Method and system for using and controlling higher dose rate ionizing radiation in short time intervals

Abstract

The present invention provides strategies for using and controlling the delivery of ionizing radiation for therapeutic and industrial irradiation therapy. The present invention uses partial pulse control, component selection and / or component configuration strategies to accurately monitor and terminate irradiation. These strategies are particularly useful for controlling the administration of drugs at high dose rates and short time scales associated with FLASH technology.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 900,505, filed on September 14, 2019, entitled “CONTROL AND OPERATION OF ANELECTRON BEAM AT FLASH ENERGY LEVELS,” and U.S. Provisional Patent Application No. 62 / 986,104, filed on March 6, 2020, entitled “METHODS AND SYSTEMS FOR USING AND CONTROLLING HIGHERDOSE RATE IONIZING RADIATION IN SHORT TIME INTERVALS,” the entire corresponding contents of the disclosures of these U.S. Provisional Patent Applications are incorporated herein by reference for all purposes. Technical Field

[0003] The present invention relates to the field of methods and systems for using ionizing radiation for therapeutic and industrial processing. More specifically, the present invention relates to such methods and systems, wherein a fractional pulse strategy is used to control ionizing radiation to deliver an accurate dose even when the dose is delivered in short time intervals resulting in the use of a higher dose rate. Background Art

[0004] Ionizing radiation includes many forms of electromagnetic radiation, as well as proton beams, electron beams, etc. Ionizing radiation can be used in industrial applications and for radiation therapy (also known as "radiotherapy") for treating humans, animals, and plants. In an illustrative example, radiation therapy generally involves the use of ionizing radiation to selectively irradiate and destroy cancerous tissue relative to normal tissue. Radiation therapy can also be used for a range of non-cancer therapies.

[0005] Ionizing radiation is generated and clinically delivered by either of two main methods: electronically generated, externally delivered beams of high energy photons or other particles (e.g., electrons, nuclei, nuclei, etc.), or brachytherapy involving interstitially placed or inserted internal sources of radioactive nuclei as intracavitary sources that decay by emitting useful forms of high energy particles (e.g., electrons, protons, alpha particles) or photons (ionizing electromagnetic radiation). Many modern external beam delivery systems take the form of linear or circular accelerating structures attached to a gantry. In many cases, these systems incorporate patient support and beam delivery and aiming devices for an overall treatment system that is capable of treating patients in a few minutes per day for certain prescribed radiation treatment courses.

[0006] Conventional radiation therapy has evolved over the last century to spare normal tissue through a combination of fractionation and target volume optimization using advances in imaging and computing techniques. This has resulted in improved tumor doses and cure rates, as well as reduced complications. These benefits have driven radiation therapy’s transformation from a treatment of last resort to one of the three pillars of oncology: surgery, chemotherapy, and radiation oncology.

[0007] In radiotherapy, the standard treatment dose SI unit definition adopted worldwide is Gray (Gy), which is defined as the energy absorbed by one joule per kg of tissue. A typical external beam radiotherapy regimen may require a total delivered dose between 45Gy and 60Gy to eradicate cancerous tumors during multiple treatments (called fractions). Conventional external beam radiotherapy treatments are usually delivered in multiple small stages, usually 1.5Gy to 2.5Gy per stage per day. In many treatment regimens, stages are usually delivered during weekdays (Monday to Friday), and stopped on weekends until the total prescribed dose has been delivered.

[0008] Conventional radiation units typically deliver radiation at a rate of 1 Gy / min to 15 Gy / min, so that each daily phase can typically be delivered in a range of no less than 2-5 minutes (up to 10 minutes or more of actual beam-on time). In some cases, such as for arc therapy or highly modulated Intensity Modulated Radiation Therapy (IMRT), Stereotactic Body Radiotherapy (SBRT), or Stereotactic Radiosurgery (SRS) type treatments, the delivery time for a phase may be more than 10 minutes. Commercial systems that deliver radiation phases at these dose rate regimens have been designed with control techniques (called dosimetry) that allow the dose prescription to be accurately delivered to the tumor volume with a delivered dose error of typically less than 5%, preferably less than 3%.

[0009] Some radiotherapy treatments deliver doses in stages higher than 2.5 Gy while reducing the total dose required for tumor control. For example, in Accelerated Partial Breast Irradiation (APBI), patients receive 5 to 10 stages over a period of 5 to 7 days, with 2.7 Gy to 5.0 Gy per stage. The total dose is reduced to 25 Gy to 34 Gy from the traditional breast cancer dose of 45 Gy to 50 Gy delivered in 3 to 6 weeks. Therefore, in conventional treatment, the dose per stage can be increased while reducing the total treatment time and reducing the dose required to achieve tumor control. Both accelerated treatment and conventional treatment deliver the same biologically equivalent dose (Biologically Equivalent Dose, BED) to the tumor bed. The BED effect is predicted by the known α / β model of tumor destruction. Another example at conventional dose rates is stereotactic radiation of early lung tumors or irradiation of single brain metastases, which deliver BED in one to five stages.

[0010] Delivering radiation in multiple stages over several days provides a biological advantage that helps to spare normal tissue. Normal tissue has better oxygenation than tumor tissue and can repair damage caused by radiation faster than tumors. Normal tissue can recover and repair damage to a certain extent during the period between stages, while tumors in most cases cannot heal to the same extent and continue to be eradicated to a greater extent by subsequent irradiation stages. In many cases, especially with early stage disease, the tumor will eventually reduce in size so that the body's normal immune system can manage the residual tumor burden.

[0011] Despite the many significant benefits of radiotherapy techniques, it is still desirable to further minimize damage to normal tissues by improving the ability to selectively target tumor tissues relative to normal tissues. The techniques used in radiotherapy over the past 25 years have focused on achieving the benefits of the therapeutic window by using complex geometry-based conformal avoidance techniques. However, even with the use of highly advanced imaging and tumor tracking robotics, many tumors are still radioresistant at conventional dose rates of 1Gy / min to 15Gy / min at doses that the normal tissues involved can tolerate. In addition to complex conformal avoidance techniques, potential treatments that can increase the dose against radioactive tumors and other tumors without harming normal tissues can greatly expand the therapeutic window experienced by current conventional dose rates and techniques. Finding more selective treatment techniques has become an important focus of radiation oncology research.

[0012] Recently, it has been discovered that radiation doses delivered within atypical short time frames (e.g., less than 10 seconds, or even less than 1 second, or even less than 0.5 seconds, or even less than 0.25 seconds, or even less than 0.1 seconds) not only result in extremely high dose rates relative to conventional radiotherapy (e.g., greater than 10 Gy / s, or even greater than 20 Gy / s, or even greater than 40 Gy / s, including up to 100 Gy / s, or even up to 400 Gy / s, or even up to 1000 Gy / s, or even up to 2000 Gy / s), but also exhibit significant selectivity for destroying cancer tumors relative to normal tissues while reducing damage to normal tissues. For example, in these very high dose delivery and short time treatment modes, some treatments may deliver a total dose of 10 Gy or even 50 Gy of radiation delivered in 0.25 seconds or less, or even in 0.1 seconds or less. Delivering such doses over these example short time intervals would produce illustrative dose rates of 40 Gy / s to 2000 Gy / s. This newer technology will aid in treating a wide range of cancerous tumors, but will be particularly beneficial in treating any previously characterized "radioresistant" tumors, as the discovered selectivity may allow the dose to be increased to the point of cure, with significantly reduced effects on normal tissue.

[0013] This new approach is known in the field of radiotherapy as FLASH irradiation or FLASH radiotherapy. The researchers report that it is desirable to deliver the FLASH dose as quickly as possible in order to better optimize the biological FLASH effect that enhances the ability of normal tissue to remain unharmed. In other words, the study showed that FLASH selectivity for target cancer tissue relative to normal tissue at a given dose tends to increase as the time interval used to deliver the dose decreases. In other words, selectivity for a given total delivered dose increases as the dose rate increases.

[0014] In a recent experiment reported in Oncology Research at the Hospital of the University of Pennsylvania, FLASH was used to treat tumors in the abdomen of mice. The tumors were "flashed" with a single pulse of radiation lasting 100 to 200 milliseconds. Remarkably, the researchers reported that tumor growth was inhibited, while healthy tissue was not damaged.

[0015] More than 30 years ago, the International Commission on Radiation Unit (ICRU) created standard definitions and nomenclature for the volume of cancerous tissue used for all radiotherapy treatments. These standard definitions and nomenclature have been adopted worldwide as standard medicolegal definitions for physician prescriptions involving lesions and normal tissues and inherent limits for prescribing curative doses of radiation. The standard definitions and nomenclature involve three major progressive and inclusive volumes: Gross Tumor Volume (GTV), which is defined as the total apparent clinical tumor extent; Clinical Tumor Volume (CTV), which is defined as the GTV plus the surrounding margin for non-apparent subclinical disease extension; and finally, Planning Target Volume (PTV), which is defined as the CTV plus the margin added for the technical delivery errors known to exist with a given delivery technology (including all motions and uncertainties of the positioning technology, treatment planning errors, etc.).

[0016] In 2019, the radiation oncology team at the Centre Hospitalier Universitaire Vaudois (CHUV) in Lausanne, Switzerland (also known as the University Hospital of Lausanne) reported the first treatment of a human patient with FLASH radiotherapy. They prescribed a FLASH dose to the PTV using a 5.6 MeV electron beam to irradiate a 3.5 cm circular skin lesion using a 5 mm bolus, so that the total depth covered by the 90% isodose was 1.3 cm. This cylindrical tissue PTV of 3.5 cm in diameter and 1.3 cm deep (30 cc of tissue) contained metastatic drug-resistant T-cell lymphoma and some normal tissue according to the ICRU definition of PTV. A single 15 Gy dose was delivered to the target volume in 0.090 seconds (90 milliseconds). This resulted in a mean dose rate of 170 Gy / s to the PTV. At 5 months after irradiation, the tumor response was rapid, complete, and durable, with all signs of cancerous lesions absent. See "Treatment of a First Patient with FLASH Radiotherapy" (Jean Bourbis, MD et al., Radiotherapy and Oncology, 139, October 2019, pp. 18-22). The oncology team stated that they are still following the patient. More than a year after treatment, the oncology team stated that the treatment site remains disease-free and there are no residual side effects to normal tissue (note that the oncology team reported transient grade 1 edema immediately after treatment).

[0017] This first human treatment and previous animal studies show that FLASH radiotherapy can greatly expand the therapeutic window, which significantly exceeds the existing state of the art using conventional dose rates and only complex conformal avoidance systems. The reason why FLASH radiotherapy works so well is still under study and is a subject of great concern in the radiation research community. In fact, the diversity of radiation researchers using several forms of radiation has confirmed the effect. The selectivity observed in animals and currently in humans seems to be regulated by dose rate structures and parameters that cannot be explained by contemporary reliable radiation biology models for lower dose rate (conventional) schemes.

[0018] In conventional models of radiation biology, DNA damage occurs due to ionization and excitation directly in nucleic acids and in intercellular water. Water interactions lead to the production of reactive oxygen species (ROS), such as peroxides, superoxides, hydroxyl radicals, singlet oxygen, and α-oxygen. Hydrogen peroxide can in turn be partially reduced to hydroxyl radicals ( · OH). These substances produced within the first femtosecond after exposure and into the picosecond include the physical and physicochemical steps of so-called ionization and molecular dissociation. As time progresses to nanoseconds after exposure, ROS begin to diffuse or move and react within the cell. This is called a multiphase chemical step. Thereafter, ROS migrate in large quantities within the cell to produce single-strand and double-strand breaks in nucleic acids and other cellular components, and this collective damage history within each cell leads to enzymatic DNA repair in the biochemical step or apoptosis in the final step called the biological step within hours and days.

[0019] With conventional dose rates, the irradiation time of tissues reaches several seconds or even minutes, while the FLASH protective effect occurs in shorter exposure times, and as the exposure time is further reduced, the effect becomes more significant. Without wishing to be bound by theory, when applying higher doses in shorter time intervals, it is assumed that the generation of oxygen and therefore ROS is temporarily saturated, and therefore exhausted in nanoseconds or even faster post-exposure time ranges during the physicochemical steps of the irradiated tissue. In FLASH irradiation, very fast dose delivery causes oxygen consumption (exhaustion), which is sufficient to produce transient hypoxia in normal (non-cancerous) tissues. It is assumed that transient hypoxia protects normal tissues from damage, which usually occurs at lower dose rates delivered in longer time intervals.

[0020] In tumors that are often hypoxic in nature, the effects of FLASH radiotherapy remain highly effective, just like conventional radiotherapy, and many researchers have even reported a slight enhancement in cancer killing. Thus, during FLASH irradiation, the tumor is still destroyed at a rate comparable to that experienced with conventional dose rates. Since large doses can also be delivered to the tumor in a single stage, the effects on hypoxic tumors are enhanced, and a single dose of, for example, 20 Gy to 40 Gy or more may be sufficient to completely destroy the tumor while greatly reducing normal tissue toxicity.

[0021] Other possible mechanisms have also been proposed and are being actively investigated. These mechanisms include, for example, cell signaling, immune response, etc. Regardless of the exact cause or causes of the FLASH effect, the fact remains that a widely observed and reproducible effect is now known to occur in FLASH treatment regimens, and one major cause appears to be at least a transient hypoxic effect that protects normal tissue to a greater extent than cancer tissue during the transient time window of beam delivery that lasts for a few microseconds.

[0022] Ionizing radiation machines rely on dosimetry to monitor and control the delivery of ionizing radiation. The dosimetry system directly or indirectly samples the beam itself in order to provide information, such as measured machine parameters related to the time-dependent amount of radiation delivered as the treatment progresses. An important function of the dosimetry system is to provide enough information so that the control system terminates ionizing radiation when the correct dose has been delivered within acceptable time tolerances and delivered dose accuracy.

[0023] Equipment manufacturers in the field of radiotherapy have developed various beam monitoring systems and associated control strategies. These systems and strategies include monitoring functions for beam uniformity or spatial homogeneity as well as beam position, direction, and dose, so that the prescribed dose and electron beam energy are accurately, uniformly, and reproducibly delivered to the target site. In therapeutic applications, industry standards and regulations guide the desired accuracy. Driven by regulatory requirements, systems and strategies also incorporate at least the principle of double contingency, which usually results in multiple beam monitoring devices or technologies in a given overall system design.

[0024] FLASH technology places higher demands on dosimetry systems in several aspects. First, beam monitors and other sensors must be selected and deployed in a way that can accurately sense the radiation fluence rate that results in the higher dose rate associated with FLASH irradiation. Some sensors provide signals that are accurately related to the beam characteristics in non-FLASH treatments, but are not sufficiently time-sensitive for controlling FLASH irradiation. Since the time range required to produce the characteristic higher dose rates seen in FLASH irradiation is much shorter, and in some cases the time range is extremely short, the beam monitors and other sensors used in FLASH treatment must be much faster than typical. Further, the components that terminate the electron beam in response to the sensed information must also be much faster than typical in order to avoid dosing errors caused by the same timing problems. Since FLASH treatment delivers significant doses in a very short time frame, the slow sensing technology and overall control response found on conventional medical radiation systems may lead to excessive errors in dose delivery.

