Dose quantification method and system

Abstract

A radiation dose quantification method and system, the method including: detecting with a detector gamma rays emitted by capture of neutrons from a composition comprising a thermal neutron capture agent in a specimen subjected to an irradiation program (the neutrons are generated by inelastic collisions of a primary beam of one or more particles of protons, deuterons, tritons and heavy ions with atomic nuclei in the specimen, the irradiation program including an irradiation time window having a beam duration including a beam on / off time window); applying a predetermined energy window or filter that accepts only detection events at the detector due to gamma rays of energies indicative of selected gamma rays resulting from capture of thermal neutrons by the thermal neutron capture agent with energies less than about 0.4 eV; applying a timing window that rejects or ignores detection events at the detector due to prompt gamma rays resulting from non-neutron capture events; and determining from the accepted detection events a radiation dose or a radiation dose map of neutron radiation received by the specimen in the irradiation program.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and the priority date of AU2021903247, filed October 9, 2021, the contents of which are incorporated herein by reference in their entirety.

[0002] The present invention relates to a radiation dose quantification method and system, particularly as applied in quantifying neutron capture events in particle radiation therapy. [Background technology]

[0003] WO 2019 / 051557 A1 discloses irradiation methods and compositions for use, inter alia, in what is called "Neutron Capture Enhanced Particle Therapy" (or NCEPT). Thermal neutrons are generated within the patient's body by beam-target nuclear interactions at and around the treatment site, and the therapeutic effect is tumor-specific. 10 B or 157 This can be enhanced by capturing thermal neutrons using neutron capture agents such as Gd-based agents, which release secondary particles with high LET (linear energy transfer), 10 B or 157 For Gd-based drugs, 478 keV ( 10 B), or 79.5keV, 182keV, 6.75MeV, 7.86MeV and 7.94MeV ( 57 Gamma rays with the respective energies of 1000 and 10000 Gd are released.

[0004] However, planning, optimizing, and delivering NCEPT is more complex than previous particle therapy approaches because the internally generated thermal neutron fluence depends on factors such as the size and depth of the treatment volume and the cellular concentration of the neutron capture agent. Summary of the Invention [Problem to be solved by the invention]

[0005] The purpose of the present invention is to facilitate radiation dose quantification in the NCEPT. [Means for solving the problem]

[0006] According to a first broad aspect, the present invention provides a method for producing a method for treating a cancer cell comprising: detecting, with one or more detectors having respective sensitive volumes, gamma rays emitted as a result of capture of neutrons by a composition in a specimen subjected to an irradiation program, the composition comprising one or more thermal neutron capture agents, the neutrons being generated by inelastic collisions between a primary beam of charged particles and atomic nuclei in the specimen, the charged particles being any one or more of protons, deuterons, tritons and heavy ions, the irradiation program comprising at least one irradiation time window having a beam duration comprising a beam-on time window and a beam-off time window; applying at least one predefined energy window or filter configured to accept only detection events at one or more detectors resulting from gamma rays having energies indicative of selected (e.g., primary or only) gamma rays resulting from capture of thermal neutrons by one or more thermal neutron capture agents, where thermal neutrons are neutrons having energies below approximately 0.4 eV; applying a timing window configured to reject or ignore detection events at one or more detectors derived from at least prompt gamma rays produced in a non-neutron capture event; determining the dose of thermal neutrons (i.e., counted gamma rays) received by the subject during the irradiation program from at least the accepted detection events, or determining a dose map of thermal neutrons received by the subject from at least the accepted detection events; The present invention provides a method for quantifying radiation dose, comprising:

[0007] Determining the radiation dose or determining the dose map can additionally employ beam data indicating the primary beam position (i.e., within the subject) and the primary beam energy corresponding to each accepted detection event.

[0008] It should be noted that applying at least one predefined energy window can be performed online (i.e., simultaneously with the collection of detection events) or offline (i.e., by filtering the detection events after data collection). However, events outside the energy window are unlikely to be useful for the present purpose. Similarly, applying the timing window can also be performed online or offline. Thus, in various embodiments, one or both of applying the energy window and applying the timing window are performed online, and in other embodiments, one or both of applying the energy window and applying the timing window are performed offline.

[0009] The detector or detectors can sense the angle of arrival of the gamma rays, which is particularly advantageous in determining the dose map.

[0010] The method includes at least approximately 10 seconds after the end of each beam-on time window. 5.8 ns time frame or 10 5.8 ns~2×10 6 The method may include detecting neutron capture gamma rays within a timing and energy window in the ns time frame.

[0011] In another embodiment, the method includes detecting all neutron capture gamma rays that fall within a predefined energy window of interest for offline processing (e.g., subsequent application of an offline timing window). The charged particles include ionizing H (i.e., protons), 4 He (i.e., alpha particles, generally considered to be heavy ions), C, O, and / or Si, specifically: 9 C.10 C. 11 C. 12 C. 15 O. 16 Includes isotopes of O and Si with higher n (generally considered heavy ions).

[0012] The composition is advantageously taken up preferentially by malignant (eg, cancerous) target tissue.

[0013] The primary beam typically obtains the appropriate energy by cyclotron or synchrotron acceleration of particles.

[0014] The method may apply multiple energy windows if one or more neutron capture agents produce gamma rays of multiple energies. Additionally, in embodiments employing multiple detectors, different energy windows may be defined for different detectors depending on the gamma rays that each detector is configured or intended to detect.

[0015] The method may include configuring a timing window to reject prompt gamma rays by rejecting gamma rays that arrive at each sensitive volume from the beginning of each beam-on time window until approximately 11 ns, approximately 12 ns, or 10-12 ns after the end of the respective beam-on time window.

[0016] The method may also include configuring a timing window to reject detection events in each sensitive volume due to fast neutrons based on the timing.

[0017] This may include configuring a timing window to reject detection events from the start of each beam-on time frame until at least 30 ns, at least 40 ns, at least 49 ns, at least 50 ns, or between 30 and 50 ns after the end of the respective beam-on time frame.

[0018] The method may also include configuring a timing window based on the timing to reject detection events in each sensitive volume due to neutrons having energies between 0.4 eV and 1 MeV.

[0019] This is from the start of each beam-on time frame to 50ns to 10ns after the end of each beam-on time frame. 4 The method may include configuring a timing window to reject detection events for up to ns.

[0020] The method may include configuring a timing window to reject detection events within a detection window where a ratio of true positive detection events to false positive detection events, as confirmed empirically or by simulation, is less than 1.4 or less than 1.5, where a true positive detection event is an event that meets the timing window and energy window and results from a neutron capture event, and a false positive detection event is an event that meets the timing window and energy window and results from something other than a neutron capture event.

[0021] Thus, ratios above 1.5 are useful, but higher ratio values ​​provide better image quality or more accurate verification of the dose delivered at one or more specific locations within the subject / target.

[0022] The method may include at least partially shielding the one or more detectors (and specifically their scintillators) with a single or multiple (e.g., four) layers of neutron absorbing and / or scattering material, the material being different from the one or more neutron capture agents. In some embodiments, the method desirably includes shielding all sides of the one or more detectors other than the side(s) of the one or more detectors facing the subject (or its associated volume).

