Apparatus for ultra-high dose rate radiotherapy

Abstract

The invention relates to a device for performing ultra-high dose rate radiotherapy on a patient, comprising: - a radiation source for providing a radiation beam, and - a linear accelerator for accelerating the radiation beam to a predetermined energy, and - a beam delivery module for delivering the accelerated radiation beam, the device being arranged for generating an accelerated radiation beam having a predetermined energy of about 50 MeV to about 250 MeV for delivering a radiation dose of at least 10 Gy in a total time of less than about 200 ms, thereby generating a radiation field for treating a target volume of at least about 30 cm 3 in diameter and / or for treating a target volume at least about 5 cm deep in a patient tissue with the ultra-high dose rate radiation dose.

Description

Technical Field

[0001] This invention relates to an apparatus for ultra-high dose rate radiotherapy. Background Technology

[0002] Cancer is a leading cause of death worldwide, and it is primarily treated with surgery, radiation therapy (RT), and chemotherapy. Despite significant advances in recent years in immunotherapy, robotic surgery, and the introduction of new molecularly targeted drugs, its incidence is rapidly increasing, while cure rates have only improved slowly.

[0003] Since the pioneering work of Röntgen and Marie Curie in the early 20th century, radiation therapy has been an important tool in the treatment of cancer. Although recent advancements in radiation therapy have made these treatments more precise and effective, remaining side effects, such as damage to healthy tissues, remain a problem limiting its use.

[0004] Delivering high therapeutic doses of radiation to tumors depends on the ability to shield normal tissue from the harmful effects of radiation. In the last century, fractionation and precise volume optimization appeared to be the most powerful tools for achieving differential effects between normal tissue and tumors, thereby minimizing side effects.

[0005] An emerging alternative and complementary solution to limit radiation damage to normal tissues is reducing irradiation time in so-called FLASH radiotherapy (RT), or FLASH therapy. Conventional radiotherapy treatment typically aims to deliver a total dose of 20 to 70 Gy per tumor, usually administered in 2 Gy per fraction over several minutes. Numerous experiments conducted in recent years have demonstrated that RT with ultrashort irradiation times (less than 100 ms) can significantly reduce side effects. Notably, it has been shown that when radiation is delivered in extremely high doses and ultra-high dose rates in ultra-intense pulses (typically with a dose per pulse greater than 1.5 Gy and an average dose rate within the pulse greater than 10), the side effects are significantly reduced. 6 When Gy is delivered, healthy tissue is spared, while the tumor tissue response remains unchanged, resulting in more effective treatment.

[0006] The paper “Treatment of the first patient with FLASH RT” from J. Bouhrhis et al., Radiotherapy and Oncology, 2019, Radiother Oncol., 2019, Jul 11, S0167-8140(19)32959-7, describes a pioneering clinical application of FLASH RT. This paper discloses the use of existing RT equipment to treat superficial skin tumors with electrons at 5.6 MeV, delivering a dose of 15 Gy in 10 pulses (1 μs each) for a total irradiation time of 90 ms, corresponding to an average dose rate of 150 Gy / s. The FLASH RT response associated with delivering 15 Gy over 90 ms was minimal compared to skin responses following conventional RT exposure using fractionated irradiations of 20 to 21 Gy. This experience demonstrates the technical feasibility and clinical safety of delivering a high single dose to patients instead of equivalent conventional doses fractionated over several minutes of irradiation.

[0007] The first key aspect of FLASH RT is the dose rate of the radiation beam: high radiation doses, typically delivered in fractions over several minutes in conventional RT, must be delivered in FLASH RT within very limited fractions of a second, usually in the millisecond range. The second key aspect of FLASH RT is that, compared to the FLASH requirement described so far for achieving healthy tissue retention in small irradiation fields (within a few centimeters), effective retention of healthy tissue in large irradiation fields (greater than or equal to 10 cm) demands much shorter delivery times.

[0008] It is known that electron loss in water is approximately 2 MeV / cm, therefore, a radiation beam of about 6 MeV can only be used to treat skin tumors or other superficial tumors. For this reason, electron beams are generally not used to treat tumors located deep within the body. FLASH electron therapy for deep tumors requires electron beams with higher energies, such as those in the range of 30 MeV to 250 MeV or higher.

[0009] Another problem arises when using RT or FLASH RT to treat large tumors. Existing RT instruments cannot treat large tumors using FLASH RT because the generated radiation beam does not have the characteristics required to deliver the desired dose under FLASH conditions.

[0010] Overall, existing technologies do not offer satisfactory solutions for treating deep and / or large tumors using FLASH RT, particularly because they are not suitable for generating ultra-high dose-rate electron beams with the energy required to treat large and / or deep tumors. Summary of the Invention

[0011] The apparatus and method according to the present invention solve the above-mentioned problems.

[0012] This invention relates to an apparatus for administering ultra-high dose rate radiotherapy to a patient, the apparatus comprising:

[0013] - A radiation source used to provide a radiation beam, and

[0014] - A linear accelerator for accelerating the radiation beam to a predetermined energy, and

[0015] - Beam delivery module for delivering an accelerated radiation beam from the linear accelerator (3) to the patient to treat the target volume with radiation dose.

[0016] The device is characterized in that it is configured to generate an accelerating radiation beam having a predetermined energy of about 50 MeV to about 250 MeV, more preferably about 120 MeV to about 150 MeV, to deliver an ultra-high dose rate radiation dose of at least about 10 Gy, preferably at most about 25 Gy, preferably at most about 35 Gy, more preferably at most about 40 Gy, within a total time of less than about 200 ms, preferably less than about 100 ms, preferably less than about 50 ms, preferably less than about 10 ms.