[0025] Therefore, there remains a strong need for improved techniques to use and control ionizing radiation, particularly at the timescales and dose rates of FLASH therapy. Summary of the invention

[0026] The present invention provides strategies for using and controlling the delivery of ionizing radiation for therapeutic and industrial irradiation treatment. The present invention modulates the pulse width of ionizing radiation pulses to accurately deliver a target irradiation dose. In some embodiments, the present invention uses partial pulse control, for which the full-width pulse is terminated in advance to stop the irradiation of the target dose. In other embodiments, the present invention dynamically modifies one or more pulse widths during treatment to accurately terminate ionizing irradiation. The pulse width can be dynamically expanded and / or reduced to help accurately deliver the target dose. In some aspects, the present invention has developed a pulse width formula by which one or more pulse widths are pre-selected and then implemented in irradiation therapy to accurately deliver the target dose. In some embodiments, dose accuracy can be further enhanced via one or more component selection and / or component configuration strategies to accurately monitor, deliver and terminate irradiation. These strategies are particularly useful for controlling the short time scale and high dose rate administration associated with FLASH technology.

[0027] As used herein, FLASH treatment refers to any treatment in which (a) the patient receives a FLASH dose in 10 seconds or less, preferably 5 seconds or less, or less than 1 second (including but not limited to 1×10 -7 seconds to 1 second, or even 1×10 -6 seconds to 1 second, or even 1×10 -4(b) a dose rate of at least 1 Gy / s, or even at least 5 Gy / s, or even at least 10 Gy / s, or even at least 20 Gy / s or higher, or even at least 40 Gy / s or higher (including but not limited to at least 1 Gy / s up to 1500 Gy / s, or even at least 10 Gy / s up to 1000 Gy / s, or even at least 20 Gy / s up to 500 Gy / s). Non-FLASH treatment refers to any treatment that does not meet one or both of these time interval and dose rate parameters.

[0028] FLASH therapy can also potentially exploit the BED concept demonstrated in conventional therapy. For example, this could allow certain tumors to be treated in less than a second with a single FLASH dose of 20 to 30 Gy, relative to treatments that require a higher total dose using conventional strategies, where the total dose is delivered in multiple stages.

[0029] According to one aspect of the present invention, an ionizing radiation system is disclosed for depositing a target dose of pulsed ionizing radiation into a matrix during treatment, the ionizing radiation system comprising:

[0030] a. an ionizing radiation unit that generates pulsed ionizing radiation and deposits the pulsed ionizing radiation into a matrix during treatment, wherein the pulsed ionizing radiation is provided as a sequence of one or more individual pulses, and wherein the ionizing radiation includes a fluence characteristic as the treatment proceeds;

[0031] b. A control system comprising at least one sensor that monitors the pulsed ionizing radiation as the treatment progresses, including monitoring the pulsed ionizing radiation during one or more individual pulses, wherein

[0032] i. at least one sensor provides an output signal indicative of a fluence characteristic of the pulsed ionizing radiation as the treatment proceeds, including providing an output signal during one or more individual pulses;

[0033] ii. the control system includes program instructions that use information including the output signal to determine dose information indicative of a cumulative dose deposited into the substrate as treatment progresses, including determining dose information during one or more individual pulses;

[0034] iii. the control system includes program instructions for determining termination information indicative of a comparison between the cumulative dose and the target dose as the treatment progresses, including determining termination information during one or more individual pulses; and

[0035] iv. The control system includes program instructions that cause the pulsed ionizing radiation to terminate when the termination information indicates that the cumulative dose sufficiently matches the target dose, wherein the program instructions are configured to cause the termination during the current individual pulse when it is determined that the target dose is reached during the current individual pulse, so that the current pulse is a partial pulse when terminated.

[0036] According to another aspect of the present invention, an electron beam irradiation system is disclosed for depositing a target dose of pulsed electron beam irradiation into a substrate during treatment, the system comprising:

[0037] a. an electron beam unit comprising a triode electron gun that assists in generating and depositing pulsed electron beam radiation into a substrate during treatment in response to a pulse voltage applied to the triode-based electron gun, wherein the pulsed electron beam radiation is provided as a sequence of one or more individual pulses, and wherein the electron beam radiation includes a fluence characteristic as the treatment progresses;

[0038] b. A control system comprising at least one annular coil sensor that monitors the pulsed electron beam radiation as the treatment proceeds, wherein:

[0039] i. at least one annular coil sensor provides an output signal indicative of a fluence characteristic of the pulsed electron beam radiation as the treatment proceeds, including providing an output signal during one or more individual pulses;

[0040] ii. the control system includes program instructions that use information including the output signal to determine dose information indicative of a cumulative dose deposited into the substrate as treatment progresses, including determining dose information during one or more individual pulses;

[0041] iii. the control system includes program instructions for determining termination information indicative of a comparison between the cumulative dose and the target dose as the treatment progresses, including determining termination information during one or more individual pulses; and

[0042] iv. The control system includes program instructions that modify the voltage applied to the triode electron gun in a manner sufficient to terminate the pulsed electron beam radiation when the termination information indicates that the real-time total accumulated dose sufficiently matches the target dose, wherein the program instructions are configured to cause the termination during the current individual pulse when determining that the target dose is reached during the current individual pulse, so that the current individual pulse is a partial pulse when terminated.

[0043] According to yet another aspect of the present invention, a method for depositing a target dose of pulsed ionizing radiation to a substrate during treatment using ionizing radiation is disclosed, comprising the steps of:

[0044] a. delivering a pulsed beam of ionizing radiation into the matrix, wherein the pulsed ionizing radiation comprises a sequence of one or more individual pulses, and wherein the ionizing radiation comprises a fluence characteristic as the treatment proceeds;

[0045] b. using at least one sensor to provide an output signal indicative of a fluence characteristic of the pulsed ionizing radiation as the treatment proceeds, including providing an output signal during one or more individual pulses;

[0046] c. using the output signal to determine dose information indicating a total cumulative dose deposited into the substrate as treatment proceeds;

[0047] d. Comparison of cumulative dose with target dose over time; and

[0048] e. terminating the pulse beam when the comparison indicates that the total cumulative dose substantially matches the target dose, wherein termination occurs during the current individual pulse when the comparison indicates that the target dose is reached during the current individual pulse, such that the current individual pulse is a partial pulse when terminated.

[0049] According to yet another aspect of the present invention, a method for depositing a target dose to a substrate during treatment using electron beam radiation is disclosed, comprising the steps of:

[0050] a. using a triode electron gun to assist in generating pulsed electron beam radiation, wherein the pulsed ionizing radiation comprises a sequence of one or more individual pulses, and wherein the ionizing radiation comprises a fluence characteristic as the treatment proceeds;

[0051] b. allowing the pulsed electron beam radiation to irradiate the substrate;

[0052] c. using at least one sensor to provide an output signal indicative of a fluence characteristic of the pulsed electron beam radiation as treatment proceeds, including providing the output signal during one or more individual pulses;

[0053] d. using the output signal to determine dose information indicating a total cumulative dose deposited into the matrix as treatment proceeds;

[0054] e. Comparison of cumulative dose to target dose as treatment progresses; and

[0055] f. terminating the pulse beam when the comparison indicates that the total cumulative dose substantially matches the target dose, wherein termination occurs during the current individual pulse when the comparison indicates that the target dose is reached during the current individual pulse, such that at the moment of termination the current individual pulse is a partial pulse.

[0056] According to yet another aspect of the present invention, an ionizing radiation system is disclosed for irradiating a substrate with a target dose of pulsed ionizing radiation during treatment, the system comprising:

[0057] a. an ionizing radiation unit that generates pulsed ionizing radiation and deposits the pulsed ionizing radiation into a matrix, wherein the pulsed ionizing radiation is provided as a sequence of one or more individual pulses, and wherein the ionizing radiation includes a fluence characteristic as the treatment proceeds;

[0058] b. A control system comprising at least one sensor that monitors the pulsed ionizing radiation as the treatment progresses, including monitoring the pulsed ionizing radiation during one or more individual pulses, wherein

[0059] i. at least one sensor provides an output signal indicative of a fluence characteristic of the pulsed ionizing radiation as the treatment proceeds, including providing an output signal during one or more individual pulses;

[0060] ii. the control system includes program instructions that use information including the output signal to determine dose information indicative of a cumulative dose deposited into the substrate as treatment progresses, including determining dose information during one or more individual pulses;

[0061] iii. the control system includes program instructions that use information including a comparison between the accumulated dose and the target dose to determine a pulse width modulation for at least one pulse; and

[0062] iv. The control system includes program instructions that dynamically cause pulse width modulation of at least one pulse when the comparison indicates that delivering one or more additional unmodulated pulses will deliver an over or under cumulative dose relative to the target dose.

[0063] According to yet another aspect of the present invention, a method for irradiating a substrate with a target dose of ionizing radiation is disclosed, comprising the following steps:

[0064] a. Providing a pulse width recipe combining multiple different pulse widths into a pulse sequence; and

[0065] b. Using a pulse width recipe to deliver a beam of pulsed ionizing radiation to the substrate in a manner that effectively deposits a target dose into the substrate. BRIEF DESCRIPTION OF THE DRAWINGS

[0066] Figure 1a An illustrative embodiment of an electron beam radiation system of the present invention for irradiating a substrate is schematically shown.

[0067] Figure 1b Shows Figure 1a An electron beam radiation system wherein the substrate is a human patient.

[0068] Figure 1c Shows Figure 1aAn electron beam irradiation system wherein the substrate is meat to be irradiated for sterilization.

[0069] Figure 1d Shows Figure 1a An electron beam radiation system wherein the substrate is a medical device in the form of a syringe to be irradiated for sterilization.

[0070] Figure 1e Shows Figure 1a An electron beam irradiation system is provided in which the substrate is a gemstone that is irradiated to modify properties (e.g., optical properties).

[0071] Figure 1f Shows Figure 1a An electron beam radiation system, wherein the substrate is a diseased animal.

[0072] Figure 2 Further details of an illustrative electron beam generating unit for use in the electron beam irradiation system of FIG. 1 are shown schematically.

[0073] Figure 3 An alternative embodiment of an electron beam generating unit which may be used in the electron beam irradiation system of Fig. 1 is schematically shown.

[0074] Figure 4 An alternative embodiment of an electron beam generating unit which may be used in the electron beam irradiation system of Fig. 1 is schematically shown.

[0075] Figure 5 An alternative embodiment of an electron beam generating unit which may be used in the electron beam irradiation system of Fig. 1 is schematically shown.

[0076] Figure 6 Schematically showing a section taken along line 6-6 Figure 5 cross section.

[0077] Figure 7 Schematically showing a section taken along line 7-7 Figure 5 cross section.

[0078] Figure 8 It is schematically shown how the voltage pulse, electron beam pulse and accumulated dose are related.

[0079] Fig. 9 An illustrative method of the present invention using partial pulse control is schematically shown.

[0080] Fig.10 An illustrative method of the present invention using dynamic pulse width control is schematically shown.

[0081] Fig.11An illustrative method of the present invention using at least one predetermined pulse width recipe is schematically shown.

[0082] Fig.12 is a graph showing how a commercially available MOBETRON electron beam machine delivers a total dose in 6MeV FLASH therapy that is linear with respect to the number of pulses, and the total dose delivered for a particular pulse count is highly uniform.

[0083] Fig.13 is a graph showing how a commercially available MOBETRON electron beam machine delivers a total dose in 9MeV FLASH therapy that is linear with respect to the number of pulses, and the total dose delivered for a particular pulse count is highly uniform. DETAILED DESCRIPTION

[0084] Detailed description of preferred embodiments of the present invention can be found below. These embodiments are exemplary, and those skilled in the art will recognize that the method and system of the present invention can be implemented without strictly complying with the specific embodiments described herein, and unnecessary restrictions should not be understood therefrom. Without departing from the present invention, those skilled in the art may conceive of many variations, changes and substitutions. Therefore, the illustrative embodiments of the present invention described herein are not intended to be exhaustive or to limit the present invention to the precise forms disclosed in the specification and the drawings. The purpose of the illustrative embodiments selected and described is to facilitate those skilled in the art to understand and appreciate the principles and implementation of the present invention.

[0085] All patents, patent applications, and publications cited herein are incorporated by reference in their respective entireties for all purposes.

[0086] The present invention is useful for accurately using and controlling the delivery of ionizing radiation to target sites to perform a wide range of treatments in therapeutic and industrial applications. For therapeutic applications, the present invention can be used to use and control the delivery of ionizing radiation to humans and non-humans (e.g., animals and plants) for or in aid of surgical or other treatments of various treatment sites in or on a patient in various therapeutic environments. Exemplary applications in the field of dermatology include preventing or treating dermal scarring, including hypertrophic scarring, dermal fibroproliferative lesions, and benign fibrous tumors (e.g., keloids). In some embodiments, electron beam radiation can be used to treat or prevent scarring caused by breast cancer surgery or reduce the severity of scarring during emergency room procedures. Other exemplary applications include treating internal conditions, such as surgical adhesions and restenosis, such as may occur when treating vascular occlusions. For example, the principles of the present invention can be used to irradiate the microvasculature of an operating bed to reduce the possibility of surgical adhesion formation. As another example, as an aid to vascular surgery, the principles of the present invention can be used to treat anastomoses of blood vessels (e.g., femoral arteries, popliteal arteries, and carotid arteries) to help prevent restenosis.

[0087] The present invention can also be used in cancer treatment therapies. In particular, the present invention is particularly useful for treating cancer using the FLASH treatment principle, because researchers have shown that depositing ionizing radiation at high dose rates over short time intervals has a remarkable ability to selectively target and destroy cancerous tissue while sparing healthy tissue to a surprisingly large extent.

[0088] The present invention can also be used to use and control ionizing radiation in a wide range of industrial applications. Examples of industrial applications include gemstone irradiation (to change properties such as optical properties), food irradiation (to prevent food-borne diseases, preservation, insect control, delay of germination and maturation, disinfection, etc.), medical device sterilization (e.g., syringes, catheters, sponges, hip implants, knee implants, spinal implants, drug delivery patches, blood collection kits, drug containers, bottles, bandages, pipette tips, etc.), and cargo inspection.

[0089] The present invention can be used to accurately use and control the delivery of ionizing radiation to the matrix or to one or more target sites in or on one or more parts of the matrix. Overall treatment can occur in one or more treatment stages. In the case of overall treatment using the FLASH principle, overall treatment preferably includes 1 to 5 treatment stages, more preferably 1 to 3 treatment stages, and even more preferably a single treatment stage. Treatment can involve various dosing regimens using FLASH strategies and non-FLASH strategies. For example, some treatments may involve a dosing regimen for depositing ionizing radiation at a dose lower than 5Gy / stage or even lower than 2Gy / stage and a dosing regimen for depositing ionizing radiation at 5Gy / stage or higher doses. The present invention is particularly useful for accurately using and controlling the delivery of a higher ionizing radiation dose per stage, for example, a dose / stage of at least 5Gy, including a dose / stage of 5Gy to 2000Gy, or even 10Gy to 1500Gy, or even 20Gy to 1000Gy, or even 40Gy to 400Gy. In some current illustrative embodiments, higher doses / phase, in the range of, for example, 5 Gy / phase to 50 Gy / phase, are generally associated with more optimal outcomes in FLASH therapy when delivered in a very short period of time.