[0023] Neutron absorption (whereby the shield acts as a passive filter) is more practical for thermal neutrons, while scattering / deflection is generally a more practical technique for fast neutrons in order to scatter a significant proportion of the fast neutrons away from the detector.

[0024] In such an embodiment, a shield may be positioned over the front surface of the one or more detectors to absorb and / or scatter thermal neutrons by the one or more thermal neutron capture agents. 10 Any traces of boron present as a dopant in the components of the dose quantification system (such as silicon substrates or PCBs) if they are or contain a B-based agent may generate background that corrupts the measurement of gamma rays resulting from the capture of thermal neutrons by the thermal neutron capture agent. This 10 In any practical implementation employing B-based drugs, some form of shielding becomes virtually essential.

[0025] Optionally, the shielding may also be arranged to cover one or more sides of one or more detectors for the same reason. 10 In the case of being or including a B-based drug, trace amounts of boron are present (or excess amounts of boron are present), and in a practical implementation, at least some shielding of the sides may be virtually essential.

[0026] Neutron absorbing or scattering materials are selected based on their neutron absorption and scattering cross sections and are thick enough to block and scatter most of the neutrons away from the detector, but thin enough not to absorb or scatter too high a percentage of the gamma rays generated by neutron capture. For example, the materials may include high density plastics (such as high density polyethylene), paraffin, cadmium, gadolinium, boron, boron carbide, lead, brass, and / or hafnium.

[0027] In some examples, the one or more neutron capture agents include 10 B Base and / or 157 For example, the neutron capture agent or agents may be Gd-based, such that the gamma ray has an energy of 478 keV. 10B-based, and / or gamma rays having energies of 79.5 keV, 182 keV, 6.75 MeV, 7.86 MeV and / or 7.94 MeV. 157 It may be Gd-based.

[0028] The method may include planning radiation therapy involving the generation of thermal neutrons within the patient's body through beam-target nuclear interactions at and around the treatment site.

[0029] In some examples, the neutron capture agent is 10 B-based, and the one or more detectors include any one or more of CdTe, CZT, LYSO:Ce, and LaBr3:Ce detectors. In these examples, the beam duration can be 1-10 μs, or approximately 1 μs. The method can include shielding the one or more detectors with thermal neutron absorbing materials including native Cd, native Gd, Pb, brass, high density plastic, and / or native Hf.

[0030] In another example, the neutron capture agent is 157 The primary beam may be Gd-based and the one or more detectors may include any one or more of LSO:Ce, BGO, and PbWO4 detectors. In these examples, the beam duration may be 10 μs to 100 ms. If the primary beam is a carbon ion beam, the beam duration may be approximately 1 ms, and if the primary beam is a helium ion beam, the beam duration may be approximately 10 μs. The method may include shielding the one or more detectors with a thermal neutron absorbing material including natural B and / or natural Hf.

[0031] The method (and system, see below) may employ any combination of the following:

[0032] [Table 1]

[0033] Pb, brass and Cd can also be used to shield the sides of the detector from fast neutrons without excessively thermalizing the neutrons.

[0034] In particular examples, such combinations that can be employed have a ratio of true positives to false positives R of greater than 1.4, or advantageously greater than 1.5. TF (as defined herein).

[0035] According to a second broad aspect, the present invention provides a method for producing a method for treating a cancer cell comprising: one or more detectors having respective sensitive volumes and configured to detect gamma rays emitted as a result of capture of neutrons by a composition in a specimen subjected to an irradiation program, the composition comprising one or more thermal neutron capture agents, the neutrons being generated by inelastic collisions between a primary beam of charged particles and atomic nuclei in the specimen, the charged particles being any one or more of protons, deuterons, tritons and heavy ions, the irradiation program comprising at least one irradiation time window having a beam duration comprising a beam-on time window and a beam-off time window; an energy gate configured to apply at least one predefined energy window or filter such that the system accepts only detection events at one or more detectors resulting from gamma rays having energies indicative of selected (e.g., predominant or only) gamma rays resulting from capture of thermal neutrons by one or more thermal neutron capture agents, where thermal neutrons are neutrons having energies below approximately 0.4 eV; a timing gate configured to receive beam data indicating a start or end of a respective beam-on time window, generate from the beam data a timing window, and apply the timing window such that the system is configured to reject or ignore detection events at the one or more detectors resulting from at least prompt gamma rays produced in a non-neutron capture event; and an output for outputting data indicative of accepted detection events (e.g., to a data analysis system configured to determine a thermal neutron dose or dose map, whether contained within the system or external thereto). A radiation dose quantification system is provided, comprising:

[0036] The system may include a data analysis system configured to determine a thermal neutron dose from at least the accepted detection events received by the subject during the irradiation program or to determine a dose map of thermal neutron radiation from at least the accepted detection events received by the subject.

[0037] The data analysis system may additionally be configured to receive beam data indicative of the primary beam position (i.e., within the subject) and primary beam energy corresponding to each accepted detection event, and to additionally determine a thermal neutron dose or dose map based on the beam data.

[0038] It should be noted that applying at least one predefined energy window can be performed online (i.e., simultaneously with the collection of detection events) or offline (i.e., by filtering the detection events after data collection). Similarly, applying a timing window can also be performed online or offline. Thus, in various embodiments, one or both of applying an energy window and applying a timing window are performed online, while in other embodiments, one or both of applying an energy window and applying a timing window are performed offline.

[0039] The detector or detectors can sense the angle of arrival of the gamma rays, which is particularly advantageous in determining the dose map.

[0040] The system may comprise or include a data logger or data analysis device configured to determine a radiation dose from the counted gamma rays received by the subject during an irradiation program, or to determine a dose map of the radiation from the counted gamma rays received by the subject.

[0041] The energy gate may include first and second comparators (eg, linear op-amps or comparators with Schmitt trigger inputs).

[0042] The system may include a pile-up rejector configured to reject pile-ups in the output signals from the one or more detectors.

[0043] The timing gates can be configured to apply a timing window to reject prompt gamma rays by rejecting gamma rays that reach their respective sensitive volumes from the beginning of each beam-on time frame until approximately 11 ns, approximately 12 ns, or 10-12 ns after the end of the respective beam-on time frame.

[0044] The timing gates may also be configured to apply a timing window that rejects detection events in the respective sensitive volumes that are due to fast neutrons based on timing.

[0045] The timing gates can also be configured to apply a timing window based on timing that rejects detection events in the respective sensitive volumes due to neutrons having energies between 0.4 eV and 1 MeV.

[0046] The timing gate can be configured to apply a timing window that rejects detection events within a detection time window where the ratio of true positive detection events to false positive detection events, as confirmed empirically or by simulation, is less than 1.4 or less than 1.5, where a true positive detection event is an event that meets the timing window and energy window and results from a neutron capture event, and a false positive detection event is an event that meets the timing window and energy window and results from something other than a neutron capture event.