[0017] The device is configured to generate a radiation field for treating at least about 30 cm with the ultra-high dose rate radiation dose. 3 Preferably about 30cm 3 Approximately 1000cm 3 The target volume, and / or the ultra-high dose rate radiation dose is used to treat a target volume located at a depth of at least about 5 cm, preferably about 5 cm to about 25 cm, in the patient's tissue.

[0018] In this invention, the device allows the generation of an accelerated radiation beam of at least about 50 MeV and about 250 MeV, more preferably about 120 MeV to about 150 MeV. Using this very high energy and total charge of the generated accelerated beam, a radiation dose of up to about 25 Gy, up to about 35 Gy, more preferably up to about 40 Gy, can be delivered over a total time in the millisecond range.

[0019] In a preferred embodiment, the device is configured to generate an accelerating radiation beam having a predetermined energy of about 50 MeV to about 250 MeV, more preferably about 120 MeV to about 150 MeV, to deliver an ultra-high dose rate radiation dose of at least about 10 Gy, preferably up to about 25 Gy, preferably up to about 35 Gy, more preferably up to about 40 Gy, over a total time of less than about 200 ms, preferably less than 100 ms, preferably less than 50 ms, and preferably less than about 10 ms.

[0020] In one implementation, the total time is less than about 1 ms.

[0021] When it comes to generating a large radiation field under FLASH conditions (ultra-high dose rate), for example for at least about 30 cm... 3 Ideally, it should be about 30cm. 3 Approximately 1000cm 3 More preferably about 30cm 3 Up to at least approximately 1000cm 3 For target volumes at depths of at least approximately 5 cm within patient tissue, existing instruments are unable to deliver the required dose under FLASH conditions, particularly because the power of the accelerating beam is insufficient to provide the required dose to the entire target volume over a total duration in the millisecond range. The same applies when the target volume is located at a depth of at least approximately 5 cm within patient tissue; existing devices are unable to deliver ultra-high dose rate radiation (i.e., FLASH).

[0022] The energy of the electron beam determines the depth to which it penetrates water or tissue. Considering existing FLASH therapy using a 6 MeV radiation beam, 85% of the dose is achieved at 2 cm. Beyond 2 cm, the beam attenuates significantly, making it impossible to treat the target volume under FLASH conditions. In other words, the energy level of the radiation beam depends on the depth of the target volume within the tissue. This is why existing devices can only be used to treat superficial target volumes under FLASH conditions.

[0023] In this invention, accelerated high-energy beams are suitable for delivering the required dose to the entire target volume, whether large or deep. For example, with a 30 MeV radiation beam, we found 85% of the dose at a depth of approximately 10 cm. Therefore, in terms of penetration capability, this type of high-energy beam is equivalent to high-energy megavolt X-rays. Increasing the energy of the radiation beam allows for adjustment of the penetration depth. A radiation beam of at least 30 MeV is required to target large or deep target volumes. Although there is no upper limit to energy, radiation beams ranging from 50 MeV to 150 MeV generally provide the necessary depth for any patient. Irradiation at these energies under FLASH conditions has never been achieved on patients, especially for large fields (diameters exceeding 10 cm).

[0024] Advantageously, compared with conventional RT, the present invention provides significantly fewer side effects in healthy tissues while maintaining the full effect on tumors.

[0025] Utilizing this invention, due to the very short treatment time and the possibility of controlling or adjusting the accelerated beam delivery method (e.g., bending the electron beam with a magnet), the accelerated beam can be easily switched from one room / patient to another. This invention is a cost-efficient device because a single accelerated beamline can serve a large and potentially unlimited number of treatment rooms. It can continuously deliver the required dose to a large number of patients.

[0026] In this invention, efficacy against multidrug-resistant tumors is significantly improved due to the ability to deliver a greater bioequivalent dose (BED) to large tumors compared to conventional RT. For example, the feature of this invention, which allows for a FLASH retention effect of approximately 33% of the prescribed dose on healthy tissue, is integrated into the treatment planning system and compared with conventional RT. This translates to the possibility of safely delivering a single FLASH dose of 28 Gy to a patient who has already received 23 fractions of palliative conventional radiotherapy at a dose of 46 Gy for the same patient and the same tumor. Such a single 28 Gy irradiation provides a bioequivalent dose (BED) to the tumor exceeding 100 Gy, which is considered highly effective, especially compared to the actual administered conventional 46 Gy.

[0027] Advantageously, this invention offers the possibility of significantly reducing the total number of radiotherapy sessions required to treat a patient with the desired therapeutic dose compared to conventional RT. For example, a total dose of 28 Gy can be delivered in a single FLASH, whereas with conventional RT it requires multiple sessions (typically about 12 or 14). In conventional RT, tumor movement needs to be monitored during radiotherapy to reduce non-monitory portions around the tumor and limit the volume of healthy tissue exposed to high doses of radiation. In this invention, the ultrafast delivery of doses in the millisecond range makes tumor movement management during irradiation irrelevant. It also allows for better conformal beam delivery, thus more effectively preserving healthy tissue.

[0028] Specifically, the accelerating beam (i.e., the radiation beam) is an ultra-high-energy electron (VHEE) beam having a charge of at least about 1000 nC, preferably at least about 1500 nC. Advantageously, the dose is proportional to the charge. In this invention, the device is configured to provide a high charge of at least 1000 nC, thereby providing a high dose.

[0029] The device according to the invention may include two complementary methods to achieve a high degree of conformality in dose distribution:

[0030] -1) Several beamlines (preferably two or three, to maintain FLASH conditions) converge simultaneously from different angles and / or from one sub-beam to another.