[0090] The present invention can be used to accurately control and deposit ionizing radiation at a wide range of dose rates. As used herein, "dose rate" refers to the average dose rate generated during the course of a treatment phase (if the overall treatment only involves a single phase, it can be the entire overall treatment). For example, for a phase in which 40Gy is delivered in 0.5 seconds, the average dose rate or the dose rate of the treatment is 80Gy / s. Similarly, a treatment that delivers 30Gy in two seconds has a dose rate of 15Gy / s. The term "instantaneous dose rate" refers to the dose deposited in the matrix within the time interval of a single pulse. For example, consider a treatment that delivers 40Gy in 5 uniform pulses, wherein the dose delivery and amplitude during the pulses are uniform and constant, and wherein each pulse lasts 0.20 seconds. In this case, each pulse delivers 8Gy in 0.20 seconds. In each pulse, the instantaneous dose rate is 40Gy / s (=8Gy / 0.20s). In some cases, the instantaneous dose rate can be quite high. For example, a pulse of 100 Gy delivered in 0.001 seconds has an instantaneous dose rate of 100,000 Gy / s during the pulse. 6 Gy / s or 10 7Instantaneous dose rates of the order of Gy / s may also be suitable. Between pulses, in the absence of ionizing radiation being delivered, the instantaneous dose rate is 0 Gy / s. Some pulse sequences may include pulses with varying pulse widths and / or varying doses delivered in each pulse. In this case, the instantaneous dose rate is different between these different pulses. As used herein, unless otherwise expressly stated, any dose rate referred to refers to an average dose rate.

[0091] By way of example, some treatment regimens may involve depositing ionizing radiation at a relatively low dose rate of less than 15 Gy / min, or even less than 3 Gy / min, or even less than 1 Gy / min. In other embodiments, such as with respect to treatment regimens associated with FLASH techniques, ionizing radiation may be deposited at a relatively higher dose rate of greater than 15 Gy / min (e.g., at least 1 Gy / s, or even 1 Gy / s to 2000 Gy / s, or even 10 Gy / s to 1500 Gy / s, or even 20 Gy / s to 500 Gy / s, or even 40 Gy / s to 400 Gy / s).

[0092] In the practice of the present invention, ionizing radiation includes any radiation that travels as particles and / or electromagnetic waves that carry sufficient energy to separate electrons from atoms or molecules, thereby ionizing those molecules. Examples of ionizing radiation include: photons, such as gamma rays, x-rays, and some ultraviolet radiation; alpha particles; beta particles; neutrons; charged nuclei; muons; pions; protons; cosmic rays; etc. Alpha particles include two protons and two neutrons, and the particle content is the same as a helium nucleus. Beta particles include high-energy, high-speed electrons or positrons. A stream of ionizing radiation in the form of electrons is called an electron beam.

[0093] Preferred embodiments use ionizing radiation in the form of electron beams. Useful electron beams can have electron beam energies selected from a wide range. In an exemplary embodiment, a useful electron beam has an energy of at least 0.1 MeV or more, including 4 MeV or more, even 6 MeV or more, even 12 MeV or more, such as up to 20 MeV, or even up to 50 MeV, or even up to 100 MeV. For FLASH treatment, electron beam energies of 4 MeV or more, even 6 MeV or more, even 12 MeV or more (e.g., up to 20 MeV, or even up to 50 MeV, or even up to 100 MeV) will be suitable.

[0094] The energy of the electron beam is a factor that affects the beam's penetration ability. Electrons with more energy tend to penetrate deeper into the matrix before stopping. Therefore, due to this correlation, determining the penetration depth of the electron beam into the water phantom allows the electron beam energy to be determined. In the practice of the present invention, the electron beam energy E is given by E=R 80 / 2.8, where R 80 is the penetration depth in centimeters when the deposited dose drops to 80% of the maximum dose in the water phantom. 80 The penetration depth is determined according to the protocol described in "AAPM's TG-51 protocol for clinical reference dosimetry of high-energy photon and electron beams," by Peter R. Almond et al., Med. Phys. 26(9), September 1999, pp. 1847-1870 (referred to in the industry as the AAPM TG51 report). Additional AAPM reports are helpful for desired penetration depth tolerances in therapeutic applications. These reports include "Comprehensive QA for radiation oncology: Report of AAPM Radiation Therapy Committee Task Group 40" by Kutcher et al., Med. Phys. 21(4), April 1994, pp. 581-618 (known in the industry as the AAPM TG-40 report) and "Task Group 142 Report: Quality Assurance of Medical Accelerators" by Klein et al., Med. Phys. 36(9), September 2009, pp. 4197-4212 (known in the industry as the AAPM TG-142 report).

[0095] For the purpose of illustration, the following will now be discussed regarding the use and control of Figure 1a The principles of the present invention are described with reference to an electron beam in an exemplary embodiment of an electron beam radiation system 10 schematically shown in FIG. The electron beam radiation system 10 is used to deposit a target dose of electron beam radiation into a substrate 14 in one or more treatment sessions. The purpose of unit 26 is to cause the electron beam 16 to irradiate the substrate 14 in one or more electron beam pulses to deposit the desired dose using an appropriate electron beam energy, dose rate, and / or treatment time.

[0096] The system 10 allows for improved accuracy and control for depositing a desired dose of electron beam energy into the matrix 14 by using control and hardware features that allow one or more pre-modulations (using a pre-selected recipe), dynamic modulation, and / or partial pulses of electron beam energy to be emitted to the matrix 14, optionally in combination with one or more complete pulses. For example, one treatment may involve depositing the desired dose in a single pre-selected pulse. Another treatment may involve depositing the desired dose in one or more full pulses, which end with a partial pulse in which the last pulse is terminated early. Another treatment may involve depositing the desired dose in one or more full pulses, wherein the full pulses cumulatively provide the total desired dose. One or more of these treatments may be implemented in one or more stages (e.g., 1 or more stages occurring over a span of hours, days, or weeks). The ability to modulate the pulse width of the ionizing radiation dose delivered to the target site provides improved accuracy in any treatment regimen, but is particularly significant for FLASH treatment.

[0097] In some treatments based on the FLASH principle, depositing the total dose in a combination of a) one or more complete pulses and b) a partial pulse at the end can improve the accuracy of depositing the target dose. For example, human patients in early FLASH treatment protocols received 15 Gy in 90 milliseconds (in a 6 cm field size with 6 MeV electrons), which corresponds to an approximate instantaneous dose rate of about 150 Gy / s. Researchers who want to further study the range of possible effects of field sizes that may be used for human clinical use may expect a range of field sizes in the range of 3 cm to 10 cm, and the dose rate desired to produce the FLASH effect may increase to the range of several hundred Gy / s or even higher.

[0098] A specific example of conventional treatment (non-FLASH) may involve delivering a total dose of 40Gy at a rate of 10Gy / min at 50 pulses per second (pps). This treatment involves 12,000 pulses or only 0.003Gy / pulse. Another conventional treatment (non-FLASH) may involve delivering a relatively low dose (e.g., 2Gy) at a pulse frequency of 20Hz within 2 minutes (120 seconds). In this treatment, a total of 2400 pulses occur, each pulse including 0.0008Gy / pulse. In conventional treatments such as these treatments, stopping the treatment a few pulses early or performing a few additional pulses on the total dose delivered has a negligible effect. The resulting error in dose delivery is almost completely unaffected by stopping the irradiation using a control system that can only stop irradiation after an integer number of pulses. Moreover, the delay in terminating the beam due to the time at which the circuit achieves termination also has a minimal effect on the total dose delivered in this non-FLASH treatment.

[0099] In contrast, in FLASH treatment, even the deficiency or excess of one pulse or even a portion of a pulse is more important. Each pulse in FLASH treatment corresponds to a significant portion of the total treatment dose. For example, an illustrative FLASH treatment may involve depositing a total of 40Gy with 8 pulses or 5Gy / pulse. If 43Gy is needed, an excess of 2Gy is deposited using a complete additional pulse, with an error of about 4.6%. Using the partial pulse control strategy of the present invention allows this excess to be avoided, so that 43Gy can be deposited more accurately by completing the treatment with a partial pulse. In short, the ability to use and control partial pulses is a key strategy to make any ionization scheme, especially FLASH treatment, significantly more accurate.

[0100] In one aspect of the implementation of the present invention, during treatment, different strategies can be used to deposit one or more modulated pulses. As an option, a pulse sequence can be deposited. As the irradiation proceeds, the cumulative dose is monitored. When the monitoring indicates that the target dose is reached, the electron beam is terminated, even in the middle of the pulse. As another option, in particular using a solid-state modulator that can dynamically adjust the pulse width very quickly, a pulse sequence can be deposited in which the pulse width of at least one pulse is dynamically changed to decrease or increase so that the electron beam can be stopped when the desired target dose is reached. This dynamically modulated pulse width is a partial pulse in the sense that its pulse width is reduced relative to other pulses when it is reduced. In other cases, in cases where a pulse of a regular size in treatment will not reach the target dose to be delivered, a pulse can be dynamically widened to complete the dose delivery, and delivering two more complete pulses will deliver an excessive excess of irradiation. In this case, the "regular" pulses are partial pulses in the sense that they have a reduced width relative to the final widened pulse.

[0101] In other words, in one aspect, the present invention relates to depositing an accurate total dose using pulse strategies in which the pulse width of the beam pulses is modulated to help ensure accurate deposition of the desired target dose. This may involve widening the pulse, narrowing the pulse, terminating the pulse early, etc. The pulse width may be dynamically monitored and controlled as the treatment proceeds. Alternatively, when the instantaneous dose rate occurring during one or more pulses can be controlled with sufficient accuracy, a pulse width recipe may be provided prior to treatment and then executed to deposit an accurate total dose. For example, if the treatment goal is to deposit a target dose of 100 Gy, such as may be useful in industrial applications where the instantaneous dose rate is 1000 Gy / s, a total pulse time of 0.1 seconds is required to deliver a total dose of 100 Gy. Example recipes may deliver the desired total dose in a single pulse lasting 0.1 seconds, two pulses lasting 0.08 seconds and 0.02 seconds, respectively, three pulses (two of which last 0.04 seconds and the last pulse lasts 0.02 seconds), etc.

[0102] As treatment progresses, a solid-state modulator will allow the pulse width to be changed very quickly and dynamically to a pulse width that is less than or greater than a preset pulse width. In principle, this will allow one or more pulses in a pulse sequence (e.g., the last pulse) to contain a reduced or increased dose (as the case may be) than the previous one or more pulses, thereby achieving greater accuracy in beam termination. The actual time to change the pulse width using a solid-state modulator is typically 1 to 2 microseconds, which is fast enough for effective changes to occur relative to the pulse repetition rate used in practice as treatment progresses. However, changing the pulse width during treatment may disrupt the system sufficiently to make the energy of each pulse more difficult to control or predict. It is relatively easy and straightforward to change the pulse frequency as treatment progresses (e.g., when using a solid-state modulator), but it does not provide as much accuracy in dose deposition as may be desired in some cases. This problem may be exacerbated where the dose rate per pulse is fixed based on the initial pulse width.

[0103] Therefore, in a preferred embodiment, it is more preferable to modulate the energy deposited by each pulse using a strategy that allows one or more partial pulses to be used in combination with one or more full pulses (e.g., using a uniform pulse width in which one or more pulses are terminated early) than to dynamically change the pulse frequency or pulse width, or to pre-specify a pulse width recipe. By using a constant pulse frequency, pulse amplitude, and pulse width together with the ability to end with one or more partial pulses, a more stable device balance can be established so that the instantaneous dose rate during the pulse and the total dose of each pulse are highly uniform and highly correlated with (e.g., proportional to) the pulse width. In summary, while dynamic variation of pulse width is feasible and is an aspect of the present invention, terminating partial pulses is the preferred method because it is easy to implement and highly accurate. Features of the present invention that contribute to the partial pulse strategy of the present invention will be further described below with respect to system 10 and its use and control.

[0104] It is desirable that the total error in dose delivery is less than 5%, or even less than 2%. Under some current regulations, a dose error greater than 5% is considered a mistreatment, but does not need to be reported to the authorities. Under some regulations, a dose error greater than 10% is not only a mistreatment, but must be reported to the authorities.

[0105] The system 10 can be used to irradiate a wide range of substrates 14. For example, Figure 1bIt is an embodiment, wherein substrate 14 is a human patient, and wherein, irradiation is delivered to the target site anywhere in or on the patient's body or body part.For example, external treatment can be related to treatment ear, nose, face, forehead, scalp, back, shoulder, neck, arm, hand, chest, abdomen, pelvic region, leg or foot.Due to the shape of the electron beam and the ability of the aiming direction of control aiming target site 12, system 10 can be used for treating the target site with various shapes and profiles.Substrate 14 is shown as a human patient, but processing can be used for disinfection in the processing of non-human and inanimate objects (such as gemstones and plastics) including plants and animals.

[0106] Figure 1c A system 10 is shown for irradiating a substrate 14 in the form of a meat product. The meat product is irradiated to sterilize it. Figure 1d A system 10 is shown for irradiating a substrate 14 in the form of a medical syringe. The medical syringe is irradiated to sterilize it. Figure 1e A system 10 is shown for irradiating a substrate 14 in the form of a gemstone. The gemstone is irradiated to modify a property (eg, an optical property). Figure 1f A system 10 is shown for irradiating a substrate 14 in the form of a diseased animal.

[0107] Now refer to Figure 1b To discuss the therapeutic uses of system 10. Due to its compact nature, self-shielding capabilities and / or mobility in many embodiments, system 10 can be used to apply electron beam radiation before or after surgery. In some applications, such as scar improvement, it is beneficial to quickly irradiate closed incisions. For example, system 10 can be used to deliver one or more electron beam radiation doses within a time period of surgery time from 0 to 24 hours, or even 0 to 5 hours, or even 0 to 1 hour, or even 0 to 30 minutes. This ability to quickly apply radiation therapy contrasts with treatment using very large and immobile machines that are housed in a separate, highly shielded environment away from the surgical site. Radiation therapy in such large, remotely housed machines is applied after a delay of hours or days after surgery, thereby losing the opportunity to achieve the best benefits of electron beam radiation therapy.

[0108] System 10 can be used to perform a wide range of treatments for which electron beam radiation provides a treatment, benefit, or other desired effect to surgery, or as an adjunct to surgery or other procedures. For example, system 10 can be used to treat skin diseases and / or provide cosmetic benefits. Exemplary applications in the field of dermatology include preventing or treating dermal scarring, including hypertrophic scarring, dermal fibroproliferative lesions, and benign fibrous tumors (e.g., keloids). In some embodiments, electron beam radiation can be used to treat or prevent scarring caused by breast cancer surgical procedures or to reduce the severity of scarring during emergency room procedures. System 10 can also be used to selectively target and disable cancerous tissue relative to surrounding healthy tissue.