[0047] The system may include a shielding disposed to at least partially shield some or all of the detector(s) (and specifically the scintillators thereof) and including a single or multiple layers of a neutron absorbing and / or scattering material distinct from the neutron capture agent(s). As discussed above, the shielding may also optionally be disposed to cover one or more sides of the detector(s).

[0048] Neutron capture agent 10 If the agent is or includes a B-based agent, the shielding is most preferably positioned to shield both the front and sides of the detector or detectors. The shielding typically includes one shield for each detector. The neutron absorbing and scattering materials are selected based on their neutron absorption and scattering cross sections, and are thick enough to block or scatter most of the neutrons, but thin enough not to absorb too high a proportion of the gamma rays generated by neutron capture. The neutron absorbing or scattering materials may include polyethylene, paraffin, cadmium, gadolinium, boron and / or hafnium.

[0049] In some examples, the one or more neutron capture agents include 10 B Base and / or 157 For example, the neutron capture agent or agents may be Gd-based, such that the gamma ray has an energy of 478 keV. 10B-based, and / or gamma rays having energies of 79.5 keV, 182 keV, 6.75 MeV, 7.86 MeV and / or 7.94 MeV. 157 It may be Gd-based.

[0050] In some examples, the neutron capture agent is 10 B-based, and the one or more detectors include any one or more of CdTe, CZT, and LaBr3:Ce detectors. The beam duration can be 1-10 μs, or approximately 1 μs. The system can include a thermal neutron shield positioned to shield some or all of the one or more detectors and including a thermal neutron absorbing material including natural Cd, natural Gd, and / or natural Hf.

[0051] In another example, the neutron capture agent is 157 The primary beam may be Gd-based and the one or more detectors may include any one or more of LSO:Ce, BGO, and PbWO4 detectors. The beam duration may be between 10 μs and 100 ms. The primary beam may be a carbon ion beam and the beam duration may be approximately 1 ms, or the primary beam may be a helium ion beam and the beam duration may be approximately 10 μs. The system may include a thermal neutron shield positioned to shield some or all of the one or more detectors and including a thermal neutron absorbing material including natural B and / or natural Hf.

[0052] It should be noted that any of the various features of each of the above aspects of the invention may be combined as appropriate and desired.

[0053] In order that the invention may be more clearly understood, embodiments thereof will now be described with reference to the accompanying drawings, in which: [Brief description of the drawings]

[0054] [Figure 1]FIG. 1 is a schematic diagram of a patient lying on a couch in a Neutron Capture Enhanced Particle Therapy (NCEPT) irradiation system, with a tumor being irradiated by a particle beam produced by the irradiation system. [Diagram 2] 1 is a schematic diagram of a dose quantification system according to an embodiment of the present invention. [Diagram 3] Schematic representation of the beam intensity IB (%) versus time t, depicting the beam microstructure of the NCEPT irradiation system of FIG. [Figure 4] 1 is a schematic plan view of a simulated target phantom / detector geometry used to model various dose quantification systems, according to an embodiment of the present invention. FIG. [Diagram 5] 5 is a plot of beam intensity IB (%) versus time t (ns) depicting the microstructure of the primary beam modeled for testing the dose quantification system of FIG. 4 . [Figure 6A] The top panel shows the simulated depth and dose profile of the 12C ion beam used to test the dose quantification system of FIG. 4, and the bottom panel shows the energy spectrum used to generate the 12C ion beam. [Figure 6B] The top panel shows the simulated depth vs. dose profile of the 4He ion beam used to test the dose quantification system of FIG. 4, and the bottom panel shows the energy spectrum used to generate the 4He ion beam. [Figure 7A] Two-dimensional spectrograms of neutron arrival times tn (ns) in the neutron capture insert (NCI) region after irradiation with polyenergetic 12C and 4He ion beams, respectively, are shown, plotting neutron energy En (eV) versus neutron arrival times tn (ns). [Figure 7B] See brief drawing description of Figure 7A. [Figure 8A]1 shows spectrograms of photon arrival time to the detector volume tγ (ns) as a function of gamma ray energy Eγ (MeV) for a 12C ion beam without NCI, a 4He ion beam without NCI, a 12C ion beam with 10B NCI, a 4He ion beam with 10B NCI, a 12C ion beam with 157Gd NCI, and a 4He ion beam with 157Gd NCI. [Figure 8B] See brief drawing description of Figure 8A. [Figure 8C] See brief drawing description of Figure 8A. [Figure 8D] See brief drawing description of Figure 8A. [Figure 8E] See brief drawing description of Figure 8A. [Figure 8F] See brief drawing description of Figure 8A. [Figure 9A] 1 shows spectrograms of neutron arrival time at the detector volume tn (ns) as a function of neutron energy En (MeV) for a 12C ion beam without NCI, a 4He ion beam without NCI, a 12C ion beam with 10B NCI, a 4He ion beam with 10B NCI, a 12C ion beam with 157Gd NCI, and a 4He ion beam with 157Gd NCI. [Figure 9B] See brief drawing description of Figure 9A. [Figure 9C] See brief drawing description of Figure 9A. [Figure 9D] See brief drawing description of Figure 9A. [Figure 9E] See brief drawing description of Figure 9A. [Figure 9F] See brief drawing description of Figure 9A. [Figure 10A] Plots comparing different detector material sensitivity (top) and RTF (bottom) for 10B and 157Gd NCI, respectively, as a function of time mask Π(t) (ns) for a realistic detector model after irradiation with a 12C ion beam. [Figure 10B]See brief drawing description of Figure 10A. [Figure 11A] Plots of sensitivity (top) and true positive / false positive rates (bottom) for the two best detector materials, 10B and 157Gd NCI, respectively, as a function of time mask Π(t) (ns) after irradiation with a 12C ion beam over the full range of irradiation time windows (i.e., beam duration) for photons only. [Figure 11B] See brief drawing description of Figure 11A. [Figure 12A] Plots of sensitivity (top) and true positive / false positive rates (bottom) for the two best detector materials for 10B and 157Gd NCI, respectively, as a function of time mask Π(t) (ns) after target irradiation with a 12C ion beam over the full range of irradiation time windows (i.e., beam duration) for all detected events. [Figure 12B] See brief drawing description of Figure 12A. [Figure 13A] Plots of sensitivity (top) and true positive / false positive fraction (bottom) for 10B and 157Gd NCI, respectively, as a function of the time mask Π(t) (ns) after target irradiation with a 12C ion beam for events recorded on a realistic detector both without a front shield material with high thermal neutron cross section and with various front shield materials (i.e. Cd, Gd, B, Hf). [Figure 13B] See brief drawing description of Figure 13A. [Figure 14A] 14A and 14B are plots of counts (N) versus 12C ion beam energy (keV) both with and without boron NCI (FIG. 14A), without boron NCI (FIG. 14B), and with boron NCI (FIG. 14C). [Figure 14B] See brief drawing description of Figure 14A. [Figure 14C] See brief drawing description of Figure 14A. [Figure 15A]15A and 15B are plots of counts (N) versus 4He ion beam energy (keV) both with and without boron NCI, without boron NCI (FIG. 15B), and with boron NCI (FIG. 15C). [Figure 15B] See brief drawing description of Figure 15A. [Figure 15C] See brief drawing description of Figure 15A. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0055] 1 is a schematic diagram of a subject 10 with a tumor 14 lying on a couch 12. The subject 10 is being irradiated with a beam 16 of primary particles (e.g., protons, helium, carbon ions, etc.) generated by an enhanced particle beam therapy (NCEPT) irradiation system. The beam 16 is generated in this example by a synchrotron accelerator (not shown) and is delivered by a treatment nozzle 18.