[0031] -2) Shape each beamline individually.

[0032] This allows for the addition of more FLASH features while maintaining a high degree of conformality.

[0033] In a preferred embodiment, the beam delivery module includes a separation member for separating the accelerated radiation beam (referred to as a single accelerated beam) into a plurality of accelerated beamlines, the accelerated beamlines delivering a radiation dose of about 7 Gy / beam, preferably about 10 Gy / beam, and more preferably about 20 Gy / beam over the total time.

[0034] In one embodiment, the linear accelerator is configured to generate a single accelerated beam comprising multiple queues of particle bunches, preferably two or three queues of particle bunches. The beam delivery module includes a separation member for separating the single accelerated radiation beam into multiple accelerated beamlines separated at defined angles, and then converging each of the accelerated radiation beamlines toward the patient to simultaneously reach the target volume. Each beamline corresponds to one queue of particle bunches.

[0035] Advantageously, in this embodiment, the linear accelerator is configured to accelerate and propagate multiple portions of the beam at discrete energies. In conventional treatment, the patient is irradiated from multiple angles to achieve the desired conformity. This is achieved by rotating the radiation source around the patient. Under FLASH conditions, i.e., durations of at most a few milliseconds, there is insufficient time to move large objects. Instead, in this embodiment, within the FLASH timescale, we use, for example, two to three trajectories to achieve the desired conformity. For example, in the total treatment time in the ms (milliseconds) range, the upper half of the accelerated beam comes from one direction, while the lower half comes from another. In this invention, we can propagate the beam through different beamlines by accelerating the beam to different energies, rather than moving the object. For example, an energy difference of at least about 10% is sufficient to separate them in a dipole magnet. Preferably, the total energy is selected based on clinical considerations.

[0036] Advantageously, the accelerated radiation beam can be split into several beamlines. In a single treatment session, the accelerated beam radiation can simultaneously (within milliseconds) reach the patient from one or more directions. The advantage of splitting the beam is that it achieves a high degree of conformality in dose delivery to the tumor.

[0037] In a preferred embodiment, the inventors have found that three (3) and preferably two (2) beams simultaneously converged in the target volume provide very satisfactory results for achieving high conformity on the tumor and optimal FLASH retention of healthy tissue along the trajectory (i.e., the path) of each individual beam (FLASH retention of healthy tissue works better at high doses (i.e., above 10 Gy per beam), for example, for delivering a total dose of 20 Gy.

[0038] The FLASH effect is required to preserve a significant amount of healthy tissue. FLASH is essentially observable at each high dose, meaning that for effective preservation of normal tissue along each beam, it is crucial that only a small amount of the beam converges on the tumor. For example, when administering 20 Gy with two beams, the FLASH retention effect along each beam trajectory should be maintained if only two beams (10 Gy each) or three beams (7 Gy each) are used, but if more beams are used, the FLASH retention effect along each beam trajectory should disappear (below 7 Gy). Advantageously, when using two or three beams, the device combines the possibility of obtaining optimal FLASH retention with very good dose distribution conformality. Both high conformality and FLASH contribute to effective protection of normal tissue, whereas in existing devices, only high conformality can be utilized.

[0039] In particular, if used more than once, such as twice, the beam arrangement in terms of emission characteristics can be different each time, for example, by simply moving the patient cabin by 90°. This can increase conformity.

[0040] In one implementation, each column has an energy difference of at least about 10%, and / or each beamline has an energy of at least about 50 MeV.

[0041] In one embodiment, the separation component is selected from a list including energy-based separation components using a magnetic spectrometer and components based on a radio frequency deflector.

[0042] In one embodiment, a radio frequency deflector is used to separate the accelerated beam into beamlines along different trajectories. In this embodiment, a single energy beam can be separated into several beamlines.

[0043] In one implementation, the particle bundles in each queue have at least about 10% different energies, and a magnetic spectrometer is used for trajectory separation in the beam delivery system.

[0044] To separate the beams by energy using a magnetic spectrometer, the linear accelerator accelerates the beams with two or more energies and transmits them to a beam delivery system. These energies preferably differ by at least about 10%. This is accomplished, for example, by changing the input radio frequency power level, moving the particle beams from one queue to another (e.g., about 10 queues of particle beams per treatment). Alternatively, it can be done within a radio frequency pulse by changing the radio frequency phase in which the particle bundles reside. The different energy beams are deflected at different angles in the first dipole, as in a magnetic spectrometer. The beams then converge simultaneously (within milliseconds) onto the target volume along different paths.

[0045] In a dipole magnet, higher-energy beams bend relatively less than lower-energy beams. All the particle clumps emerge from the linear accelerator along the same line, but bend at different angles in the first dipole. Given a certain length, they move along trajectories that are far apart from each other. At a sufficient distance, they can bend backward toward the patient and converge on the tumor.

[0046] Advantageously, using energy-based separation components of a magnetic spectrometer is a preferred solution, for example, because it is cheaper than components based on radio frequency deflectors.

[0047] The beam delivery module with radio frequency deflectors uses a radio frequency field instead of a static magnetic field to deflect the beam. Its pulse pattern is the same as that of a linear accelerator, so each beam can be deflected individually.

[0048] Specifically, after separation in the main dipole, the accelerated radiation propagates along different beamlines. After the radiation is deflected back to the patient, these beamlines converge on the tumor at an angle, typically 30° to 90°, more preferably 30° to 60°, particularly 30° to 60°. Preferably, a deflection element for each beamline guides the beamline to the patient at a defined angle. The number and angle of the beams are carefully optimized in conjunction with clinical dose distribution considerations.