[0109] Advantageously, system 10 can be used to perform a therapy known as "FLASH" treatment. The so-called FLASH treatment uses very short time intervals and very high dose rates in one or more stages, usually only in a single stage. FLASH treatment shows the ability to deliver high-energy electron beam energy in a short dose interval to selectively target and disable cancerous tissues, with minimal damage if there is damage to surrounding healthy tissues. In particular, researchers have found that delivering at least 1 Gy / s, even at least 5 Gy / s, even at least 10 Gy / s, even 20 Gy / s or higher, even 30 Gy / s or higher, even 50 Gy / s and higher, even up to 1000 Gy / s, or even up to 2000 Gy / s significantly reduces healthy tissue toxicity while maintaining anti-tumor activity.

[0110] The FLASH technique used by the system 10 in electron beam therapy can use electron beam energies, such as 4 MeV or higher, even 6 MeV or higher, even 12 MeV or higher, such as up to 20 MeV, or even up to 50 MeV, or even up to 100 MeV. The FLASH technique can deliver a total electron beam dose in a single treatment or a single stage, such as a dose of at least 5 Gy, including a dose of 5 Gy to 2000 Gy, or even 10 Gy to 1500 Gy, or even 20 Gy to 1000 Gy per stage. The FLASH technique can deliver an electron beam dose in a relatively short interval, such as a treatment in the range of 0.01 milliseconds to 3 seconds, or even 0.01 milliseconds to 1 second, or even 0.1 milliseconds to 500 milliseconds. It will be appreciated that Figures 1a to 1f The system 10 and its Figure 2The illustrated components are capable of producing electron beams with energies of 6 to 12 MeV or even higher at very high dose rates (e.g., on the order of 40-400 Gy / s in the illustrative embodiment). The high dose rate makes electron beams practical for gemstone irradiation. This allows the irradiation of gemstones to be completed in a short period of time. The use of electrons can avoid the heavy shielding required for the use of gamma or cobalt irradiators. Because the energy used is relatively low compared to other types of ionizing radiation, the risk of activating gemstones is significantly reduced.

[0111] As an alternative to using system 10 to implement FLASH radiotherapy, other embodiments may use less energy, dose rate, and / or dose delivered in one or more stages over a suitable time period. For example, for some therapies, the electron beam energy delivered to the target site 12 is in the range of 0.1 MeV to 12 MeV, preferably in the range of 0.2 MeV to 6 MeV, more preferably in the range of 0.3 MeV to 4 MeV, and even more preferably in the range of 0.5 MeV to 2 MeV. In some ways of implementing such therapy, an operating range of 1 MeV to 2 MeV will be desired. In such an embodiment, in a treatment regimen involving one or more stages, the electron beam system provides a radiation dose of up to about 20 Gy (e.g., up to about 15 Gy, up to about 10 Gy, up to about 5 Gy, or up to about 2 Gy). In such embodiments, the electron beam system can provide radiation to the target site 12 at a rate of at least about 0.2 Gy / min, at least about 1 Gy / min, at least about 2 Gy / min, at least about 5 Gy / min, or at least about 10 Gy / min. In such embodiments, the electron beam energy can be delivered to the target site 12 over a time period ranging from 0.01 milliseconds to 5 minutes, or even 0.1 seconds to 3 minutes during various stages. Exemplary embodiments in this area use the system 10 to irradiate the cut tissue proximate to the surgical incision 24 after wound closure in order to help reduce or prevent excessive formation of scar tissue that might otherwise develop as the incision subsequently heals.

[0112] Figures 1a to 1fThe electron beam radiation system 10 generally includes an electron beam generating unit 26 that emits a linearly accelerated, straight-through electron beam 16. Using feedback control techniques as described in U.S. Pat. No. 10,485,993, the system 10 emits the electron beam 16 with high stability and precision to achieve one or more desired penetration depth settings over a wide operating range. The feedback principle described in U.S. Pat. No. 10,485,993 allows the beam penetration depth, beam energy, dose and / or dose rate to be quickly adjusted and controlled in continuous or very small increments within the corresponding operating range. The ability to adjust these characteristics continuously or in small increments provides great flexibility to customize dose, energy, dose rate and / or penetration depth for specific patient needs. This is a significant advantage over conventional machines that have only a limited number of energy settings and / or provide beams with lower stability that are subject to coarse setting adjustments.

[0113] The penetration depth of electron beam therapy is the R measured in water according to the protocol described in "AAPM's TG-51 protocol for clinical reference dosimetry of high-energy photon and electron beams" by Peter R. Almond et al., Med. Phys. 26(9), September 1999, pp. 1847-1870 (referred to in the industry as the AAPM TG51 report). 80 Penetration Depth. Note that while this protocol focuses on electron beams with average incident energies in the range of 5 MeV to 50 MeV, the same protocol is applicable to lower or higher energies that may optionally be used in the practice of the present invention. In addition, this report provides a protocol for determining the R50 penetration depth. This is the depth in water at which the absorbed dose drops to 50% of the maximum dose. The same depth-dose data obtained from this protocol also provides the R 80 The penetration depth is the penetration of the electron beam dose into the water phantom, at which point the dose drops to 80% of the maximum dose. The maximum dose depth is referred to as Dmax. 80 The beam and dosimetry calibration of the machine settings for penetration depth were defined using a 5 cm diameter, circular, 30 cm long zero degree tip applicator in water at a source to skin distance (SSD) of 50 cm. The specific energy output was measured at Dmax.

[0114] For example, if this testing shows that a particular machine configuration produces an R of 2 cm 80 penetration depth, the configuration is considered to provide R at the target site 12 80Penetration depth. The machine can be calibrated or otherwise evaluated to determine a plurality of machine configurations to correspond to a corresponding plurality of penetration depths. At the time of the procedure, the care provider selects a particular penetration depth appropriate for the procedure. The machine is set to the corresponding configuration. The procedure is then performed using the principles of the present invention to deliver a stable and precise electron beam as the procedure is performed.

[0115] Electron beam energy and penetration depth are strongly correlated. See B. Grosswendt, "Determination of Electron Depth-Dose Curves for Water, ICRU Tissue, and PMMA and Their Application to Radiation Protection Dosimetry," Radiat. Prot. Dosimetry (1994) 54(2): 85-97. Depending on the embodiment, the relationship can be linear or nonlinear. In general, using an electron beam with higher energy results in a higher penetration depth.

[0116] Still reference Figures 1a to 1f The system 10 includes a feedback control system 28 that is configured to allow precise and stable control and adjustment of the penetration depth, electron beam energy, electron beam dose, treatment time and / or electron beam dose rate provided by the electron beam 16 using a feedback strategy (such as the feedback strategy described in U.S. Pat. No. 10,485,993).

[0117] As another example, as further described below, the feedback control system 28 is integrated into the system 10 in a manner that allows measurement of electron beam characteristics (e.g., fluence) that are highly correlated to the electron beam dose deposited into the target site 12 to be monitored so that the electron beam 16 can be terminated when the total desired dose is delivered. Advantageously, the feedback control system 28 and other components of the system 10 incorporate features that allow the electron beam to be terminated in the middle of a pulse. This approach more accurately delivers the target dose with a significantly reduced risk that the dose will be too high (delivering too many pulses) or too low (delivering too few pulses) compared to conventional systems that are only capable of controlling complete pulses.

[0118] like Figures 1a to 1fAs shown, the control system 28 includes at least one monitoring sensor for detecting one or more characteristics of the electron beam related to the deposited dose at a specified depth. In addition, the AAPM TG-51 uses a water phantom to provide a calibration scheme for correlating the sensed one or more characteristics with the deposited dose. This scheme allows different sensors to be calibrated to the deposited dose, so that the scheme can adapt to calibration in non-FLASH and FLASH treatment schemes. The calibration scheme has been described in PR Almond, PJ Biggs, BM Cruisey, WF Hanson, MS Huq, R. Nath; and in D. WO Rogers in Med. Phys. 26, 1847-1870, 1999 "AAPM's TG-51 protocol for clinical reference dosimetry of high-energy photon and electron beams". Once the output signal of one or more sensors is calibrated and related to the deposited dose, the output signal can be used to monitor ionizing radiation to determine the cumulative dose deposited in the matrix as the treatment proceeds. This allows the ionizing radiation to be terminated based on this feedback monitoring when the control system 28 determines that the cumulative dose deposited in the matrix reaches the target dose.

[0119] The monitoring in this embodiment includes at least two sensors in the form of a first sensor 31 and a separate second sensor 34. In other embodiments, more sensors may be included. Alternatively, multiple sensor capabilities may be combined into a single sensor component. The first sensor 31 measures a first characteristic (s1) of the electron beam 16. The first sensor 31 sends a corresponding first sensor signal 32 to the controller 38. The signal 32 corresponds to the value of one or more characteristics s1 measured by the first sensor 31. The second sensor 34 measures one or more second characteristics s2 of the electron beam 16. The second sensor 34 sends a corresponding second sensor signal 36 to the controller 38.

[0120] In the illustrative embodiment described further below, the sensor 31 is in the form of a toroidal coil sensor. In other illustrative embodiments described below, the sensor 34 is in the form of an array of two or more ion current chambers deployed at the periphery of the electron beam channel. The toroidal coil sensor is advantageous in many treatment situations, but is particularly advantageous in the FLASH treatment regimen because the toroidal coil sensor senses information quickly enough to provide excellent control of the electron beam 16 at the time scale involved in FLASH treatment or lower dose rate treatment. Moreover, the toroidal coil sensor can be easily configured to handle the higher fluence levels associated with FLASH treatment and the lower fluence levels used in non-FLASH treatments. In some embodiments, multiple toroidal coil sensors can be used to sense different fluence levels to allow even more accurate sensing over a wide range of fluences.

[0121] Suitable toroidal coil sensors are commercially available, such as those manufactured by Pearson Electronics, USA, under the model designation 110. In another alternative embodiment, TibaRay, Inc. of Sunnyvale, California, has developed a real-time beam monitor that can be used to accurately correlate the dose deposited at the FLASH dose rate. Those skilled in the art will appreciate that other alternative beam monitors can be used in the control system 28 of the present invention without departing from the spirit and scope of the present invention.

[0122] Typically, the electron beam is homogenized over about 70% to 80% of the inner cross-sectional area of ​​the beam radially closest to the beam centerline. Outside this inner region, in the peripheral region of the beam cross section, the beam fluence (also referred to as flux) decreases faster with increasing radial distance from the beam centerline. The beam energy also decreases, but to a lesser extent. Although the fluence in the peripheral region decreases faster with increasing radial distance from the beam center, the fluence in the peripheral region is still highly correlated with the homogenized inner region. This correlation is particularly accurate when the beam profile across the cross section is approximately constant at a specific centerline position of the beam. This means that the fluence characteristics of the inner and peripheral regions of the electron beam are accurately correlated with the deposited dose. The stability of the peripheral region, its lower fluence, and its high correlation with the homogenized region and the deposited dose allow the ion chamber to be deployed in the peripheral region, with many advantages.

[0123] For example, the peripheral deployment of the ion current chamber array in the peripheral region is advantageous because it allows the ion current chamber to be used as an electron beam sensing device in both FLASH and non-FLASH treatment schemes. Conventional deployment of the ion current chamber in non-FLASH schemes tends to place the device closer to the central axis of the electron beam 16 and behind a scattering foil used to flatten the beam. Although the beam energy and dose rate are often higher in the central region of the beam, the scattering foil used in conventional systems provides uniform beam energy and dose rate to the ion chamber system. Therefore, the central portion of the ion chamber is exposed to a relatively uniform energy and dose rate that is far below the saturation capacity of many ion chambers.

[0124] On the other hand, the higher dose rates of the electron beam used in FLASH therapy may tend to saturate the capacity of some ion cavities if placed along the beam centerline, rendering the chamber useless for sensing beam characteristics, even if flattened by a scattering foil system. However, dose rate and fluence tend to decrease with increasing radial distance from the center of beam 16. Therefore, ion current chambers deployed around the periphery of the channel through which beam 16 travels are exposed to smaller electron beam fluences that may be below the saturation threshold of the ion current chambers.

[0125] In short, the peripheral deployment of the ion current chamber allows the sensing device to be used more effectively to monitor electron beams at lower as well as higher dose rates, with much less risk of saturation when used relative to electron beams at higher dose rates. As an additional advantage, an array of such devices around the perimeter allows beam uniformity to be assessed, since excessive differences between sensed measurements can indicate beam problems sufficient to trigger subsequent actions (e.g., beam adjustment, termination, etc.). Many ion chambers are suitable for monitoring dose rates up to about 15 Gy / min or even 20 Gy / min. In some embodiments, it will be desirable to deploy one or more ion chambers in a peripheral region at a location on a particular cross section where the dose rate is less than 20 Gy / min or even less than 15 Gy / min. In some embodiments, the fluence at a particular deployment site at a cross-sectional location is in the range of 0.01% to 70%, even 0.01% to 50%, or even 0.01% to 30% of the fluence at the beam centerline of the cross section.

[0126] Typically, the beam monitoring signal using a beam monitor (e.g., a toroidal coil sensor) depends on the amount of beam current passing through the center of the toroidal coil, rather than the energy or dose rate of the beam particles. As known to those skilled in the art, beam fluence refers to the number of particles per unit area per unit time passing through a plane perpendicular to the beam. In contrast, the amplitude of the ion cavity signal tends to vary with high fluences such as seen in the FLASH fluence, and varies less with beam energy due to the correlation of beam scattering with beam energy. Taking into account the characteristics of the two sensors, the system 28 can control the energy of the beam particles by taking the ratio of the beam monitoring signal to the ion cavity signal and then feeding the signal to control the microwave or RF power level. The ratio can also be used by the control electronics to provide interlocking of the beam energy. Interlocking refers to terminating the electron beam when the beam energy is outside a predetermined energy window.

[0127] Readings from sensor 31 and optional sensor 34, as well as one or more optional additional sensors (if any), can be used by control system 28 in various control strategies. For example, as treatment progresses, controller 38 can use one or both of the sensed characteristics s1 and s2 to determine characteristics of electron beam 16 so that the total dose of electron beam energy delivered to target site 12 can be monitored to allow rapid termination of the electron beam after a full pulse or a partial pulse, as appropriate, when the target dose is reached or, optionally, when the target dose is about to be reached (taking into account any lag time in the system terminating the beam in response to the sensed characteristics s1 and / or s2). For example, if system calibration indicates that 0.50 Gy of energy is delivered within the time of sensing and terminating beam 16, control system 28 can be configured to send a beam termination signal when the cumulative dose delivered to target site 12 is less than 0.50 Gy of the desired target dose.

[0128] As another example, in accordance with the control strategy described in U.S. Pat. No. 10,485,993, the controller 38 may use the sensed information to derive an analog characteristic A of the electron beam energy from the detected characteristics s1 and s2 exhibited by the signals 32 and 36. As a result, measuring at least two different characteristics of the beam and using these characteristics to derive an analog characteristic allows the control system 28 to easily control the characteristics of the electron beam 16, such as energy, dose, dose rate, treatment duration, penetration depth, etc., with high accuracy.