[0056] As described in WO 2019 / 051557, in accordance with NCEPT, subject 10 may include: 157 Gd and / or 10 A dose of a thermal neutron absorbing nuclide is administered, such as a composition containing B. The composition is selected to be preferentially absorbed by the tumor 14.

[0057] Control of the penetration depth of the primary particles in the specimen is achieved by controlling the beam energy and shape, thereby positioning the Bragg peak of the beam as desired relative to (and within) the desired target volume.

[0058] The subject is then irradiated with the beam 16 of primary particles in a desired scanning pattern, depth, duration, beam energy, etc. according to a pre-established irradiation program that includes one or more irradiation (or "beam on") periods, generally of uniform duration, each followed by a period of no irradiation (or "beam off"). This may include moving the couch 12, and thus the target volume, between or between irradiation periods, while minimizing movement of the subject.

[0059] During irradiation, a small percentage of the primary particles of the beam 16 undergo inelastic collisions with atomic nuclei in the subject 10, resulting in the generation of various nuclear fragments, including short-range, high-LET charged particles and neutrons, which are emitted from the point of impact in the subject, thereby depositing their energy in the region surrounding the path of the beam 16. A portion of the neutrons so generated are absorbed by thermal neutron absorbing nuclides of the administered composition, resulting in the generation of relatively biologically effective high-energy charged particles that irradiate the target volume and thus the tumor 14.

[0060] 2 is a schematic diagram of a dose quantification system 20 according to an embodiment of the present invention, in which a subject 10 is shown undergoing irradiation with a beam 16 of primary particles extracted from a synchrotron, as described above. The dose quantification system 20 is configured to be employed in conjunction with or as part of an NCEPT irradiation system, and is configured to determine both direct ion dose and dose due to neutron capture, including distinguishing between photons resulting from neutron capture and photons attributable to other processes.

[0061] The dose quantification system 20 has a gamma ray detector 22 (which in this embodiment includes a scintillator 24 and a photodetector 26) for detecting gamma rays emitted by the subject 10, and an RF signal input 30 for receiving a train of RF pulses from the synchrotron, which come directly from the synchrotron and are indicative of the beam microstructure. Although there is a transmission delay, the train of pulses is strictly periodic, so that subsequent triggers of the system 20 can be adjusted accordingly to take into account the delay.

[0062] Alternatively, the pulse structure can be extracted directly from the primary beam (as opposed to an RF signal from a synchrotron, cyclotron, etc.). This can be accomplished by inserting a hodoscope into the path of the beam as it exits nozzle 18. The hodoscope may, for example, include a fiber optic detector (with a plastic scintillator) coupled to a single silicon photomultiplier tube. The output of such a configuration (low detection efficiency but fast rise time) can be used to provide a direct timing signal to a data acquisition system, independent of the synchrotron or cyclotron RF signal.

[0063] The gamma ray detector 22 is positioned to detect gamma rays emitted by the subject in response to irradiation (directly or indirectly), specifically in a cloud of thermal neutrons 32 resulting from collisions of the beam 16 of primary particles with atomic nuclei in the subject 10 (some of these collisions occur within and adjacent to the target volume). The beam 16 is generated to have a spread Bragg peak (SOBP) by varying the energy of the beam 16, thereby varying or spreading the depth of the Bragg peak. A region 34 within the thermal neutron cloud 32 exhibits the spread Bragg peak (SOBP) of the beam 16. The SOBP 34 typically coincides with (at least approximately coincides with) or defines the target volume. The SOBP 34 can be passively shaped (i.e., by placing a ridge filter in the path of the beam 16) or dynamically provided by "painting" the target volume slice by slice with a monoenergetic primary particle beam.

[0064] Although FIG. 2 depicts one gamma ray detector 22, it should be understood that in a practical system, the system 20 will generally include multiple gamma ray detectors, for example, arranged in a ring or cylinder around the subject 10, or arranged partially in a ring or cylinder (such as mounted on a C-shaped gantry around the subject 10).

[0065] The scintillator 24 of the gamma ray detector 22 is selected to have high detection efficiency for the gamma ray energies of interest. This is achieved through choosing a high density / high atomic number scintillator material that has low self-absorption at the energies of interest. In this embodiment, the scintillator 24 is an LSO (Lu2SiO5:Ce) scintillator, although in alternative embodiments, the detector 22 may be a LaBr3:Ce based detector.

[0066] Advantageously, but not necessarily, the detector 22 senses the angle of arrival of the detected gamma rays. For example, in an embodiment of the system 20 including one or more detectors 22, the system 20 can be used to construct a pre-treatment image by detecting radiation (including the angle of arrival) emitted by a radiotracer analog of a neutron absorber administered to the subject, the analog having pharmacokinetics comparable to that of the intended neutron absorber. For example, as a neutron capture agent, 10 When boron is used in the form of B-BPA, a suitable radioactive tracer is 18 F-BPA, 131 I-BPA, 18 When gadolinium is used as the neutron capture agent in the form of Gd-TPP-DOTA, suitable radiotracers include Gd-TPP-DOTA (an MRI contrast agent) or Gd- 44 Sc, 177 Lu or 68 It is a radioactive tracer that replaces Ga.

[0067] In this procedure, performed for treatment planning, a radiotracer analog is injected into the subject and system 20 is used to determine (i) the spatial distribution of the radiotracer (and thus the expected spatial distribution of the neutron capture agent) and (ii) the contrast ratio that can be achieved between the tumor, lesion or other pathological tissue and non-cancerous or normal tissue. This information can be input into the treatment planning system so that the additional dose due to neutron capture can be estimated and the distribution of neutron capture within the subject during irradiation can be predicted. Finally, system 20 can be used to quantify the neutron capture distribution (e.g., at specific locations and orientations for a single collimated detector, or throughout the volume for a multi-detector collimated imaging system) and validated against the predictions of the treatment planning system.

[0068] Similarly, embodiments of the system 20 including multiple detectors 22 can be configured to use the gamma rays detected from neutron capture to estimate the distribution of neutron capture events and provide an accurate dose map. Such embodiments do so using the angles of arrival of the detected gamma rays and by back-projecting the detector responses.