[0049] It is well known that in RT and particle therapy, it is advantageous to deliver the dose to the target volume from different directions to achieve optimal conformality of dose distribution. In conventional RT instruments, a moving linear collimator is used to optimize the dose that can be delivered to the target volume. However, mechanical movement is not feasible within the FLASH timescale (millisecond range, i.e., the ms range). In one embodiment, the solution of the present invention is to provide different beamlines, preferably two or three, which will converge precisely at the same location in the target volume at exactly the same time (i.e., within the millisecond range). This allows for the preservation of healthy tissue through high conformality of beam delivery and the FLASH effect.

[0050] The number of paths (i.e. beamlines) is preferably two or three, because with more paths / beamlines, the FLASH effect, which is essentially run at a high dose each time, will be significantly reduced or completely suppressed.

[0051] Advantageously, the present invention can have two complementary approaches to achieve optimal conformal dose distribution; the first is controlling the shape of each accelerating beamline, and the second is splitting the initial beam into several beamlines that converge simultaneously within the tumor. Overall, the present invention has the unique ability to provide highly conformal radiation delivery and the optimal parameters required for treating large tumors in FLASH mode.

[0052] In one embodiment, the apparatus includes a beamforming member for controlling conformal irradiation of the beam arriving at the target volume, such as a shaping member in a delivery system, preferably after the linear accelerator. For example, the beamforming member includes a focusing member that provides control over the lateral dimensions of the accelerated beam or accelerated beamline to achieve optimal beam shaping and optimal therapeutic conformity for target volumes with complex shapes.

[0053] Multiple components can be used to control the lateral beam profile. For example, each major element of the device can have beam collimation, i.e., the beam in the radiation source (i.e., the injector), the linear accelerator (i.e., the linear accelerator (linac)), and the beam delivery system. Collimation in the radiation source and linear accelerator will provide the same shape, typically circular, for different beamlines, while collimation in the beam delivery system will provide independent shapes for different lines. The quadrupole for final focusing in the beam delivery system can also be used to adjust the focal point shape, for example, from circular to elliptical. Preferably, the most important collimation should be the collimation located at the end of the linear accelerator, and there can be a device with only this collimation.

[0054] In one embodiment, the radiation dose comprises radiation pulses of an accelerated radiation beam, each radiation pulse comprising at least one particle bundle, and the device is configured to deliver an ultra-high dose rate radiation dose at a rate of at least about 2 Gy / radiation pulse, preferably at least about 5 Gy / radiation pulse, more preferably at least about 10 Gy / radiation pulse, wherein the dose rate in the radiation pulse is at least about 10. 6 Gy / sec, preferably at least about 10 7The radiation pulses are typically less than 10 Gy / sec, and preferably less than 3. Therefore, the device is configured to deliver radiation under the FLASH conditions required to achieve the FLASH effect, even under large-field irradiation (greater than or equal to 10 cm), and with a total treatment time of 25 Gy in the range of milliseconds (less than 50 ms, preferably less than 10 ms), and a total number of radiation pulses less than 10 and preferably less than 3.

[0055] In one embodiment, the device is configured to deliver a dose with homogeneity (in other words, uniformity) covering at least about 85% of the target volume. Advantageously, homogeneity can be achieved through a combination of radiation source design (e.g., particularly the shape of the laser spot profile in the injector), linear accelerator design (e.g., control of the focusing grid and wakefields), and delivery modules (e.g., beam extension and collimation at the end of the linear accelerator). For example, collimation involves passing the beam through an aperture that cuts off the outer portion and provides a defined shape to the beam.

[0056] In one embodiment, the radiation source is an electron source. Therefore, the dose is delivered to the patient in the form of electrons.

[0057] Preferably, the radiation source is a high-current electron source.

[0058] In one embodiment, the radiation source is an electron source, and the device further includes a conversion module for converting the electron beam into a photon beam. Therefore, the dose is delivered to the patient in the form of photons.

[0059] In one embodiment, the radiation source is a proton source. Therefore, the dose is delivered to the patient in the form of protons.

[0060] In one embodiment, the radiation source (2) is configured to deliver the radiation dose in sequence of queues of particle bundles over the total time, the queues of particle bundles having the capability of up to ten queues of 250 nC particle bundles.

[0061] In one embodiment, the radiation source is selected from a list including radio frequency laser-driven injectors (referred to as RF guns) and thermionic injectors.

[0062] The RF gun consists of a radio frequency cavity system (S, C, or X band) and a short-pulse (1-2 ps) laser system. The laser strikes the cathode of the cavity system and emits an electron beam of approximately 1 nC. The beam is accelerated to, for example, approximately 5 MeV.

[0063] Thermionic implanters are based on thermionic emission, which is achieved by a continuous electron beam generated by a heated cathode. For example, the beam is focused and accelerated to about 5 MeV by a radio frequency cavity system.

[0064] The linear accelerator is designed to accelerate a beam from a radiation source to a final energy of at least about 30 MeV.

[0065] In one embodiment, the apparatus is configured to scan the target volume. During scanning, successive regions are irradiated, each under FLASH conditions. Between successive FLASH irradiations, the target regions are moved by resetting the beam trajectory in the beam delivery system. Thus, in a single scan, a volume is covered by a series of independent FLASH stereo pixels.

[0066] In one embodiment, the linear accelerator includes a radio frequency acceleration structure that accelerates the radiation beam (i.e., the required total charge) over the required total time.

[0067] In one embodiment, the linear accelerator is configured to accelerate one to at least ten queues of particle clusters, each queue being approximately 250 ns long and each queue containing 250 1 nC particle clusters, within 10 ms, thereby satisfying the FLASH condition. Preferably, the linear accelerator is configured to operate in burst mode at frequencies up to approximately 1000 Hz, and preferably in the range of approximately 100 Hz to 1000 Hz.