[0129] In addition, the controller 38 can use the control signal 40 in different ways to implement other feedback controls. As an example, the control signal 40 can be used to cut off the electron beam according to the interlocking protocol. As another example, the control signal 40 can be used to adjust one or more power supplies that generate the electron beam to tune the electron beam energy as desired. In some embodiments, this power-based control can be achieved by the microwave source 66 (see Figure 2 or Figure 3 ) and / or electron source 70 (see Figure 2 or Figure 3 ). Using a feedback control strategy, feedback based on the modulator or magnetron (e.g., feedback that adjusts the modulator output voltage or the magnetron frequency) allows the electron beam energy to be adjusted stepwise or continuously within a desired operating range (e.g., 0.1 MeV to 12 MeV in some embodiments, or even 6 MeV to 20 MeV in other illustrative embodiments, or even up to 50 MeV, or even up to 100 MeV).

[0130] As another example, the modulator output voltage can be adjusted to affect the current and microwave power supplied to the magnetron. The magnetron power can be adjusted, which affects the amount of power delivered to the accelerator 76 ( Figure 2 and Figure 3 ). In addition to or as an alternative to these strategies, feedback control strategies can be used with respect to other system characteristics used to establish the electron beam, including gun voltage, etc. The gun voltage can be adjusted to affect the emission rate, phasing, capture, and energy spectrum of the electrons.

[0131] In addition, the electron source 70 (see Figure 2 ) and RF source 65 (see Figure 2 ) are typically pulsed at the same rate (i.e., the same pulse repetition frequency), but the pulse widths are not necessarily the same. The control system 28 can control the pulse frequency of these components and the degree to which the frequencies are synchronized or offset. The controller 38 can be configured to be able to independently turn on or off each of the electron source 70 and the RF source 65, so as to turn on the system 10 and allow it to warm up, to operate the electron beam during treatment, or even to quickly terminate the electron beam in the middle of a pulse.

[0132] In many cases associated with beam actuation and termination, it is easier and faster to turn the electron gun on and off than to turn the magnetron on and off. This means that a preferred embodiment involves turning off the electron gun when the target dose is reached to terminate the electron beam more quickly. As another result of the faster actuation of the electron gun, in many operating modes, the magnetron pulse width is typically fixed, while the pulse width of the electron gun can be adjusted to different widths depending on the dose required per pulse. Narrower gun pulses produce less dose per unit time, and wider pulses produce more dose per unit time, until the gun pulse is as wide as the magnetron pulse. The amplitude of the electron gun and / or magnetron pulse can also be changed to control the output, but this is a slower process. Therefore, the amplitude of the magnetron and electron gun pulses is usually kept constant throughout the treatment. Maintaining a uniform pulse amplitude is particularly important for FLASH treatment, in which the total treatment time is very short, so that amplitude changes may not reach stability or even reach new levels within the time frame of the treatment.

[0133] As another control strategy, the control system 28 can use the sensing information to provide current to the upstream steering coils to steer the beam 16 in real time and / or continuously correct any beam offset or symmetry errors. As another control function of the control system 28, if a problem with the electron beam is detected, the sensor readings can be used to terminate the beam 16 and limit the amount of radiation deposited into the target site. For example, the loss of the scattering foil may result in an excessive dose being delivered. Thus, the control system 28 provides one or more protective interlocks to shut off the beam in such a situation.

[0134] As another method of implementing feedback control, the control signal 40 can be used to adjust the settings of one or more physical system components (e.g., one or more electron beam absorbers), the selected position settings of which can be used to modulate the electron beam energy. One such adjustable component is a variable thickness electron beam absorber, which can be adjusted to present different thicknesses, and therefore different absorptions, to the electron beam. Such absorber-based control can be implemented with a single absorber plate that provides a selectable thickness range, a variable thickness belt, or a rotating body that includes a degree of rotation to present variable thickness absorption to the electron beam. Using the feedback control strategy of the present invention, absorber-based feedback allows the electron beam energy to be adjusted stepwise or continuously within a desired operating range.

[0135] When any absorber is used to help tune the electron beam, the control system 28 desirably includes a monitor that confirms that the absorber is in the correct installation position. If the monitor provides a signal indicating that the position is incorrect, an interlock protocol is triggered, which prevents the electron beam from being turned on. Similarly, in those embodiments in which the system 10 includes multiple absorbers with different thicknesses, a specific absorber or a combination of absorbers is an appropriate absorber selection for performing a specific treatment at a desired penetration depth. Therefore, the control system 28 desirably includes a monitor that checks whether the installed absorber matches the machine settings for a specific treatment. If an inappropriate absorber is installed for the selected process, an interlock protocol is triggered, which prevents the beam from being turned on. As an additional safety function, a specific treatment will generally involve the delivery of a specific radiation dose. The control system 28 desirably monitors the delivered dose in real time and initiates an interlock protocol to shut off the electron beam to avoid overdose.

[0136] Some embodiments of the present invention combine both power-based feedback control and absorption-based feedback control of electron beam energy, dose, dose rate and / or thus penetration depth.

[0137] Figure 2 Exemplary features of one embodiment of a suitable electron beam generating unit 26 that may be used in system 10 are schematically shown in FIG. Figure 2Unit 26 incorporates features that assist in providing partial pulse control in accordance with the present invention.

[0138] like Figure 2 As seen in FIG. 1 , the electron beam generating unit 26 generally includes a first housing 64 that houses a modulator 65, a microwave source 66, a microwave network 68, an electron source 70, and a linear accelerator 76. A second housing 83 houses a collimator assembly 80. A rotational coupling system 95 facilitates rotatably mounting one or more field defining members to be incorporated into the unit 26. By way of example, the system 10 (e.g., Figures 1a to 1f The unit 26 of the example (illustrated) includes a first field defining member in the form of an applicator 86 and a second field defining member in the form of a shield 88, the first field defining member and the second field defining member being integrated into the unit 26. The coupling system 95 generally combines a first subassembly 96 and a second subassembly 98, wherein the first subassembly 96 and the second subassembly 98 are rotatably coupled to each other. The rotational coupling allows relative rotation between the two subassemblies 96 and 98 about an axis of rotation that is parallel to the central axis of the linear electron beam path 90 and is desirably colinear and coincident therewith. The coupling system 95 also incorporates automatic distance detection, automatic lighting functions, and other functions. Details of the rotational coupling system 95 and its functionality are further described in U.S. Patent No. 62 / 941,327, filed on November 27, 2019 in the name of Turk et al., entitled “ELECTRON BEAM RADIATION SYSTEM WITH ADVANCED APPLICATOR COUPLING SYSTEM HAVING INTEGRATED DISTANCE DETECTION AND TARGET ILLUMINATION” and attorney case number IOP0006 / P1.

[0139] An external power source 72 supplies power to the modulator 65 via a power cable 73. Alternatively, the power source 72 and the power cable 73 may be included with the other components within the housing 64. An exit window 78 is provided at the interface between the linear accelerator 76 and the collimator assembly 80. A scattering foil system 82 and an ion chamber 84 are housed in the collimator assembly 80 along with the first sensor 31 and the second sensor 34. The unit 26 generates an electron beam that is directed from the accelerator 76 along a generally linear electron beam path 90 directly through the applicator 86 to the target site 12 (also at Figures 1a to 1f ). An optional field-defining shield 88 is placed at the exit of the applicator 86.

[0140] A wide range of sensor devices can be used as sensor 31 and / or sensor 34. Typically, such sensors have the functionality of allowing the sensing of beam characteristics of a wide range of electron beam fluence rates and energy levels (e.g., electron beam fluence rates and energy levels associated with FLASH and non-FLASH treatments). An example of such a sensing device includes a gas-filled detector, in which radiation ionizes the gas to generate a detectable amount of carriers, which are related to the dose or dose rate of the ionizing radiation passing through the detector. The detection signal is typically a current level related to the fluence or fluence rate. Alternatively, these devices can form a signal by counting pulses. Ionization chambers, proportional counters, and Geiger-Muller counters are examples of this type of gas detector. In a preferred embodiment, the second sensor 34 is in the form of an ion cavity array disposed around the periphery of the collimator assembly 80, which defines a channel through which the electron beam 16 flows. Peripheral deployment allows sensing of beams of higher doses and dose rates to be measured with a much smaller risk of the ion cavity being saturated by the full flux of the beam 16 at its center. The array deployment allows the uniformity of the beam 16 to be monitored.

[0141] Scintillation detectors are another type of detector that can be used to detect the properties of ionizing radiation. These detectors include materials that emit light when excited with ionizing radiation. The luminescence intensity generates a current in the photocathode that is related to the dose or dose rate. The luminescence itself can usually generate a low-intensity current. Therefore, an amplifier (e.g., a photomultiplier tube) can be used to enhance the signal.

[0142] Semiconductor detectors can also be used to detect ionizing radiation. These detectors include one or more inorganic and / or organic semiconductor materials that generate a current level related to the energy deposited in the material by the incident ionizing radiation. Semiconductor detectors are known to be more suitable for detecting ionizing radiation in the form of beta particles (e.g., electron beams) or gamma radiation because they may be susceptible to damage by heavier particles.

[0143] Thermoluminescence dosimeters can also be used as sensing devices. These devices typically include a material, usually a crystalline material, that emits light when exposed to incident ionizing radiation. The light emitted is related to the absorbed dose.

[0144] Chemical detectors may also be used. In these detectors, incident ionizing radiation causes a measurable chemical change in the medium via mechanisms such as oxidation, reduction, dissociation, etc. The level of the change is related to the amount of energy absorbed. An example of such a detector is a Frick dosimeter.

[0145] Calorimetric sensors can also be used. These sensors measure the radiation dose by measuring the temperature rise of the medium.

[0146] Inductive or toroidal coil sensors may also be used. Many embodiments include two toroidal coils, which may be examples or components of inductive or toroidal coil sensors herein. Each toroidal coil may be schematically viewed as being disposed in a ring around a central hole. Thus, for example, material with ionizing radiation may flow through the central hole without being obstructed by the coils. One toroidal coil emits an electric field. This induces an electric field in a second coil. The passage of ionizing radiation through the central hole increases the current in the second coil by an amount related to the flux of the ionizing radiation. In practice, a toroidal coil sensor, toroidal coil, or toroidal current monitor (commonly referred to as a toroidal coil) is a toroidal current-voltage converter, in which the current to be measured typically flows through the central hole of the toroidal coil. The output signal is related to the instantaneous dose rate. The output signal may be calibrated and integrated to accurately provide information (e.g., real-time cumulative dose, etc.).

[0147] In a preferred embodiment, the first sensor 31 includes at least one toroidal coil sensor. Toroidal coil sensors are very practical devices for measuring gun current and beam current because toroidal coil sensors are commercially available in a variety of sizes and shapes and can be specified to have rise and decay profiles in the low nanosecond range, which helps to ensure that pulse shape and amplitude are accurately sensed. Toroidal coil sensors are fast and accurate enough to detect electron beam characteristics, thereby providing meaningful control even at higher electron beam doses and dose rates that occur in short time intervals. The beam can be projected through the central hole area of ​​the toroidal coil with minimal beam obstruction. Toroidal coil sensors are rarely contaminated and require less maintenance. Toroidal coil sensors are also robust to the electron beam 16, even at FLASH treatment levels. In a more preferred embodiment, the first sensor 31 includes at least one toroidal coil sensor and the second sensor 34 includes one or more ion chambers.

[0148] like Figure 2The electron beam generating unit 26 shown is a type that uses linear acceleration technology to increase the electron beam energy to a desired level. It is well known to use a linear accelerator structure to generate an electron beam for therapeutic purposes. In addition, the electron beam generating unit 26 is a "straight-through" type system. As is well known in the art, the straight-through system aims the electron beam at the target site along a substantially linear path from the exit window 78 of the linear accelerator 76 to the target site 12. This helps to ensure that the large amount of beam current generated is used. In contrast, the curved system wastes a larger proportion of the beam current due to absorption in the curved magnet slit. The beam current waste in the curved system usually produces significantly greater background radiation per unit delivered dose. The linear, straight-through beam line minimizes this beam loss and better optimizes the dose per unit current that reaches the target site. This means that the linear system requires less shielding. Therefore, the straight-through system tends to be smaller, lighter and more compact than the alternative system that uses heavy magnets and heavy shielding to aim the electron beam at the target site on a curved path. An additional advantage of a straight-through system is that the energy can be changed rapidly because there are no eddy current diffusion time limitations or hysteresis of a bent-beam system.

[0149] An example of such a system suitable for intraoperative procedures is described in U.S. Pat. No. 8,269,197 assigned to IntraOp Medical Corporation. Another example of such a system suitable for intraoperative procedures is an electron beam machine available from IntraOp Medical Corporation under the trade name MOBETRON. Typically, linear straight-through systems such as these systems are the result of designing a compact linear accelerator that can be assembled when vertically positioned at ceiling heights common in many surgical locations (e.g., treatment rooms or operating rooms). These compact systems avoid complex curved systems that often generate extraneous background radiation that requires a large amount of shielding. Advantageously, the principles of the present invention can be incorporated into the MOBETRON electron beam machine, which will provide a mobile FLASH treatment system including intraoperative FLASH treatment. Strategies for configuring and operating the MOBETRON electron beam machine and other linear electron beam machines in FLASH treatment mode are further described below.

[0150] Still reference Figure 2 , modulator 65 receives power from the power output of power source 72 via cable 73. Power source 72 can be any suitable power source. Alternatively, power source 72 can be part of a continuous power supply from an electric utility. Alternatively, power source 72 can be battery powered, thereby allowing cable-free operation of electron beam generating unit 26. Modulator 65 receives power from power source 72 (which can be line power, battery power, or any suitable power source) and converts it into short pulses of high voltage that are applied to microwave source 66. Microwave source 66 converts the voltage into microwave or RF energy. The pulses generated by the modulator have a high voltage that can be controlled by control system 28 (see Figures 1a to 1f) controls the frequency, pulse width, amplitude and duty cycle.

[0151] Examples of suitable microwave sources for use as microwave source 66 include a magnetron or a klystron to provide power to linear accelerator 76. A magnetron is more preferred because it is less expensive and simpler to incorporate into system 10.

[0152] Many suitable embodiments of magnetrons operate using X-band, S-band or C-band frequencies. X-band equipment is more preferred because other embodiments of unit 26 tend to be heavier when using S-band or C-band equipment. X-band frequency technology also tends to minimize the diameter of the accelerator structure and therefore minimize weight. An illustrative example of a suitable magnetron operating at X-band frequencies is model L-6170-03 sold by L3 Electronics. This magnetron is capable of operating at a peak power of approximately 2.0 megawatts and an average power of 200 watts.

[0153] The microwave network 68 transmits microwave or RF power from the microwave source 66 to the linear accelerator 76. The microwave network 68 typically includes a waveguide (not shown), a circulator (not shown), a load (not shown), and an automatic frequency control system (not shown). The use of these components in accelerator systems is well known to those skilled in the art and has been described in the patent literature. See, for example, U.S. Pat. No. 3,820,035. In short, microwaves from the RF source pass through the circulator before entering the accelerator guide to protect the RF source from the reflected power from the accelerator 76. On the contrary, the power not absorbed in the accelerator 76 is reflected back into the circulator and shunted into a water-cooled or air-cooled dummy load. In a preferred embodiment, air cooling is preferred because air cooling reduces weight and minimizes maintenance issues. The AFC circuit is used to keep the resonant circuit tuned to the microwave frequency. Air cooling works in the implementation of the present invention because the average power of the magnetron (e.g., 200W in the illustrative embodiment) is relatively low for an electron beam. In contrast, x-ray machines typically involve average powers in the range of 1kW to 3kW. The ability to use air cooling for the electron beam is one factor that helps the preferred electron beam machine of the present invention be compact and lightweight.