[0069] Advantageously, the scintillator 24 has a low cross section for interaction with neutrons, or more precisely, for activation when exposed to neutrons (since such interactions would increase the background). However, in this embodiment, this potential problem is addressed by including in the system 20 a multi-layer neutron shield 28, optionally positioned to cover the front surface of the detector 22, and in this embodiment, to cover the sides of the detector 22 (note that in the figure, the shield 28 is not to scale). Provided that the shield material is different from the neutron capture isotope used during the NCEPT treatment, the neutrons can be almost completely absorbed or scattered by the layers of the shield, which have a high thermal neutron cross section and a high fast neutron scattering cross section, without significantly attenuating the neutron capture gamma photon fluence. The shielding 28 is constructed according to these criteria, and in this embodiment includes polyethylene, paraffin, cadmium, gadolinium, boron, boron carbide, and / or hafnium (depending on the selection of neutron capture isotopes used during NCEPT treatment), with a thickness selected to be (i) thick enough to block or scatter most of the neutrons, but (ii) thin enough not to absorb too high a proportion of the neutron capture gamma rays (which are the gamma rays of interest). The shielding 28 in this embodiment has up to six layers, each of which is approximately 1 mm to 2 cm thick, although these thicknesses can be easily modified or optimized according to the application and the selection criteria mentioned above. Moreover, natural forms of the shielding materials (i.e., without enrichment of their constituent isotopes) are contemplated. Enriched forms of these materials (i.e., enriched with the most absorbing or scattering isotopes) could be used, but the cost of enrichment is not justified by the potential benefits.

[0070] It should be noted that in some applications, the system 20 need not include shielding 28. For example, the problem of neutron activation of the detector 22 (which can increase background radiation) increases as the detector ages. Also, it may take as little as 10 4 If the former is not a concern, or if the latter is within 10 ns from the start of the beam-on window, 4 If events detected after ns are excluded, then shield 28 may not be necessary.

[0071] It is envisaged that the shielding 28 serves sufficiently to reject neutrons from the detector 22, but alternatively (or in addition) this may be done by scattering at least some of the problematic neutrons before they reach the detector 22. This may be done by placing a suitable material between the subject and the detector 22, selected to transmit the gamma rays of interest with sufficient efficiency so as not to interfere with the measurement, but to scatter such problematic neutrons before they reach the detector. Suitable materials and their dimensions may be determined by simple experimentation or simulation. Many polymers (particularly low density polymers) meet these criteria.

[0072] The photomultiplier tube 26 of the detector 22 is selected to accommodate high count rate enhancement through the use of pile-up elimination circuitry, as described below, In this embodiment, the photomultiplier tube 26 is a silicon photomultiplier tube.

[0073] The RF pulse train indicates when the beam 16 from the synchrotron is on and when it is off (i.e., when the subject 10 is being irradiated or not), so that data collection can be controlled according to the irradiation time slots of the irradiation program. Specifically, as described in more detail below, the system 20 controls data collection to occur when the subject 10 is not being irradiated (i.e., generally between successive irradiation time slots) and to begin a preselected time after the completion of each irradiation time slot (e.g., as measured from the start or end of the respective irradiation time slot).

[0074] The system 20 also includes a detection window start delay 36 and a timing gate 38. The timing gate 38 is configured to control when detection events from the detector are rejected based on the timing of the detection events of the detector 22 relative to the beam-on and beam-off time frames (as discussed in detail below). The detection window start delay 36 ensures that this is aligned with the beam-on and beam-off time frames. The detection window start delay 36 receives as input the aforementioned RF pulse train or a trigger signal fed through the detection system and applies an appropriate signal propagation delay to the timing gate 38 so that the timing gate 38 can generate a time mask Π(t) (time frame during which detection events are rejected) for each beam-on time frame whose start coincides with the start of the respective beam-on time frame. This time mask Π(t) is of a preselected duration. The timing gate 38 outputs a low signal if the time mask Π(t) is implemented (i.e., detection events are rejected) and outputs a high signal otherwise.

[0075] Note that in some embodiments, system 20 can be configured as a data logger, i.e., a high bandwidth pulse detection system that records all gamma ray detection events in list mode, with each recorded detection event including the time of arrival (i.e., timestamp), the energy of the event, and the identity of the detector that recorded the detection event. In such embodiments, the detection events can then be processed offline after the delivery of treatment.

[0076] Data collection continues for each beam-on time frame for a preselected data collection window DCW. The data collection window DCW is typically set to extend after the end of each beam-on time frame by the amount of time that gamma rays of interest are expected (or known) to be received or effectively detectable, which depends on the timing and length of time that thermal neutrons (as defined herein) interact with the neutron capture agent. In this embodiment, the data collection window DCW extends for at least approximately 10 minutes from the end of each beam-on time frame. 5.8 After at least approximately 10 ns 6 ns later, or 10 5.8 ns~2×10 6 The final time mask, Π(t), has an end point after 10 ns, which is substantially larger than the beam-off time window, so that data continues to be collected until a time equal to the collection window, DCW, has elapsed after the end of the final time mask, Π(t).

[0077] Note that the data collection window DCW can be specified as the data collection duration (which occurs after the beam-on window ends) or as a data collection start and data collection end. Data collection start may be within the time mask, but data collection does not actually begin until the time mask Π(t) ends, since detection events are rejected while the time mask Π(t) is being enforced by timing gate 38.

[0078] The system 20 includes a pulse pile-up rejector 40 (e.g. in the form of a deconvolution filter) having active circuitry configured to receive the output pulses of the gamma ray detector 22 and deconvolute the input pulse waveform with the combined impulse response of the scintillator and associated electronics, converting it into a sequence of short impulses with peak amplitudes proportional to the energy stored in the detector. The pulses from the scintillator exhibit fast rise times and (relatively) slow decay times (approximately 35 ns in total for the example of an LSO detector). Thus, if multiple events occur within a short time window, they may overlap (and linearly add up). The pulse pile-up rejector 40 deconvolves this using a model of the impulse response of the scintillator and preamplifier electronics, converting the pulses into a train of Dirac delta impulses (i.e. very short in duration and with pulse heights proportional to the stored energy). A second output 42b of the pulse pile-up rejector 40 represents the peak energy E of each pulse. P The arithmetic unit 10 outputs a signal indicating

[0079] Pulse pile-up rejector 40 is employed regardless of whether system 20 is configured for on-line or off-line processing.

[0080] The system 20 includes a first AND gate 44 that receives the mask signal from the timing gate 38 and pulses that have passed through the pile-up rejector 40 from the gamma ray detector 22, and outputs only those pulses that are received when the gate signal from the timing gate 38 is low.

[0081] The system 20 includes first and second comparator devices 46, 48 with Schmitt trigger inputs (faster than standard linear op-amps) configured to provide an energy gate. Together, they define an energy window (energy E L Energy E H) to select the gamma ray of interest. Prompt gamma rays result from neutron capture by thermal neutron absorbing nuclides. The first comparator device 46 determines at its non-inverting input the maximum desired energy E of the pulse output by the gamma ray detector 22. H At its inverting input, it receives a signal representing the peak energy E P A second comparator device 48 receives at its non-inverting input a signal indicative of the peak energy E P and at its inverting input receives a signal indicative of the minimum desired energy E of the pulse output by the gamma ray detector 22. L Thus, both the first comparator device 46 and the second comparator device 48 receive a signal indicative of the energy E P But, E H and E L The output has high power only if it is within an energy window defined by

[0082] The system 20 includes a second AND gate 50 having three inputs and receiving the outputs of the first AND gate 44, the first comparator device 46 and the second comparator device 48. As a result, the second AND gate 50 selects a signal that is within the data collection timing window and within the peak energy window (i.e., E H and E L Only when a pulse that is between and is received from the gamma ray detector 22 will it have a high output.