[0068] In one embodiment, the linear accelerator is configured to accelerate the beam with an acceleration gradient exceeding at least about 35 MeV / m.

[0069] In one embodiment, the linear accelerator operates at frequencies selected from a list including X-band, C-band, or S-band, preferably X-band.

[0070] In one embodiment, the linear accelerator is a linear accelerator based on a multi-GHz radio frequency system.

[0071] Preferably, the linear accelerator is a high-current linear accelerator, such as a high-current X-band linear accelerator. For example, the total charge of 2500 nC required for pre-collimation treatment consists of 10 rows of 250 nC / particle bundles. The length of one bundle is 250 ns, therefore the current is 1 A.

[0072] In one embodiment, the device includes components for stabilizing the beam to achieve a maximum radiation dose variation of approximately ±2% over a month. For example, the beam will be stabilized via feedback. Just before delivery to the patient, the beam will travel along a straight forward trajectory (if the delivery module includes an energy-based separation component using a magnetic spectrometer). A series of radiation pulses (a queue of particle bundles) are captured by diagnostic and machine parameters and adjusted to bring the charge to the desired value. Once completed, the beam will be directed at the patient. Feedback will also be provided during treatment by monitoring the dose of each radiation pulse (the queue of particle bundles) and correcting for deviations in subsequent radiation pulses (the queue of particle bundles).

[0073] In one embodiment, the device is configured to provide dose uniformity within at least about 80%, preferably at least about 85%, of the target volume at a depth of at least about 15 cm, preferably about 20 cm, in the tissue. A key advantage is less intratumoral dose variation.

[0074] In one embodiment, the dose is delivered in 3 to 20 radiation pulses, preferably 10. Advantageously, the number of pulses should be as small as possible, ideally one to three. The number of radiation pulses depends on the charge amount of each (RF) pulse, and this charge amount is primarily limited by the capability of the radiation source. It also depends on the stability of the beam delivery, wherein the beam passing through the linear accelerator preferably reaches about 1 Å. Finally, it is also related to the cost of the installed linear accelerator power system.

[0075] In one embodiment, the device includes at least two beam delivery modules, each configured to treat one patient. In this embodiment, multiple treatment rooms can be provided by a single electron source and a single linear accelerator. It is well known that a large portion of the equipment cost is in the system up to the linear accelerator, i.e., from the radiation source to the linear accelerator. Adding more delivery modules is highly cost-effective. Furthermore, since treatment time is much shorter than patient preparation time, the throughput of a facility with multiple delivery modules increases proportionally to the number of delivery modules.

[0076] The present invention also relates to a method for treating a patient's tumor target volume with ultra-high dose rate radiation, the method comprising:

[0077] - Provide an apparatus according to the invention;

[0078] - The device is configured to generate an accelerating radiation beam with a predetermined energy of about 50 MeV to about 250 MeV, more preferably about 120 MeV to about 150 MeV, to deliver an ultra-high dose rate radiation dose of at least about 10 Gy, preferably up to about 25 Gy, preferably up to about 35 Gy, more preferably up to about 40 Gy in a total time of less than about 200 ms, preferably less than about 100 ms, preferably less than about 50 ms, preferably less than about 10 ms.

[0079] - Deliver the radiation dose to a depth of at least 30 cm. 3 Preferably about 30cm 3 Approximately 1000cm 3 The target volume and / or the target volume located at a depth of at least about 5 cm, preferably about 5 cm to about 25 cm, in the patient's tissue.

[0080] The specific advantages of the method are similar to those of the apparatus of the present invention described herein, and therefore will not be repeated here.

[0081] In one implementation, the treatment includes:

[0082] - Deliver the radiation dose to a target volume located at a depth of at least about 10 cm in the patient's tissue and / or a target volume having a diameter of at least about 10 cm.

[0083] In one embodiment, the treatment comprises administering the dose in the form of radiation pulses of an accelerated radiation beam, the dose having a dose of at least about 2 Gy / radiation pulse, preferably at least about 5 Gy / radiation pulse, more preferably at least about 10 Gy / radiation pulse, the dose rate in the radiation pulse being at least about 10. 6 The dose is Gy / sec, and preferably, the total number of radiation pulses is less than 10, more preferably less than 3. In other words, the treatment includes administering the dose under conditions required to achieve the FLASH effect with large-field irradiation (diameter greater than or equal to 10 cm), i.e., the dose in the radiation pulse is at least 2 Gy and preferably higher, and the dose rate in the pulse is 10. 6 The total treatment time for a 25 Gy dose is in the range of milliseconds (less than 50 ms, preferably less than 10 ms), and the total number of radiation pulses is less than 10 and preferably less than 3.

[0084] The dose can be delivered in any number of radiation pulses. Preferably, the number of radiation pulses is less than 20. In one embodiment, the treatment comprises administering a dose delivered in 1 to 10 radiation pulses, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 radiation pulses.

[0085] In one implementation, the treatment includes administering the total dose in a single session.

[0086] In other embodiments, the treatment comprises administering the dose in several divided doses, such as two or three times. Preferably, the number of doses is less than three, which is suitable for achieving a FLASH effect.

[0087] In this invention, a large target volume refers to a target volume having a diameter of at least about 5 cm (equal to or greater than) and, if the target volume is not spherical, then the diameter means a dimension spanning the entire target volume. The target volume can be of any size or shape. For example, the diameter can be from about 5 cm to about 30 cm, preferably from about 5 cm to about 20 cm.