[0154] If the microwave source 66 (e.g., a magnetron) is mounted on a rigid assembly (not shown) with the linear accelerator 76, the microwave or RF power can be injected into the accelerator structure through a fixed waveguide. Alternatively, a flexible waveguide can be used in the microwave network 68. As an option for implementing the feedback principle of the present invention, in the case of a magnetron, the microwave or RF power supplied to the linear accelerator 76 through the microwave network 68 can be modulated by varying the pulsed high voltage supplied to the magnetron from the power supply 72. Such modulation of the voltage of the power supply 72 correspondingly allows the energy level, dose, dose rate and / or penetration depth of the electron beam 16 to be controlled and adjusted to many different desired settings with excellent precision using the feedback strategy of the present invention. For a klystron, the same approach can be used. Alternatively, the input microwave power to the klystron can be varied.

[0155] In parallel with the microwave source 66 supplying microwave or RF energy to the linear accelerator 76, the electron source 70 supplies electrons to the linear accelerator 76. The electron source 70 typically includes an electron gun and features that connect the gun to the linear accelerator 76. Many different embodiments of the electron gun are known and suitable. For example, some embodiments use a dipole or triode electron gun in which a high voltage is applied between the cathode and the anode. Many commercially available electron guns operate in a voltage range between 10 kV and 17 kV, but in some embodiments, electron guns operating at other voltages may also be used. The voltage is typically DC or pulsed. In the case of a triode gun, a lower grid voltage is also applied between the cathode and the grid. The grid can disable or enable the beam 16, and the grid voltage can be continuously varied to inject more or less gun current. The grid voltage applied to the electron gun has a voltage that can be controlled by the control system 28 (see Figures 1a to 1f ) controlled frequency, pulse width, amplitude and duty cycle. Those skilled in the art of linear accelerator design are able to understand and select the appropriate gun design for the linear accelerator 76 to be used.

[0156] A triode electron gun is preferred for the partial pulse control strategy of the present invention. Although a diode gun is simpler in construction, it tends to be slow to turn on and off due to the large voltage swings typically required (e.g., in the range of 5 kV to 20 kV). A triode gun is more complex, but the additional grid element allows the gun current to be controlled with a much smaller voltage swing (e.g., about 200 volts or even less). As a result, within 100 nanoseconds, the gun current can be completely shut off, and the electron beam terminated. This time frame is fast enough to terminate the electron beam in a wide range of electron beam therapies, including FLASH therapies that occur at high doses and high dose rates over a time frame that may span only a portion of a second, while delivering the desired dose.

[0157] Exemplary embodiments and descriptions of a triode electron gun are described in U.S. Patent Nos. 3,651,360, 9,257,253, and U.S. Patent Application Publication No. 2019 / 0272969. See also Arvind Jain et al., Design and Operating Experience of Triode Electron Guns for Industrial Electron Accelerators, WEPMA011, APAC 2007, Raja Ramana Center for Advanced Technology (RRCAT), Indore, India, pp. 348-350; D. Bhattacharjee et al., Development of Electron Guns for Linacs and DC Accelerator, J. of Physics: Conference Series 390 (2012012071; S. Mahadevan et al., Improved Version of the Triode Electron Gun, Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors, and Associated Equipment, Volume 438, Issue 2-3, December 11, 1999, Pages 573-576.

[0158] An example of a commercially available electron gun suitable for the practice of the present invention is the product designation M592 electron gun sold by L3 Electronics (formerly Litton). In some embodiments, the injector cathode of this particular gun operates at 10 kV to 14 kV and has an emitting surface of very small diameter. This design is intended to provide low emissivity and good capture efficiency while maintaining low energy spread. Typical pulse widths for operation may be in the range of 0.5 to 6 microseconds.

[0159] The microwave or RF source is pulse modulated by a modulator 65. Preferably, the modulator 65 is solid state based rather than tube based to reduce weight and improve portability. A solid state based modulator also allows for rapid reprogramming of key parameters, which is particularly helpful for rapid modulation suitable for high dose rates and fast treatment times associated with FLASH operation (e.g., pulse width). The pulse repetition frequency (PRF) can be selected from a wide range, such as from about 1 to about 500 pulses per second, and the pulse width can be selected from a wide range, such as from about 1 to 25 microseconds. Some treatments may be performed at these frequencies and pulse widths for specific durations, such as from about 10 to about 25 microseconds in some treatments. -6 seconds, or from about 10 -5 seconds, or from about 10 -4 The gun may be pulse modulated by a different modulator system. In the practice of the invention, the pulse width, pulse amplitude, pulse frequency and pulse duty cycle applied to the electron gun are respectively related to the electron beam 16 (see Figures 1a to 1f ) are related to the pulse width, pulse amplitude, pulse frequency, and pulse duty cycle of the electron gun. Therefore, adjusting these characteristics of the electron gun often adjusts the electron beam characteristics, even if similar characteristics are fixed with respect to the voltage applied to the microwave or RF source.

[0160] The linear accelerator 76 is configured to receive microwave or RF power from the microwave network 68. The linear accelerator 76 is also configured to receive electrons from the electron source 70. The linear accelerator 76 is coupled to the microwave network 68 and the electron source 70 in a manner that effectively uses the microwave or RF power to accelerate the electrons to provide an electron beam 16 having an energy level within a desired operating range.

[0161] Various linear accelerator structures will be suitable for the implementation of the present invention. For example, the linear accelerator 76 can have a structure that implements any of a variety of different cavity coupling strategies. Examples of suitable structures include structures that provide side cavity coupling, slot coupling, and center hole coupling. CJKarzmark, Craig S.Nunan and Eiji Tanabe, Medical Electron Accelerators (McGraw-Hill, New York, 1993). The linear accelerator 76 can also have a structure that implements various different symmetry strategies. Examples of suitable structures include structures that provide periodic, bi-periodic, or tri-periodic symmetry. Examples of suitable accelerator structures can also implement a series of standing wave or traveling wave strategies. Examples of suitable linear accelerators 76 can also be selected to operate in many different bands of microwave or RF power. Examples of suitable power bands include S-band (2-4 GHz), C-band (4-8 GHz), X-band (8-12 GHz), and higher frequencies. David H. Whittum, "Microwave Electron Linacs for Oncology," Reviews of Accelerator Science and Technology, Vol. 2 (2009) pp. 63-92. In some illustrative embodiments, linear accelerator 76 uses a low profile structural design that incorporates an on-axis dual-period cavity operating at X-band frequencies. U.S. Pat. No. 8,111,025 provides more details of charged particle accelerators, radiation sources, systems and methods, side-coupled X-band accelerators and on-axis and side-coupled S-band and C-band accelerators are other suitable examples.

[0162] The linear accelerator 76, its attached electron source 70, and one or more other components of the electron beam generating unit 26 can be mounted on a strong backing material (not shown) or other suitable support member inside the housing 64. The linear accelerator 76 and the electron source 70 can be encapsulated in lead or other shielding materials (not shown) as desired to minimize radiation leakage. The higher the resonant frequency of the accelerator guide, the smaller the diameter of the structure. This results in a lighter weight housing to limit leakage radiation. The advantage of a linear straight-through machine is that the shielding requirements are not as strict as those of a machine using a beam bending strategy. This allows a straight-through electron beam radiation machine to be more easily deployed in a conventional operating room for intraoperative procedures, rather than being deployed in a remote location in a heavily shielded room or requiring heavy shielding to be added to the operating room, which increases the cost and structural issues of allowing operation.

[0163] During operation, the network, linear accelerator, and microwave source 66 experience heating. It is desirable to cool the unit 26 (particularly the units 65, 66, the circulators and loads in the microwave network 68, and the accelerator structure 76) in order to dissipate this heat. A variety of strategies can be used to achieve cooling. For example, the accelerator structure 76 and the microwave source 66 can be water-cooled, as is known. In addition, implementation of the present invention allows operation at low duty cycles for which air cooling would be quite sufficient. The ability to implement air cooling simplifies the construction of the unit 26 and helps make the unit 26 smaller and more compact. The result is a corresponding system 10 (see Figures 1a to 1f ) are easier to deploy and use during intraoperative procedures.

[0164] An exit window 78 is provided at the beam exit of the linear accelerator 76 to help maintain the vacuum within the accelerator. The window 78 is preferably strong enough to withstand the pressure difference between the accelerator vacuum and the ambient atmospheric pressure, such as a difference of about 15 psi in some cases, but the window 78 is preferably thin enough to avoid excessive beam interception and / or bremsstrahlung generation. Balancing these factors, in many embodiments, the window 78 can be formed of titanium. Alternatively, beryllium or other metals or composite materials can also be used.

[0165] The accelerated electron beam 16 exits the linear accelerator 26 through the exit window 78 and then continues on a linear path through the collimator assembly 80, which receives, widens, and flattens the beam. To implement the feedback strategy of the present invention, one or more sensors, such as sensors 31 and 34, may be deployed in or around the collimator assembly 80 to detect two or more independent characteristics of the beam 16, or to detect redundant characteristics of the beam 16 for safety purposes.

[0166] The collimator assembly 80 may include a housing 81. The housing 81 may be constructed of a material that helps contain the bremsstrahlung radiation, or the collimator design itself may be sufficient to contain the bremsstrahlung radiation. Inside the housing 81, a scattering foil system 82 and an ion chamber 84 are provided. Note that the ion chamber 84 and the sensor 34 are shown as two different components, but the ion chamber 84 may be used as at least a portion of the sensor 34. Figure 2 84 is also schematically shown in the figure. In actual implementation, in some embodiments, it may be desirable to deploy the (one or more) ion chambers 84 peripherally in the peripheral area of ​​the electron beam. Further, the sensor 31, which is expected to be a toroidal coil sensor (as described herein) in many cases, is shown as being upstream of the scattering foil system 82. In some embodiments, the sensor 31 can be downstream of the scattering foil system 82, and in some embodiments, particularly very close to the downstream of the scattering foil system 82.

[0167] The scattering foil system 82 has multiple functions. For example, electron beam systems typically produce electron beams with small lateral dimensions, which are on the order of 1 mm to 3 mm wide, much smaller than a typical treatment field. The scattering foil system 82 helps widen the electron beam 16. The scattering foil system 82 also helps flatten the electron beam 16. In many embodiments, the beam passes through the scattering foil system 82 to help shape the isodose curve at the treatment plane at the target site 12.

[0168] In an illustrative embodiment, the scattering foil system 82 helps expand the acceleration beam 16 from a cross-section of several square millimeters to a cross-section of several square centimeters. Dose uniformity over the treatment field is a desired goal for simplifying dose planning for therapeutic applications. For example, the collimator assembly 80 with or without the applicator 86 can be used to provide a flat electron beam dose profile so that the coefficient of variation of the beam dose over the full width at half maximum (FWHM) of the beam is less than ±50%, less than ±40%, less than ±30%, less than ±20%, less than ±10%, less than ±5%, less than ±2.5%, or less than ±1%. Those skilled in the art will recognize that the coefficient of variation of the electron beam energy over the FWHM can have any value within this range, for example, approximately ±5%. In some embodiments, the collimator can be used to widen the electron beam to a field size of 1 cm to 25 cm wide.

[0169] A typical scattering foil system 82 includes at least one, even two or more, or even three or more scattering foils (not shown). The distance between the two or more foils may vary depending on the energy range of the unit, the field size required for the therapeutic application, and the geometry and material of the mass element in the treatment head. Typically, the electron scattering foils may be designed using techniques such as empirical design iterations or Monte Carlo simulations. Other means of providing uniformity may rely on magnetic phenomena. For example, steering coils may be employed to grid the beam across a programming region. Alternatively, a quadrupole magnet system may be used to modify the beam size at the target plane. The first subassembly 96 of the coupling system 95 is attached to the exit end of the collimator assembly 80. At the same time, the applicator 86 is attached to the exit end of the second subassembly 98. A field limiting shield 88 (also referred to as an "insert") is attached to the exit end of the applicator 86. Because the second subassembly 98 is rotatably coupled to the first subassembly 96, this means that the applicator 86 and the attached shield 88 are able to rotate relative to the first subassembly 96 about the axis 192 (see Figures 5 to 7 ) and therefore rotate relative to the collimator assembly 80 and other upstream components of the unit 26. The rotation helps to help ensure that proper alignment of the field defining the opening (e.g., the exit of the shield 88) and the treatment site (e.g., a tumor, scar, incision, etc.) is achieved.

[0170] If the applicator 86 is metallic and can be in contact with the target site, it is desirable that the applicator 86 be electrically isolated from upstream components of the system 10 (e.g., the coupling system 95, the collimator assembly 80, etc.). This can be achieved in various ways, such as by inserting an insulating coupling between the applicator 86 and the second subassembly 98, between the applicator 86 and the substrate 14 (e.g., the patient), or by forming the applicator from an inherently insulating material (e.g., polymethyl (meth)acrylate, commonly referred to as PMMA, quartz, ceramic, etc.).

[0171] The accelerated and collimated electron beam 16 is aimed at the target site 12 by the applicator 86 and the field limiting shield 88. The applicator 86 and the shield 88 are configured so that the electron beam continues to pass straight to the target site 12 on the linear electron beam path 90. In many embodiments, the applicator 86 and the shield 88 further help define the shape and flatness of the electron beam 16. The applicator 86 also makes it easier to aim the electron beam while minimizing manipulation, contact or interference with the patient or the target site. In addition, the use of the applicator 86 and the shield 88 helps to avoid stray radiation and minimize the dose delivered to healthy tissue by limiting the radiation field.

[0172] Applicator 86 and / or shield 88 can optionally include one or more other components to help further modify the electron beam characteristics. For example, by spreading thin (0.5-1mm) plastic sheets or sheets made of low atomic number materials into the slots arranged to receive them in applicator 86 and / or shield 88, the energy reduction of low bremsstrahlung can be achieved. Materials with higher electron density can also be used, and can be thinner for the same absorption. Applicator 86 and / or shield 88 can also be combined with one or more elements used as secondary scattering components. These elements can be made of low atomic number materials of suitable shape, which help to further scatter the electrons in the volume of applicator 86 and / or shield 88. Examples of these materials include aluminum, carbon and copper and combinations of these materials, but are not limited to these materials. These materials can be located in the applicator 86 for applying the required energy and field size by Monte Carlo calculation or empirically determined position.

[0173] In some embodiments, a transparent or partially transparent applicator 86 and / or shield 88 may be beneficial. For example, such an applicator design may allow for easier observation of the treatment site. An applicator and / or shield made at least in part of PMMA, quartz, etc. will allow such observation.

[0174] Unit 26 can be positioned in any orientation or position relative to the target site, regardless of the patient's orientation. In many embodiments, the distance from the outlet end of applicator 86 (or the end of the field that limits shielding member 88, if present) to the surface of the target site can be changed from contacting the target site to a distance of up to about 10cm from the patient's surface. This distance can be determined by any suitable measurement technique (e.g., by mechanical measurement or electronic rangefinder). Advantageously, the connection system 95 includes a function that allows automatic determination of the distance. In certain embodiments, the system and / or applicator can be positioned manually to achieve any orientation or position relative to the target. In certain embodiments, the system and / or applicator can be positioned using one or more motor drivers for automatic control of orientation and position. For example, applicator 86 can be placed by hand and maintained in place by a suitable support structure (not shown). So the electron beam machine will dock (i.e., align) to applicator 86. Applicator 86 is desirably electrically isolated from other components of system 10, particularly in the treatment of applicator contact or close to substrate 14 (e.g., patient).