[0083] System 20 includes a data logger and controller 52 configured to receive the signal from second AND gate 50 and log the received signal. Data logger and controller 52 records the number of detections within each beam micropulse (i.e., each individual data collection window) and the arrival time of each beam micropulse so that each micropulse can be correlated to a treatment plan (this is more important in an embodiment of system 20 where a raster-scanned pencil primary beam is used, where the beam is stepped in space and energy; in passive scattering particle therapy systems, the beam is the same during the treatment fraction). Data logger and controller 52 also receives beam data (e.g., indicating the x,y position of beam 16 and the beam energy) corresponding to each beam-on time window, which are stored in a manner that allows detection events recorded by data logger and controller 52 to be associated with the beam data (such as by employing a timestamp) and, in turn, with the instantaneous location of irradiation by beam 16 within the subject.

[0084] The data logger and controller 52 is also configured to provide a trigger signal to the detection window start delay 36, and is user operable to select and set values ​​for the preselected time mask Π(t) and the data collection window DCW. The data logger and controller 52 may be incorporated into a data acquisition system. The data logger and controller 52 (or such a data acquisition system) may be additionally configured to perform data analysis, including determining radiation dose, and / or transmit logged data to a data analysis system or computing device (not shown), whether provided as part of the system 20 or as an external system / device. In this embodiment, the data analysis is performed offline by the data analysis system.

[0085] The data analysis, whether performed by the data logger and controller 52, the data analysis system described above, or by another computing device, involves determining the radiation dose (i.e., thermal neutron dose) received by the subject and / or a dose map (whether shown as a neutron capture distribution or a dose distribution) based on the logged detection events. This is done using conventional techniques. For example, the beam 16 may be a raster-scanned energy modulated pencil beam (which, as described above, essentially "paints" the target volume with a primary ion dose one voxel at a time). The analysis thus involves correlating the x, y position and energy of the beam with the detected neutron capture photons so that detection events can be correlated with the instantaneous beam position. The data collected by the system 20 is then used to determine the neutron capture or dose distribution, and the neutron radiation dose. The dose is determined as deposited energy (Gy) per unit mass, and then converted to gray equivalent (GyE) or biological dose, as desired.

[0086] Advantageously, the analysis may additionally employ pre-exposure CT or MRI anatomical (structural) imaging for treatment planning, pre-exposure estimation of the distribution of neutron capture agents (measured using PET or SPECT imaging and neutron capture agent radiotracer analogs, as discussed above), and post-exposure PET imaging to indirectly confirm the spatial ion dose distribution. The expected neutron dose is calculated based on the treatment plan (which uses CT or MRI images and neutron capture agent distribution estimation to calculate beam parameters that achieve the desired dose distribution, including ion and neutron capture doses). The total dose delivered is estimated based on PET images captured after irradiation (which provide an indirect estimate of the ion dose distribution) and the neutron capture distribution determined by the system 20. If the system 20 has a single detector 22 (or a limited number of detectors), an estimation of the complete (or high-resolution) 3D neutron capture distribution may not be possible, in which case the results from the system 20 are verified against the expected neutron capture distribution from the treatment plan. This can be facilitated by comparing results with previous plans / results, such as by applying machine learning to neutron capture agent distribution estimates and structural information to obtain a good estimate of the true neutron capture distribution from limited projection angles.

[0087] Figure 3 shows the beam intensity I versus time t. B t], depicting the microstructure of the beam 16 [References 29, 30]. As can be seen, the illumination comprises a repeating pattern that continues throughout the entire illumination time frame (or "beam duration"). The pattern comprises a "beam-on" time frame with a pulse P of width PW, repeated with a pulse repetition interval PRI, and successive "beam-off" time frames having a duration of PRI-PW. Each data acquisition time frame is subject to a data acquisition window DCW and a time mask Π(t) as described above. In this example, the data acquisition window DCW starts at the end of the time mask Π(t). The beam duration therefore refers to the time frame from the start of the first beam-on time frame to the end of the last beam-on time frame.

[0088] As discussed above, in NCEPT, the specimen 10 contains one or more thermal neutron absorbing / capturing nuclides (e.g., 157 Gd and / or 10 A dose of the composition comprising the compound B) is administered. Moreover, the irradiation program may vary depending on the location and nature of the target volume and other clinical symptoms. Roughly speaking, the system 20 is configured to apply a time mask that is at least the beam-on time window (PW) plus the time window during which prompt gamma rays are emitted by non-neutron capture (depending on the detector characteristics, but estimated to be 11 ns). This minimum time mask is most suitable for a detector that is close to the performance of an ideal gamma detector (i.e., perfect absorption, infinite energy resolution, no dead time), but in practice, a larger time mask is more desirable since it gives better results.

[0089] However, in practice, "fast neutrons" (E > 1 MeV) and "intermediate energy neutrons" (defined for this purpose as 0.4 eV ≤ E ≤ 1 MeV) potentially fall within the energy window for neutron capture prompt gamma detection (i.e., energy E L Energy E H 29 or 30 ns after the beam pulse ends (provided that the detector itself is not activated with long-lived radioisotopes). Thus, detection of fast neutrons can be significantly reduced by using a time mask Π(t) of up to 50 ns, with increasing benefits as the time mask increases.

[0090] Thus, system 20 is advantageously configured to apply a time mask of at least the beam-on time window (PW) plus the approximate arrival time of the fast neutrons. In a particular example, a preferred time mask is the beam-on time window (PW) plus 49 ns.

[0091] The duration of the data collection time window DCW is selected according to the time frame during which the majority of gamma rays (as defined above) resulting from thermal neutrons reach the detector 22. Because thermalization takes time, this is approximately 12 ns to 10 ns from the start of the beam-on time window. 6 It has been found that the beam-on time window is between 12 ns and 10 ns from the beginning of the beam-on time window, with very little occurring outside of that window. Thus, in principle, the system 20 can detect the beam-on time window between 12 ns and 10 ns from the beginning of the beam-on time window. 6 ns or 2×10 6 A data collection time window DCW of up to 100 ns can be employed. However, as will be shown below, because the majority of photons resulting from neutron capture arrive at detector 22 at least 60 ns later than photons generated by other processes, system 20 is configured to apply a time mask Π(t) that extends at least 60 ns from beam off (i.e., Δt≧PW+60 ns), and in the particular example shown in FIG. 1, system 20 is configured to apply a time mask of Π(t)=PW+60 ns.