[0088] In this invention, the deep target volume refers to the target volume located at a depth of at least about 5 cm in the tissue, preferably at a depth of about 5 cm to 30 cm in the tissue, more preferably at a depth of about 5 cm to about 25 cm, and even more preferably at a depth of 10 cm to 20 cm.

[0089] In this invention, ultra-high dose rate radiation refers to FLASH radiotherapy or FLASH therapy. FLASH radiotherapy can be defined as a radiotherapy treatment in which, compared to conventional RT doses, the preservation of healthy tissue is equivalent to at least a dose reduction of approximately 33%, while maintaining the integrity of the effect on the tumor.

[0090] As used herein, the terms “treatment” or “treatment” refer to the treatment of a tumor or a subject diagnosed with a tumor. Such treatment may be administered in an amount or dose sufficient to or effectively kill tumor cells (i.e., a therapeutically effective amount), slow tumor growth, reduce tumor size, or completely eliminate the tumor from the subject. The term also includes the selection of a treatment or treatment plan, and the provision of treatment options to a healthcare provider or subject.

[0091] In some implementations, as described herein, the method of treating a patient's tumor target volume with ultra-high dose rate radiation further includes administering one or more adjunctive therapies selected from the group consisting of: therapeutic agents (e.g., chemotherapeutic agents, radioprotective agents, or radiosensitizers), immunomodulators (e.g., immune checkpoint inhibitor molecules, immune checkpoint activator molecules, chemokine inhibitors, macrophage migration inhibitory factor (MIF) inhibitors, growth factors, cytokines, interleukins, interferons, antibodies that bind to immune system cells (e.g., bispecific antibodies that bind to T cells and tumor antigens), cellular immunomodulators (e.g., CAR-T cells), vaccines, oncolytic viruses, and any combination thereof), anti-aging agents, radiosensitizers, nanoparticles, or combinations thereof. Adjunctive therapies may be administered concurrently, as adjuvants, or in a neoadjuvant procedure.

[0092] As used herein, the term "about" applies to numerical values ​​or ranges, and refers to a range of values ​​that a person skilled in the art would consider equivalent to the stated value (i.e., plus or minus ten percent). For example, "about 10 cm" means 10 cm + / - 10%, i.e., 9 cm to 11 cm. In this invention, dose refers to the total radiation dose delivered to the patient, in Gy. The dose may be administered in several doses.

[0093] As used herein, the term "patient" is recognized in the art and refers to mammals, including dogs, cats, rats, mice, monkeys, pigs, and most preferably, humans. In some embodiments, the patient is a patient requiring treatment or a patient with cancer. The term does not indicate a specific age or sex. Therefore, it is intended to cover adult patients and neonatal patients, whether male or female.

[0094] As used herein, the term "radio wave pulse" refers to a radio wave pulse used in a linear accelerator. Linear accelerators use radio wave pulses of microwave power to accelerate a radiation beam from a radiation source, such as an electron beam from an electron source. For example, these radio wave pulses are approximately 250 ns long and can be repeated in burst mode at a repetition rate of 1 kHz (i.e., a period of 1 ms). Preferably, for long-term operation, the optimal repetition rate is approximately 100 Hz. For example, the frequency of the microwave is in the X-band, specifically 12 GHz, but could also be in the C-band (5.7 GHz) or S-band (3 GHz).

[0095] As used herein, the term "radiation pulse" refers to a particle pulse following a linear accelerator. Each pulse accelerates at least one queue of particle clusters, for example, accelerating an electron beam if the radiation beam is an electron beam, or accelerating a proton beam if the radiation beam is a proton beam. For example, the particle clusters are approximately 10 ps long and occur once every 1 ns, thus there are 250 particle clusters in a 250 ns radio wave pulse. Each particle cluster has a charge of 1 nC, producing a total charge of 2500 nC (before collimation), and the average current during the pulse is 1 A.

[0096] The embodiments of the apparatus described herein are also applicable to methods modified as necessary according to the present invention.

[0097] The embodiments described herein for any method are also applicable to apparatuses modified as necessary according to the present invention. Attached Figure Description

[0098] Other particular advantages and features of the invention will become more apparent from the following non-limiting description of at least one embodiment of the invention with reference to the accompanying drawings, wherein...

[0099] - Figure 1 and Figure 2This refers to the apparatus according to the invention based on the first embodiment;

[0100] - Figure 3 A simulation of the use of the FLASH therapy of the present invention in a patient with a large (10 cm diameter) lung cancer is shown;

[0101] - Figure 4 The study showed the evolution of cognitive retention in the rat brain after 10 Gy brain irradiation with a 6 MeV electron beam;

[0102] - Figure 5 The simulation shows the radiation dose measured by irradiation of the human chest cavity using a single electron beam with an energy range of 25 MeV to 140 MeV. Detailed Implementation

[0103] This detailed description is intended to illustrate the invention in a non-limiting manner, as any feature of an embodiment can be advantageously combined with any other feature of a different embodiment.

[0104] Figure 1 and Figure 2 This refers to the apparatus 1 according to the invention based on the first embodiment.

[0105] The device 1 includes a radiation source 2, a linear accelerator 2, and a beam delivery module 3. The device 1 is configured to deliver a radiation dose to a target volume 5 (not shown) of a patient.

[0106] The radiation source 2 is a high-current electron source, specifically a radio frequency laser-driven optical injector. The optical injector generates electron beams and accelerates them to relative energies. The optical injector consists of a set of coupled resonant cavities powered by a klystron modulator system. Short laser pulses strike the backplate of the first cavity, causing electron emission via the photoelectric effect to form a beam. The backplate of the photocathode is coated with Cs₂Te to improve quantum efficiency and uses a laser with a wavelength of 262 nm. A microwave field of approximately 110 MV / m accelerates the beam. Continuous laser pulses during the RF pulse form a beam train. Continuous RF pulses generate multiple beam trains.