[0175] Applicator 86 can have a variety of shapes, such as being shaped to produce a circular, square, irregular or rectangular field on the target site. Some useful applicators include a cylindrical path through which the electron beam passes. Another example of an applicator design called a scanning horn produces a long and narrow field by having a scattering element in the applicator, which preferably scatters electrons along the length of the field. In some embodiments, a scanning horn can be used to limit the irradiated area to a strip of about 2 cm to about 10 cm in length and about 0.2 cm to about 1 cm in width.

[0176] Figure 2 It is shown how absorbers 89 can be mounted on an applicator 86 in a manner that effectively tunes the electron beam to adjust the electron beam energy, dose, dose rate, penetration depth, etc. By having a library of absorbers 89 with subtle, step-by-step differences in electron beam absorption, different adjustments of the electron beam in subtle increments can be delivered to a treatment site, such as site 12. At the same time, a feedback strategy (such as that described in U.S. Pat. No. 10,485,993) can optionally be used to stabilize the electron beam with high precision before tuning through the absorber 89. In order to change another penetration depth setting, one or more different absorbers 89 are presented to the beam and / or the machine can be set to produce electron beams with different energy levels presented to one or more absorbers 89. Different absorbers 89 can be installed manually or automatically. U.S. Pat. No. 10,485,993 also describes how to use absorbers to help adjust the electron beam.

[0177] Figure 2An absorber 89 is shown mounted to the applicator 86. The absorber 89 can be located in other locations and still provide effective tuning. Typically, the absorber 89 is deployed in the path 90 of the electron beam between the exit window 78 and the target site 12. Many suitable embodiments of the absorber 89 are made of one or more low-Z materials with an atomic number of 4 or more. Exemplary materials that can be used to form the absorber 89 include carbon, aluminum, beryllium, and combinations of two or more of these materials. Higher Z materials can be used, but there is a risk of generating excessive bremsstrahlung.

[0178] Figure 2 The machine vision capability integrated with the unit 26 is shown. In some embodiments, machine vision is achieved by mounting one or more endoscopes 93 to the applicator 86. The endoscope 93 allows real-time video imaging of the target site 12. The endoscope 93 or other machine vision capabilities help to allow the target site 12 to be observed without being blocked by the applicator 86, the shield 88 or the unit 26 or other components of the system 10. As an advantage, when the system 10 is set and aimed at the target site 12, the endoscope 93 allows real-time observation of the target site 12. This can help ensure that the system 10 is properly aimed at the site 12 without excessive misalignment or tilt. The operator can also observe the captured image information during treatment to observe the site 12. This will allow the operator to capture image information to record treatment. Moreover, the operator can observe to ensure that as the treatment proceeds, the matrix 14 (e.g., the patient) will not move out of the appropriate setting. The endoscope 93 is very suitable for this because endoscopes are usually flexible and inexpensive for easy installation, capturing high-quality, real-time images.

[0179] FLASH treatment times are very short (typically less than 5 seconds or even less than 1 second or even occurring in tenths or thousandths of a second or milliseconds or on the order of microseconds). It is highly desirable to provide an accurate dose per pulse to allow accurate use and control of ionizing radiation in FLASH treatment. In one aspect, the accuracy of the dose per pulse is limited by the ability of the system 10 to quickly produce stable, uniform beam pulses. To achieve this goal, the system 10 including the unit 26 can be configured with one or more optional features that are incorporated into the circuitry that generates the gun pulses, the shape of the pulses that power the microwave or RF energy pulses, an automatic frequency control function, and / or timing that allows the microwave or RF power and gun pulses to be synchronized (generating an electron beam) or asynchronous (not generating an electron beam).

[0180] The circuitry generating the gun pulses is desirably configured to generate a more stable pulse shape with faster rise and decay times to achieve better repeatability and less sensitivity to temperature drift. To achieve this, an electronic switching device is incorporated into the design of the gate pulse circuit that allows switching to occur quickly enough to effectively actuate within the time scale associated with FLASH therapy. In addition, the shape of the high voltage pulses that power the magnetron is preferably configured for more stable magnetron operation. To achieve this, the control of the switching device for the solid-state modulator (the high voltage power supply that provides the high voltage pulses to the magnetron) is preferably modified to make the slope of the rise and fall times more vertical. Moreover, the automatic frequency control system desirably can be configured to provide accurate tracking of the magnetron frequency to the linear accelerator resonant frequency. To achieve this, the frequency response of the AFC servo system can be increased (faster response time) by adjusting the control software of the magnetron tuner motor to provide a more effective frequency response within the time scale of a typical FLASH therapy.

[0181] The control system 28 desirably can be configured to allow microwave or RF power pulses and gun pulses to be energized in an unsynchronized or uncoordinated state (no beam is generated) until thermal stability is achieved for the system 28. Once thermal stability is achieved, the pulses can be synchronized, or switched to coincide, to generate a beam for treatment.

[0182] As an advantage, embodiments of the system 10 (e.g., a MOBETRON electron beam machine) can be configured so that an operator can select from one or more non-FLASH treatment modes and one or more FLASH treatment modes. Typically, if the non-FLASH mode is not already working, the non-FLASH mode can be switched to the FLASH mode by increasing the dose per pulse and implementing partial pulse control. Increasing the dose rate by pulses can be achieved by implementing one or more strategies selected from increasing the amplitude of the electron beam current, increasing the duty cycle of the electron beam current, increasing the pulse width, and / or increasing the ratio of the dose rate to the electron beam current.

[0183] For example, increasing the amplitude of the beam current may be accomplished by one or more of increasing the gun voltage, increasing the grid voltage, modifying the RF system (including the magnetron and, if necessary, the modulator) to compensate for the increase in RF power required to accelerate the higher gun current, modifying the design of the linear accelerator cavity to improve the capture ratio of the gun current, and / or increasing the length of the linear accelerator to reduce the required RF power. Increasing the duty cycle of the beam may be accomplished by one or more of increasing the gun and / or RF pulse width and / or increasing the pulse repetition frequency of the beam pulses. Increasing the ratio of dose rate to beam current may be accomplished by one or more of decreasing the distance from the beam source (flattening filter) to the treatment plane to focus the beam in a smaller treatment area (inverse square law), and / or modifying the scattering foil and / or the flattening filter to reduce the number of electrons scattered out of the treatment field.

[0184] Figure 3 Shows Figure 2 In addition to using a different applicator 100 and an alternative field-defining shield 102, Figure 3 The system 10 is similar to Figure 2 The system 10 shown is the same. In this illustration, the applicator 100 is larger than the applicator 86 ( Figure 2 ) is longer, and the shield 102 is longer than the shield 88 ( Figure 2 ) is small and helps to shape a more tightly defined electron beam field. Figure 3 The modularity of the system 10 with respect to independently selecting and using different applicators and / or shields to easily accommodate the needs of a variety of different electron beam treatments and environments is illustrated. Applicators (e.g., applicator 86) are modular in the sense that a library may include an inventory of two or more applicators, each of which may be interchangeably mounted on the unit 26. Similarly, shields (e.g., shield 88) are modular in the sense that a library may include an inventory of two or more shields, each of which may be interchangeably mounted on the unit 26.

[0185] Figure 4 Another alternative embodiment of the electron beam generating unit 26 is shown. In addition to the microwave source 66 and a portion of the microwave network 68 being outside the housing 64, Figure 4 System 10 and Figure 2 The same is true for the system 10. According to conventional implementations, by incorporating one or more rotary joints into the network 68, rotational movement between the two ends of the network 68 can be implemented.

[0186] Figure 5 , Figure 6 and Figure 7 An alternative embodiment of a portion of unit 26 of system 10 is shown, wherein Figure 2The sensor 31 is in the form of a toroidal coil sensor 180, and Figure 2 The sensor 34 is in the form of an array of ion chambers 182 deployed around the periphery 184 of the electron beam channel 186 within the collimator assembly 80. In this embodiment, the annular coil sensor 180 includes an annular housing 188 surrounding a sensing component (not shown). The central hole 190 is open and provides an unobstructed aperture for the passage of the electron beam. The central axis 192 of the channel 186 generally corresponds to the central axis of the electron beam (beam) flowing along the path 90 to the target site 12. The three ion chambers 182 are deployed as a uniform array to sense the characteristics of the beam around the channel. By detecting the characteristics at multiple areas around the channel periphery, the readings from the ion chambers 182 can indicate whether the beam is uniform (e.g., the readings are roughly similar) or whether the beam is non-uniform (e.g., the readings are not sufficiently similar).

[0187] Figure 7 An array of ion chambers 182 is shown including three ion chambers 182 symmetrically disposed about a central axis 192. In other embodiments, the array may include two ion chambers 182 or more than three ion chambers 182, such as 4 to 8 ion chambers 182. In some embodiments, even a single ion chamber 182 may be used in place of the array where beam sensing with ion chamber redundancy and the ability to monitor multiple peripheral regions is not desired.

[0188] Figure 8 It is schematically shown how the electron gun pulse characteristics are related to the output signal of a beam monitor (eg sensors 31 and / or 34 described above), and how the output signal is then related to the cumulative dose deposited to the target site. Figure 8 A graph 200 is included of electron gun voltage as a function of time. Graph 200 shows that the electron gun voltage is applied as pulses 202 (full) and 203 (partial) over time. The pulses have a frequency that is the inverse of the period T. Each pulse 202 is characterized by a pulse width W. The pulses are flat at the top, indicating that the voltage is advantageously constant and uniform during the pulse. Each pulse 202 also has a rising profile 206 and a decaying profile 208. Profiles 206 and 208 are generally vertical, indicating that the pulses start and end quickly. The last pulse 203 is similar to pulse 202, except that pulse 203 is a partial pulse. The electron gun voltage is turned off at time t to end pulse 203. Time t corresponds to the time when the target dose 226 has been deposited to the treatment site. The dashed portion of pulse 203 shows the portion of pulse 203 that does not occur due to the termination of the electron gun voltage.

[0189] Still reference Figure 8, graph 210 shows the amplitude of the output signal of the beam monitor as a function of time. In this illustration, the beam monitor is a toroidal coil sensor used as sensor 31 (see, for example, Figure 2 ). As treatment proceeds, the output signal is related to the instantaneous dose rate. Graph 210 shows how the beam monitor detects the electron beam dose rate as pulses 212 (full) and 203 (partial) as a function of time. The horizontal time scale of graph 210 matches the time scale of graph 200 to show how pulses 202 / 203 are synchronized and occur at the same time and with the same frequency as pulses 212 / 213. Each pulse 212 also has a rising profile 216 and a decay profile 218. Profiles 216 and 218 are generally vertical, indicating that the pulses start and end quickly. Pulse 213 is a partial pulse that ends at time t to show how the termination of partial pulse 203 quickly ends pulse 213, thereby showing the rapid termination of the electron beam using the partial pulse control strategy. The dashed portion of pulse 213 shows the portion of pulse 213 that does not appear due to the partial pulse control strategy.

[0190] Still reference Figure 8 , graph 220 shows the cumulative dose 225 deposited by the electron beam of graph 210 as a function of time. The horizontal time scale of graph 220 matches the time scale of graphs 210 and 200 to show how the cumulative dose is synchronized with the electron gun pulses 202 / 203 and the electron beam pulses 212 / 213. Graph 220 shows how the cumulative dose increases linearly in the rises 224 that occur during each pulse 202 / 203 and 212 / 213. The increase is linear because the individual pulses in graphs 200 and 210 have uniform amplitudes during their duration. Between each rise 224 is a plateau 227 during which the instantaneous cumulative dose remains constant. This corresponds to the area of ​​graphs 200 and 210 where no pulses occur. Therefore, the cumulative dose does not increase.

[0191] Graph 220 shows the desired target dose 226. Graph 220 shows how the cumulative dose reaches the target dose 226 at time t, which is the time when pulses 202 / 203 and 212 / 213 stop. This shows how partial pulse control can stop dosing in the middle of pulse 213 or 203 when the desired target dose 226 is reached. This provides a substantially more accurate dosing than methods that only control complete pulses. Partial pulse control is particularly advantageous in FLASH treatment regimens where complete pulses, or even partial pulses, are a significant portion of the target dose 226 (e.g., at least 10%, or even at least 5%, or even at least 3%, or even at least 1%).

[0192] Fig. 9Schematically shows the method for implementing Figure 8 A method 250 of a dose control strategy for a linear accelerator is provided. In step 252 of method 250, an electron gun control function applies a voltage to the electron gun in a pulsed form. The grid gun control electronics generate the amplitude, pulse width, and pulse frequency of the control voltage applied to the electron gun grid. The grid voltage controls the gun current injected into the linear accelerator and ultimately controls the beam current leaving the accelerator. For example, this can produce Figure 8 2. Voltage pulse 202 of graph 200 in FIG.

[0193] After a voltage pulse is applied to the electron gun, an electron beam is generated and pulsed at the target site. The beam current flows out of the accelerator and into the sensor 31 (see Figures 1a to 1f and Figure 2 ) in the form of a beam monitor. For the purposes of this discussion, sensor 31 is in the form of a toroidal coil sensor. The electron beam passes through the center of the toroidal coil sensor and, as treatment progresses, induces an output signal which is measured by associated electronics in step 254. The signal is Figure 8 The graph 210 shows an accurate real-time representation of the amplitude and shape of beam pulses 212 and 213.

[0194] As treatment progresses, the signal amplitude of pulses 212 and 213 is related to the instantaneous dose rate. In step 256, the output of the loop coil sensor is fed to the control system 28 ( Figures 1a to 1f ) is a dose conversion function. This function applies a dose conversion function that is calibrated to convert the output signal of the loop coil sensor into a dose rate associated with the dose delivered to the target site as a function of time. The dose rate can be integrated to provide a cumulative dose at any time during treatment. The cumulative dose profile is given by Figure 8 The curve graph 220 shows.

[0195] In step 258, the control system 28 evaluates whether the cumulative dose signal at a particular time is equal to the total target dose 226. If at time t i If the answer to the evaluation of is yes, the control system 28 sends a signal 260 to terminate the voltage applied to the electron gun, thereby terminating the electron beam at time t. If time t occurs in the middle of the pulse 203 / 213, the pulse is terminated as a partial pulse, thereby accurately delivering a cumulative dose that matches the target dose 226. If the answer is no, the method 250 is repeated.

[0196] Electron source 70( Figure 2) is typically the rate determining factor for the temporal resolution of the system operation. Thus, controlling the gate allows for rapid termination of the electron beam. For example, a typical gate cycle time for an electron gun may be on the order of about 0.1 microseconds (about 100 nanoseconds). This means that step 258 may be implemented by controlling a gate mechanism for such a gun to allow the electron beam to be terminated with an accuracy of about 0.1 microseconds. It should also be noted that control of the gate mechanism allows for control of the amplitude, pulse width, pulse frequency, and duty cycle of the electron gun pulses.

