiation includes protons or other ions.

28. A radiation therapy treatment device according to claim 27.

29. The ionizing radiation includes protons.

29. A radiation therapy treatment device according to claim 28.

30. The thicknesses of the six polycarbonate plastic plates are 1, 2, 3, 7, 7, and 14 cm when wet.

30. A radiation therapy treatment device according to claim 29.

31. 1. A method for reducing the range of ionizing radiation between 1 cm and 34 cm in 1 cm increments, comprising the steps of passing said ionizing radiation through a universal range shifter comprising six polycarbonate plastic plates; method.

32. The ionizing radiation includes protons, helium, carbon, argon, or neon.

32. The method of claim 31 .

33. The ionizing radiation includes protons.

32. The method of claim 31 .

34. The thicknesses of the six polycarbonate plastic plates are 1, 2, 3, 7, 7, and 14 cm when wet.

34. The method of claim 33.

Images