[0092] In addition, it has been determined that the duration of the time mask Π(t) affects the number of false positive events (referred to herein as "false positives"), which is also affected by the total exposure time (i.e., beam duration), the neutron absorber / capture agent, the type of gamma ray detector 22, and the material used for the shielding 28. The system 20 takes these factors into account and is specifically configured to operate in a regime that has a high or optimized ratio of true positive events (referred to herein as "true positives") to false positive events. Examples of these regimes (with individual options ranked) are listed in Table 1A (for carbon ion beams) and Table 1B (for helium ion beams).

[0093] The composition 10 B and 157 In the case of a mixture of G, it is envisioned that a detector 22 (e.g., LSO) will be selected that works well for both gamma ray energies, but it is recognized that this selection requires some compromise. There are also few good choices for thermal neutron shielding materials for the optional shielding 28 (e.g., Cd or Hf). The optimal beam duration is also a compromise. For example, for a carbon ion beam, a beam duration of 10 μs is acceptable for both agents, while for a helium ion beam, a beam duration of 10 μs is acceptable for both agents. 10 B is within the acceptable range, 157 It is optimal for G. A timing or time mask Π(t) of 60 ns (ie, extending 49 ns from the end of each beam-on window) is acceptable for both agents.

[0094] [Table 2]

[0095] [Table 3]

[0096] Alternatively, the system 20 may include 10 Optimized for B, some 157 It may include multiple detectors 22 (optionally using thermal neutron shielding 28) optimized for G.

[0097] Simulation Example The desirable properties of system 20 were determined and evaluated in two parts using a series of simulations.

[0098] First, a Monte Carlo simulation model was constructed that included a target phantom irradiated with a helium or carbon ion beam with a spread-out Bragg peak (SOBP) with a depth range of 60 mm. Because neutrons are generated with initial momentum primarily parallel to the beam [14, 17], to minimize the number of neutrons that directly interact with the simulated detector, the detector was simulated positioned near the Bragg peak and oriented toward the region of interest.

[0099] Three target phantoms were used in the simulation: i) A solid homogeneous block of polymethylmethacrylate (PMMA); ii) pure 10 B insert is a solid block of PMMA located at the distal end of the SOBP; iii) pure 157 A solid block of PMMA with a Gd insert located at the distal end of the SOBP.

[0100] The energy and arrival time (relative to the time of primary particle generation) of all neutrons entering the insert region of each phantom were scored. Also, the arrival time (again relative to the time of primary particle generation) and energy of photons leaving the phantom through a band parallel to the insert region were scored. Based on these results, appropriate time masks and energy windows for neutron capture discrimination were determined.

[0101] The time mask and energy window were applied to all particles reaching an ideal detector (i.e. simulated as having perfect absorption, infinite energy resolution and no dead time) and the number of true positive, false positive, true negative and false negative classifications (taking the known origin of each detected event as ground truth) were counted. True positive and true negative detections were defined as detections correctly classified as neutron capture and non-capture, respectively.

[0102] False positives were defined as detections that met the timing and energy tolerance windows but were not associated with a neutron capture event. False negatives were defined as detections that were associated with a neutron capture but failed to meet the timing and / or energy tolerance windows. The former could be due to anomalously fast or slow thermalization of the neutron prior to capture, resulting in late arrival of the photon and a low probability long tail in the time distribution of neutron capture. Failure to meet the energy tolerance window could be due to Compton scattering of the emitted photon in the phantom (lower energy and changing the photon trajectory), Compton scattering in the detector (in the case of a realistic detector model) and subsequent escape of the scattered photon (only a portion of the photon's energy is deposited in the detector), or detection of particles other than photons in the detector (e.g. fast neutrons, protons or other fragments).

[0103] In the final part of the study, the same evaluation was performed for true positive / true negative / false positive / false negative detection using a realistic detector simulation model. Several alternative detector materials were evaluated, including direct detection CdTe, CZT (for boron neutron capture), LaBr3:Ce, LSO (Lu2SiO5:Ce), BGO and PbWO4 scintillator-based detectors (for boron and gadolinium neutron capture). These detectors were simulated both without shielding and with thin layers of several alternative thermal neutron shielding materials.

[0104] Materials and Methods Geant4 version 10.2.p03 was used for all simulations because it has previously been found to provide the best agreement with experimental fragmentation measurements in particle therapy [Refs. 18, 19, 20]. Electromagnetic interactions were modeled using the Standard Physics option 3 model in Geant4 (G4EmStandardPhysics_option3) and other physics models used in the simulations (including hadronic interactions) are listed in Table 2.

[0105] [Table 4]

[0106] 4 is a schematic plan view of a simulated target phantom geometry 60 (not to scale). Each of the three simulated target phantoms 62 measures 300×300×300 mm. 3 The first one was a homogenous block of PMMA, while the second and third ones each contained a pure PMMA cube. 10 B and net 157 A 10 mm cube of Gd neutron capture insert (NCI) was included, with its centre embedded at a depth of 140 mm within the PMMA phantom (thus located at the distal end of the diffuse Bragg peak described below) and centred in the lateral and vertical directions. The physical properties of the materials used in the simulations (including elemental composition and density) were based on the standard materials library defined by the US National Institute of Standards and Technology (NIST) [Ref 21].

[0107] 12 C and 4 Polychromatic energy beams 66 of He were synthesized with energies ranging from 225 to 294 MeV / u and 113 to 156 MeV / u, respectively, with a spread-out Bragg peak extending to 60 mm, to obtain a nearly flat biological dose at depths of 85 mm to 145 mm within the phantom (the procedure used to obtain a flat biological dose is described in reference [1]). The ion beam 66 was rotationally symmetric, with a Gaussian beam profile of 20 mm FWHM, and was generated at the center 68 of the front surface 70 of the phantom 62 and translated parallel to the z-axis of the phantom. For each beam and phantom combination, 10 8particles were simulated. The "beam entry point" (i.e., beam generation point) of beam 66 was defined as the origin (0,0,0) of the simulation coordinate system. The deposited energy in the target phantom 62 by each ion beam 66 was scored as a function of depth over the 1 / 10 full width of the ion beam 66 and normalized to the deposited energy at the beam entry point 68.

[0108] Neutron and gamma characterization For phantoms (ii) and (iii) (i.e., when NCI 64 was used), the energy and arrival time of neutrons entering the insert region 64 were recorded. 50 logarithmically spaced time bins (0.1 ns to 10 ns) showing neutron arrival times (horizontal axis) and kinetic energies (vertical axis) were plotted. 8 ns) and 50 logarithmically spaced energy bins (10 -5 eV~10 10 A two-dimensional spectrogram was constructed having a wavelength (eV) of 1000 Hz. For each particle, the time relative to the moment the incident carbon or helium particle was generated at the surface 70 of the phantom 62 was measured.

[0109] The energies and arrival times of photons and neutrons entering the detector were scored to generate a spectrogram of energy (horizontal axis) versus photon arrival time (vertical axis). Arriving photons were split into 1000 equally spaced energy bins (ranging from 0 to 10 MeV, each with a width of 10 keV) and 100 logarithmically spaced arrival time bins (0.1 ns to 10 10 The arriving neutrons were distributed across 130 logarithmically spaced energy bins (10 -10 MeV~10 3 MeV range) and 100 logarithmically spaced arrival time bins (0.1 ns to 10 10 The particles were dispersed in a time domain (range of ns). Again, the time was measured relative to the moment of generation of the primary particles.