[0107] exist Figure 1 and Figure 2 In the illustrated embodiment, the optical injector operates in the S-band (specifically 2.9985 GHz), has 1.5 units, and accelerates the beam to 5 MeV. The optical injector is powered by a klystron and requires approximately 30 MW of input power.

[0108] The optical injector generates a charge beam of 0.308 nC, with a spacing of 1 / 3 ns between the beams, producing an average current of approximately 1 A during the pulse. Each column contains 953 beams. Each beam is approximately 300 micrometers long.

[0109] The linear accelerator 3, or linear accelerator (linac), is a high-current X-band linear accelerator. Figure 1 and Figure 2 In the illustrated embodiment, the linear accelerator has parameters for eight half-meter-long accelerating structures, operating with a beam load gradient of 35 MV / m. The linear accelerator is powered by two 50 MW peak power X-band klystrons and a radio frequency pulse compressor. The linear accelerator accelerates the beam to therapeutic energy. In this embodiment, the linear accelerator consists of repeating RF units, each comprising a klystron modulator, a radio frequency pulse compressor, a waveguide network, and multiple accelerating structures.

[0110] exist Figure 1 and Figure 2 In the illustrated embodiment, the linear accelerator accelerates a 5 MeV beam from the injector to an adjustable energy of up to 140 MeV. The linear accelerator operates in the X-band, specifically at 11.994 GHz. One RF unit consists of a modulator driving a 50 MW klystron, a pulse compressor, and four acceleration structures. The pulse compressor has a power gain coefficient of 2.8. Each acceleration structure is 0.5 cm long and operates in a 2π / 3 phase-leading traveling wave mode. Each RF unit provides a 70 MeV energy gain to the beam. The acceleration gradient for a nominal beam current of approximately 1 A is as high as 35 MV / m. The maximum energy provided by two RF units is 140 MeV.

[0111] The combination of magnetic elements and RF focusing controls the characteristics of the beam. The acceleration structure is equipped with high-order mode damping to transmit a high-current beam without instability.

[0112] The beam delivery module consists of normally conductive magnets; a main dipole magnet to deflect and separate beams of different energies, the dipole magnet providing a trajectory to enter the patient at a predetermined angle, and a quadrupole magnet to guide the beam and then control the irradiation point size of the beam entering the patient.

[0113] The beam delivery system shown in this embodiment consists of a separating magnet and a bending magnet (as a separating component) to separate a single accelerated beam into multiple beamlines and guide these beamlines to the patient. The separating magnet is used to direct the discrete energy sequence of the single beam into the multiple beamlines. The multiple beamlines diverge after the separating magnet. A bending magnet near the center of each beamline guides the particle trajectory back to the target volume. A quadrupole in each beamline also extends the beam from a millimeter size in a linear accelerator to a final treatment size that can be greater than 15 cm.

[0114] exist Figure 1 and Figure 2In the illustrated embodiment, the separating magnet has a length of 55.5 cm and a semi-aperture diameter of 15 mm. The bending magnet has a length of 80 cm and a semi-aperture diameter of 25 mm.

[0115] The quadrupole in the beamline has a length of 20 cm and a half-aperture of 18 mm to 35 mm.

[0116] Figure 3 This illustrates a simulation of the use of the FLASH therapy of the present invention in a patient with large lung cancer. In this example, the device according to the present invention was used to simulate FLASH-RT treatment in a patient with T4-N0 lung cancer having a tumor size of 10 cm.

[0117] In Figure 3 In this case, the tumor is located near key organs such as the brachial plexus and esophagus, such as... Figure 2 As shown, this patient would normally receive 46 Gy divided into 23 doses during conventional RT, which provides a tumor biologically equivalent dose (BED) of 46 Gy. Simulations of FLASH treatment using the device according to the invention allow for the safe delivery of a single dose of 28 Gy. This corresponds to a highly curative BED of 115 Gy for tumors. Advantageously, due to the FLASH conditions, this simulation incorporates 33% of normal tissue preservation factors.

[0118] Figure 4 The evolution of cognitive preservation in the rat brain following 10 Gy brain irradiation with a 6 MeV electron beam is shown. Experimental data are taken from P. Montay-Gruel et al., Radiother Oncol, 2017; 124: 365-9. The curves are logistic fits to the data. This figure shows how the neuroprotective effect, assessed by a novel object recognition test (vertical axis: percentage of recognition rate), varies with the total time of delivery of 10 Gy (horizontal axis: milliseconds). It clearly highlights the necessity of delivering radiation within less than 200 ms, preferably less than 100 ms, and more preferably less than 50 ms, as proposed in this invention to improve FLASH protection.

[0119] Figure 5 This diagram shows a simulation of radiation dose measurements penetrating the human pleural cavity using a single electron beam with an energy range of 25 MeV to 140 MeV. The thin lines correspond to dose variations (isodose) at a maximum depth of 20 Gy. The thick lines represent tumor volumes of 8 cm in diameter at a depth of 11 cm. Figure 5 This indicates that an energy level exceeding 50 MeV is required to avoid insufficient dose to deeper portions of the tumor, as described in this invention.

[0120] Although the embodiments have been described in conjunction with several implementations, it will be apparent to those skilled in the art that many alternatives, modifications, and variations will be or are obvious. Therefore, this disclosure is intended to cover all such alternatives, modifications, equivalents, and variations within the scope of this disclosure, for example, particularly with regard to different devices that may be used.