[0197] Fig. 9 The present invention is shown to monitor the total dose delivered to the patient during a treatment session as the treatment progresses. If the target dose level has been reached, the present invention allows the electron beam to be terminated during a pulse, thus only delivering a portion of the final pulse.

[0198] Fig. 9 The control method 250 desirably monitors the electron beam and evaluates the cumulative dose at a frequency suitable for providing accurate control of electron beam termination. In a suitable embodiment, control occurs at a frequency greater than the frequency of pulse 212, or even at least 5 times the frequency of pulse 212, or even at least 10 times the frequency of pulse 212, or even at least 50 times the frequency of pulse 212, or even at least 100 times the frequency of pulse 212. Monitoring the electron beam at a higher frequency tends to provide more accurate control of the total delivered dose. For example, assuming a 50% duty cycle, monitoring at a frequency of 10 times the pulse frequency allows the dose to be controlled to within 1 / 5 of a pulse. Conversely, monitoring at a frequency of 50 times the pulse frequency at a 50% duty cycle allows the dose to be controlled to within 1 / 25 of a pulse.

[0199] Method 250 provides a method in which, as treatment progresses, dose monitoring is used to deliver all pulses except the last pulse at a fixed pulse width, and the last pulse is delivered at a smaller pulse width or by terminating the radiation mid-pulse. The pulse width of the smaller portion of the last pulse is dynamically determined in real time by monitoring the cumulative dose delivered to the target site. Early termination of the last pulse is much faster and less complex than dynamically adjusting the last pulse width to provide the desired final dose portion.

[0200] Fig.10 Another illustrative method 350 for implementing the dose control strategy of the present invention is schematically shown. In step 352 of method 350, the electron gun control function applies voltage to the electron gun in pulse form. The grid gun control electronics generates the amplitude, pulse width and pulse frequency of the control voltage applied to the electron gun grid. The grid voltage controls the gun current injected into the linear accelerator and ultimately controls the beam current leaving the accelerator.

[0201] After applying a voltage pulse to the electron gun, an electron beam is generated and pulsed at the target site. The beam current flows out of the accelerator and enters the sensor 31 ( Figures 1a to 1f and Figure 2 ) is a detection aperture of a beam monitor in the form of a . For the purposes of this discussion, sensor 31 is in the form of a toroidal coil sensor. The electron beam passes through the center of the toroidal coil sensor and induces a real-time signal that is measured by associated electronics in step 354. This signal can be an accurate real-time representation of the amplitude and shape of the beam pulse.

[0202] In step 356, the output signal of the loop coil sensor is fed to the control system to determine whether the current pulse width is too wide or too narrow so that applying one or more additional pulses will exceed the target dose. If too wide or too narrow, pulse width modulation is required to deliver one or more subsequently modified pulses in a manner that effectively allows the target dose to be accurately achieved.

[0203] In step 357, the control system applies dynamic pulse width modulation to increase and / or decrease the pulse width of one or more additional pulses such that the target dose is delivered.

[0204] In step 358, the control system evaluates whether the cumulative dose at a particular time is equal to the desired target dose. i If the answer to the evaluation of is yes, the control system sends a signal to terminate the voltage applied to the electron gun, thereby terminating the electron beam at time t. If the answer is no, the method 350 is repeated. In parallel, as a safety protocol, the total cumulative dose delivered to the target site can be monitored so that the beam can be terminated in an emergency if the target dose is reached while pulses are still in progress or while one or more pulses may still occur.

[0205] Fig.10 The present invention is shown to monitor the total dose delivered to a patient during a treatment session as treatment progresses, and to allow dynamic modulation of pulse width as treatment progresses so that termination of the electron beam occurs when a predetermined total dose level is reached.

[0206] Fig.11 Another illustrative method 450 for implementing the dose control strategy of the present invention is schematically shown. In step 452 of method 450, a pulse width recipe combining multiple pulse widths is provided. The pulse width recipe is created so that pulses implementing the recipe's pulsed ionizing radiation deposit a desired target dose to a substrate.

[0207] In step 454, pulsed ionizing radiation is deposited into the substrate using the pulse width recipe by irradiating the substrate with ionizing radiation.

[0208] When the pulse width recipe is complete, irradiation of the substrate is terminated in step 456. In parallel, as a safety protocol, the total cumulative dose delivered to the target site can be monitored so that the beam can be terminated in an emergency if the target dose is reached while the pulse recipe is still ongoing.

[0209] Fig.12 is a graph showing how a commercially available MOBETRON electron beam machine delivers a total dose in 6MeV FLASH therapy that is linear with respect to the number of pulses, and the total dose delivered for a particular pulse count is highly uniform.

[0210] Fig.13 is a graph showing how a commercially available MOBETRON electron beam machine delivers a total dose in 9MeV FLASH therapy that is linear with respect to the number of pulses, and the total dose delivered for a particular pulse count is highly uniform.

[0211] The invention will now be described with reference to the following representative examples.

[0212] Example 1

[0213] Table 1:

[0214]

[0215]

[0216] The data in Table 1 show that the MOBETRON electron beam machine is operable to generate a FLASH dose rate at a 6MeV energy level, and the FLASH output (Gy / s) is related to the distance (cm) between the flattening filter and the position of the measurement FLASH output along the electron beam path (inverse square law). The data also show the influence of field size on output when the beam parameters of MOBETRON are adjusted to operate with a FLASH dose rate. In this experiment, for the FLASH dose rate, the MOBETRON pulse width is set to 4.0 μs, and the pulse rate is set to 45 pulses / second (PPS). The output is compared with the standard (non-FLASH) MOBETRON output of 10Gy / min. (1.6 μs pulse width and 30PPS). The measurement is carried out in air using a Marcus chamber. The distance is measured from the standard MOBETRON treatment distance when the applicator is in the appropriate position.

[0217] Example 2

[0218] Table 2:

[0219]

[0220]

[0221] The data in Table 2 were obtained in the same manner as Table 1, but with the MOBETRON operating at 9 MeV. The data in Table 2 lead to the same conclusion, namely that the MOBETRON electron beam machine can be operated to generate FLASH dose rates at the 9 MeV energy level, with the FLASH output (Gy / s) being related (inverse square law) to the distance (cm) between the flattening filter and the location along the electron beam path where the FLASH output is measured.

[0222] Example 3

[0223] The MOBETRON was operated to determine if the dose per pulse was sufficiently uniform that termination with partial pulses would achieve accurate dose delivery.The MOBETRON was operated at a nominal dose rate of 30 Gy / s as this was the maximum dose rate that did not saturate the electronics of the dosimetry system used for the experiment. Fig.12 The results for 1, 2, 5 and 10 pulses at 6 MeV are shown in Table 3 below. The pulse width was 3.7 μs (microseconds) and the gate voltage was 6 volts at 6 MeV.

[0224] Table 3:

[0225]

[0226]

[0227] Example 4

[0228] The MOBETRON was operated to determine if the dose per pulse was sufficiently uniform that termination with partial pulses would achieve accurate dose delivery.The MOBETRON was operated at a nominal dose rate of 30 Gy / s as this was the maximum dose rate that did not saturate the electronics of the dosimetry system used for the experiment. Fig.13 The results for 1, 2, 5 and 10 pulses at 9 MeV are shown in Table 4 below. The pulse width was 3.7 μs and the gate voltage was 5.7 volts at 9 MeV.

[0229] Table 4:

[0230]

[0231]

[0232] The corresponding entire contents of all patents, patent applications and bulletins cited herein are incorporated by reference for all purposes. The above detailed description is given only for the purpose of understanding clearly. Any unnecessary limitations should not be understood therefrom. The present invention is not limited to the exact details shown and described, because changes that are obvious to those skilled in the art will be included in the present invention defined by the claims.

Claims

1. An ionizing radiation system for depositing a target dose of pulsed ionizing radiation into a matrix during treatment, the ionizing radiation system comprising: a. an ionizing radiation unit that generates the pulsed ionizing radiation and deposits the pulsed ionizing radiation into the matrix during the treatment, wherein the pulsed ionizing radiation is provided as a sequence of one or more individual pulses, and wherein the ionizing radiation comprises a fluence characteristic as the treatment proceeds; and b. A control system comprising at least one sensor that monitors the pulsed ionizing radiation as the treatment proceeds, including during the one or more individual pulses, wherein i. the at least one sensor provides an output signal indicative of the fluence characteristics of the pulsed ionizing radiation as the treatment proceeds, including providing the output signal during the one or more individual pulses; ii. the control system comprises program instructions for using information including the output signal to determine dose information indicative of a cumulative dose deposited into the substrate as the treatment proceeds, including determining the dose information during the one or more individual pulses; iii. the control system includes program instructions for determining termination information indicative of a comparison between the cumulative dose and the target dose as the treatment proceeds, including determining the termination information during the one or more individual pulses; and iv. The control system includes program instructions, which cause the pulsed ionizing radiation to terminate when the termination information indicates that the cumulative dose sufficiently matches the target dose, wherein the program instructions are configured to cause the termination during the current individual pulse when the determination indicates that the target dose is reached during the current individual pulse, so that the current pulse is a partial pulse at the termination moment.

2. The system according to claim 1, wherein: The pulsed ionizing radiation includes a pulsed electron beam.

3. The system according to claim 1, wherein: The pulsed ionizing radiation includes a linearly accelerated pulsed electron beam.

4. The system according to claim 1, wherein: The pulsed ionizing radiation includes a pulsed proton beam.

5. The system according to claim 1, wherein: The pulsed ionizing radiation comprises a pulsed beam of electromagnetic energy.

6. The system according to claim 1, wherein: The substrate is a human patient or a diseased animal.

7. The system according to claim 1, wherein: The substrate is selected from the group consisting of a gemstone, a food, a cargo, or a medical device.

8. The system according to claim 3, wherein: The linearly accelerated electron beam has an energy in the range of 4 MeV to 100 MeV.

9. The system according to claim 1, wherein: The sequence of individual pulses includes at least one full-width pulse and at least one partial-width pulse, wherein the at least one partial-width pulse is generated by prematurely terminating a corresponding full-width pulse prior to completion of a full-width pulse.

10. The system according to claim 1, wherein: The sequence of individual pulses comprises at least one pulse having a pulse width that is dynamically modulated as the treatment progresses.

11. The system according to claim 1, wherein: The ionizing radiation unit includes a solid-state modulator.

12. The system of claim 1, wherein: The ionizing radiation unit includes a tripole electron gun.

13. The system of claim 1, wherein: The sequence of individual pulses has a constant frequency and a constant amplitude.

14. The system of claim 1, wherein: The output signal corresponds to the fluence of the ionizing radiation.

15. The system of claim 1, wherein: The at least one sensor includes at least one toroidal coil sensor.

16. The system of claim 1, wherein: The at least one sensor includes a plurality of loop coil sensors.

17. The system of claim 1, wherein: The pulsed ionizing radiation is a beam having an inner region and a peripheral region; the inner region constitutes 70% to 80% of the cross-sectional area of ​​the beam, and the peripheral region constitutes 20% to 30% of the cross-sectional area of ​​the beam; and wherein the at least one sensor is positioned in a manner effective to sense beam characteristics in the peripheral region.

18. The system of claim 17, wherein: The sensor array is deployed in a manner effective to detect beam characteristics in the surrounding area.

19. The system of claim 18, wherein: The sensor array includes a plurality of ion chambers.

20. The system of claim 17, wherein: At least one sensor is positioned in a manner to sense a fluence characteristic of the beam, wherein the fluence characteristic is in the range of 0.01% to 70% of the fluence at a corresponding centerline of the beam.

21. The system of claim 2, wherein: The ionizing radiation unit comprises a triode electron gun, and wherein the program instructions which when executed cause termination of the pulsed electron beam comprise program instructions which when executed turn off the triode electron gun.

22. The system of claim 2, wherein: The sequence of one or more individual pulses is configured to deposit a dose of at least 1 Gy into the matrix per stage.

23. The system of claim 22, wherein: The dose is 5 Gy to 50 Gy per phase.

24. The system of claim 23, wherein: The dose rate is at least 1 Gy / s and is delivered in intervals of 10 seconds or less.

25. The system of claim 24, wherein: The dose rate is at least 30 Gy / s and the time interval is 1 second or less.

26. The system of claim 24, wherein: The time interval is in the range of 0.01 milliseconds to 3 seconds.

27. The system of claim 24, wherein: The dose rate is in the range of 1 Gy / s to 1500 Gy / s.

28. An electron beam irradiation system for depositing a target dose of pulsed electron beam irradiation into a substrate during a treatment, the system comprising: a. an electron beam unit comprising a tripole electron gun that assists in generating and depositing the pulsed electron beam radiation into the substrate during the treatment in response to a pulse voltage applied to a tripole-based electron gun, wherein the pulsed electron beam radiation is provided as a sequence of one or more individual pulses, and wherein the electron beam radiation includes a fluence characteristic as the treatment progresses; b. A control system comprising at least one annular coil sensor that monitors the pulsed electron beam radiation as the treatment proceeds, wherein: i. the at least one annular coil sensor providing an output signal indicative of the fluence characteristics of the pulsed electron beam radiation as the treatment proceeds, including providing the output signal during the one or more individual pulses; ii. the control system comprises program instructions which, when executed, use information including the output signal to determine dose information indicative of a cumulative dose deposited into the substrate as the treatment progresses, including determining the dose information during the one or more individual pulses; iii. the control system comprises program instructions which, when executed, determine termination information indicative of a comparison between the cumulative dose and the target dose as the treatment proceeds, including determining the termination information during the one or more individual pulses; and iv. the control system includes program instructions which, when executed, modify the voltage applied to the triode electron gun in a manner sufficient to terminate the pulsed electron beam radiation when the termination information indicates that the real-time total accumulated dose sufficiently matches the target dose, wherein the program instructions are configured to cause the termination during the current individual pulse when the determination indicates that the target dose is reached during the current individual pulse, So that at the termination moment the current individual pulse is a partial pulse.

29. An ionizing radiation system for irradiating a substrate with a target dose of pulsed ionizing radiation during treatment, the system comprising: a. an ionizing radiation unit that generates the pulsed ionizing radiation and deposits the pulsed ionizing radiation into the matrix, wherein the pulsed ionizing radiation is provided as a sequence of one or more individual pulses, and wherein the ionizing radiation comprises a fluence characteristic as the treatment proceeds; b. A control system comprising at least one sensor that monitors the pulsed ionizing radiation as the treatment proceeds, including during the one or more individual pulses, wherein i. the at least one sensor provides an output signal indicative of the fluence characteristics of the pulsed ionizing radiation as the treatment proceeds, including providing the output signal during the one or more individual pulses; ii. the control system comprises program instructions for using information including the output signal to determine dose information indicative of a cumulative dose deposited into the substrate as the treatment proceeds, including determining the dose information during the one or more individual pulses; iii. the control system comprises program instructions for determining a pulse width modulation for at least one of the pulses using information including a comparison between the accumulated dose and the target dose; and iv. The control system includes program instructions that dynamically cause pulse width modulation of at least one pulse when the comparison indicates that delivering one or more additional unmodulated pulses will over or under deliver the cumulative dose relative to the target dose.

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