[0121] Figure Labels

[0122] 1. Apparatus according to the first embodiment

[0123] 2. Radiation source

[0124] 3. Linear accelerator

[0125] 4. Beam delivery module

Claims

1. An apparatus (1) for administering ultra-high dose rate radiotherapy to a patient, the apparatus comprising: -Radiation source (2), used to provide a radiation beam, and - A linear accelerator (3) for accelerating the radiation beam to a predetermined energy, and - Beam delivery module (4), for delivering an accelerated radiation beam from the linear accelerator (3) to the patient to treat the target volume with radiation dose, Its features are, The device (1) is configured to generate an accelerating radiation beam with a predetermined energy of 50 MeV to 250 MeV to deliver an ultra-high dose rate radiation dose of 10 Gy to 40 Gy in a total time of less than 200 ms. The device (1) is configured to generate a radiation field for treating at least 30 cm² with the ultra-high dose rate radiation dose. 3 The target volume, and / or the target volume located at a depth of at least 5 cm in the patient tissue treated with the ultra-high dose rate radiation dose, wherein the linear accelerator (3) is configured to generate a single accelerated radiation beam comprising multiple queues of particle bundles, wherein the beam delivery module (4) includes a separation member for separating the single accelerated radiation beam into multiple accelerated beamlines, the multiple accelerated beamlines delivering a radiation dose of 7 Gy / beam to 20 Gy / beam over the total time, and the multiple accelerated beamlines being separated at a defined angle, wherein each of the beamlines then converges to the patient to simultaneously reach the target volume, each beamline corresponding to several queues of particle bundles, and The beam delivery module includes a magnetic spectrometer.

2. The apparatus (1) according to claim 1, wherein the accelerating radiation beam has a predetermined energy of 120 MeV to 150 MeV.

3. The apparatus (1) according to claim 1, wherein the ultra-high dose rate radiation dose is 10 Gy to 25 Gy.

4. The apparatus (1) according to claim 1, wherein the ultra-high dose rate radiation dose is 10 Gy to 35 Gy.

5. The apparatus (1) according to claim 1, wherein the total time is less than 100 ms.

6. The apparatus (1) according to claim 1, wherein the total time is less than 50 ms.

7. The apparatus (1) according to claim 1, wherein the total time is less than 10 ms.

8. The apparatus (1) according to claim 1, wherein the target volume is 30 cm³. 3 Up to 1000 cm 3 .

9. The device (1) according to claim 1, wherein the target volume is located 5 cm to 25 cm deep in the patient tissue.

10. The apparatus (1) of claim 1, wherein the single accelerating radiation beam comprises two or three queues of particle bundles.

11. The apparatus (1) according to claim 1, wherein each queue has an energy difference of at least 10%, and / or each beamline has an energy of at least 50 MeV.

12. The apparatus (1) according to claim 1, wherein the apparatus (1) includes a beamforming member for controlling conformal irradiation of the beam reaching the target volume.

13. The apparatus (1) according to claim 12, wherein the beamforming member is a forming member following the linear accelerator.

14. The apparatus (1) of claim 1, wherein the radiation dose comprises radiation pulses of an accelerated radiation beam, each radiation pulse comprising at least one particle bundle, the apparatus (1) being configured to deliver the ultra-high dose rate radiation dose at a rate of at least 2 Gy / radiation pulse, the dose rate in the pulse being at least 10 6 Gy / sec, total number of pulses less than 10.

15. The apparatus (1) of claim 14, wherein the apparatus (1) is configured to deliver the ultra-high dose rate radiation dose at a rate of at least 5 Gy / radiation pulse.

16. The apparatus (1) of claim 14, wherein the apparatus (1) is configured to deliver the ultra-high dose rate radiation dose at a rate of at least 10 Gy / radiation pulse.

17. The apparatus (1) of claim 14, wherein the dose rate in the pulse is at least 10. 7 Gy / sec.

18. The apparatus (1) according to claim 14, wherein the total number of pulses is less than 3.

19. The apparatus (1) of claim 1, wherein the apparatus (1) is configured to deliver the dose with homogeneity covering at least 85% of the target volume.

20. The apparatus (1) according to claim 1, wherein the radiation source (2) is an electron source.

21. The apparatus (1) of claim 1, wherein the radiation source (2) is configured to deliver the radiation dose in the order of a queue of particle bundles over the total time, the queue of particle bundles having the capability of up to ten queues of 250 nC particle bundles.

22. The apparatus (1) according to claim 1, wherein the accelerating radiation beam is an ultra-high energy electron beam having a charge of at least 1000 nC.

23. The apparatus (1) according to claim 1, wherein the accelerating radiation beam is an ultra-high energy electron beam having a charge of at least 1500 nC.

24. The apparatus of claim 1, wherein the radiation source is selected from the list including radio frequency laser-driven injectors and thermionic injectors.

25. The apparatus (1) of claim 1, wherein the linear accelerator (3) comprises a radio frequency acceleration structure capable of accelerating the radiation beam over the required total time.

26. The apparatus (1) of claim 1, wherein the linear accelerator (3) operates at a frequency selected from a list including the X-band, C-band or S-band.

27. The apparatus (1) according to claim 1, wherein the apparatus (1) is configured to scan the target volume.

28. The apparatus (1) according to claim 1, wherein the apparatus (1) comprises at least two beam delivery modules (4), each delivery module being configured to treat a patient.

29. The apparatus (1) of claim 1, wherein the plurality of accelerating beamlines deliver a radiation dose of about 7 Gy / beam, or about 10 Gy / beam, or about 20 Gy / beam over the total time, wherein about represents a range of plus or minus ten percent of the stated value.

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