[0110] Optimization of detector materials, beam-on duration and shielding The second part of the study determined the precision with which photons resulting from thermal neutron capture in the neutron capture insert could be distinguished from photons due to other processes, using several alternative detector models.

[0111] With reference to FIG. 4, an ideal detector 72 was modeled as a simple geometric volume configured to record the identity, generation process, arrival time and energy of particles entering the detector volume. The detector volume was cubic and had dimensions of 50 mm×50 mm×50 mm. The detector 72 was positioned as shown in FIG. 4 with the normal vector of its front surface 74 pointed to the center 78 of the distal edge of the SOBP region of the phantom 62 (hence pointed to the coordinate point (0,0,145 mm). The front surface 74 of the detector 72 was located 47.32 cm from the center 78 of the distal edge of the SOBP and made an angle θ=60 degrees (about the vertical or y-axis) with respect to the ion beam 66.

[0112] The realistic detector models used the same geometry as the ideal detector. Table 3 lists the different detector materials that were used in modeling the realistic detectors. 10 For the detection of gamma photons via B neutron capture, LaBr3, CZT, LYSO:Ce and CdTe are suitable because they offer the highest energy resolution, while 157 For detection of the higher energy photons emitted during Gd neutron capture, high density LSO:Ce, BGO and PbWO4 are more suitable (it was assumed that several scintillator crystals or semiconductor detectors were stacked and optically / electronically coupled to form a single detector).

[0113] [Table 5]

[0114] Figure 5 shows the beam intensity I versus time t (ns). BFigure 1 shows a plot of the beam microstructure (%) over the first 500 ns of the illumination, depicting a pattern that repeats over the entire illumination time window. Total illumination time windows of 1 μs, 10 μs, 1 ms, 10 ms and 100 ms were simulated.

[0115] The timing microstructure of the beam was modeled as a train of pulses P with a time window PW of 200 ns and a “beam on” time window PW of 11 ns (5.5% duty cycle). 9 of primary particles were used, and particles were injected periodically at a constant rate during each nanospill. For every particle depositing energy in the detector, the particle type, production process, arrival time, total deposited energy, and location of energy deposit within the detector were scored. The summation of all individual energy deposits resulting from multiple interaction events (e.g. multiple Compton interactions) was determined. The photoscintillation process was not modeled; it is possible to model it in Geant4, but would increase run times by several orders of magnitude and is therefore not important for our purposes. The area under the output pulse from the photodetector was assumed to be proportional to the deposited energy.

[0116] Because the ion beam, target geometry and composition were the same as in the first part of this work, the phase space record of the prompt gamma photons generated in the previous simulation (including energy, time, position and processes responsible for particle generation within the phantom) was used to drive this simulation, significantly reducing the simulation time required.

[0117] To distinguish between neutron capture photons in the NCI region and photons unrelated to neutron capture, energy windows and time masks were defined based on the results presented in the first part of the study. Energy deposited in the detector during the mask-out interval was not scored. Eight different time masks were investigated: 0ns: do not apply time mask; · 11ns: apply time mask only during beam-on time window; 11ns+T prompt = 22 ns total: apply a time mask of the beam-on time window plus the prompt gamma emission time window (determined based on the results of the first part of the study); and 11ns+T prompt +T neutron = 30, 40, 50, 60, 70, 80 ns total: apply a time mask of the beam-on time window plus the prompt gamma emission time window plus the neutron emission time window (determined based on the results of the first part of the study).

[0118] As discussed above, each time mask was applied from the start of each nanospill and encompassed the entire exposure ("beam on") interval. The following performance metrics were calculated for each exposure interval, each ion beam (carbon, helium) and each detector model (ideal plus each of the realistic models): Sensitivity, defined as the number of true positive, false positive, true negative, and false negative detections, normalized by the number of photons reaching the detector; and The rates of true positive, false positive, true negative and false negative detections, as defined above.

[0119] (1) a sensitivity performance metric of raw true positives and false positives, and (2) a selectivity metric, the ratio of true positives to false positives (R TF ) a series of separate comparisons were performed to optimize different aspects of the detector design, as follows:

[0120] Comparison of detector materials Performance metrics were evaluated for each of the different detector materials, with a fixed exposure time window and over various time mask intervals. 10 For the B NCI target, a 1 μs exposure time window was chosen based on the results of the first part of the study, because after this time window the relative numbers of 511 keV and 2.23 MeV photons begin to increase, making it difficult to distinguish between background and the 478 keV photons due to boron neutron capture. 157For the Gd NCI target, the exposure time window was less important for absolute sensitivity and selectivity, and a 1 ms exposure time window was chosen. The exposure time window was then optimized as follows:

[0121] Comparison of irradiation duration The exposure durations for various time mask intervals determine the sensitivity and R TF The effect of the ion beam on the photon-energy-depositing properties of the detector was evaluated for the best performing materials identified above. First, it was performed for only photons that deposit energy in the detector, and then for all particles that deposit energy in the detector. The detectors selected for this comparison were: 10 B NCI is a CdTe detector, 157 In the case of Gd NCI, the detector was an LSO.

[0122] Comparison of shielding materials The best performing detector material (see above) (i.e. 10 B CdTe for NCI, 157 A variety of different front shielding materials with high thermal neutron cross sections were evaluated using a 50 mm x 50 mm x 1 mm layer of the evaluated material, applied only to the front of the detector. 10 For the B NCI phantom, (natural) gadolinium, cadmium and hafnium were evaluated as potential thermal neutron shielding materials, 157 In the case of phantoms using Gd NCI, (natural) boron, cadmium and hafnium were evaluated.

[0123] result In FIG. 6A, in the upper part, 12 The depth and dose profile of the C ion beam (normalized to the entrance dose) is shown, with the normalized dose D versus depth d (mm) in the phantom. N The solid curves show the doses and the dashed curves show the predicted biological doses. The "x" at (140,0) indicates the proximal aspect of the NCI region.

[0124] In FIG. 6A, in the lower part, 12 The energy spectrum used to generate the C ion beam is shown, with the normalized energy weight W versus beam energy E (MeV / u). N is plotted as

[0125] In FIG. 6B, in the upper part, 4 The depth and dose profile of the He ion beam (normalized to the entrance dose) is shown, with the normalized dose D versus depth d (mm) in the phantom. N The solid curves show the doses and the dashed curves show the predicted biological doses. The "x" at (140,0) indicates the proximal aspect of the NCI region.

[0126] In FIG. 6B, in the lower part, 4 The energy spectrum used to generate the He ion beam is shown, with the normalized energy weight W versus beam energy E (MeV / u). N is plotted as

[0127] 7A and 7B show the multi-color energy 12 C and 4 Neutron arrival time t in the NCI region after irradiation with each of the He ion beams n (ns) (In these examples, 10 The spectrogram shows the neutron energy E n (eV) and neutron arrival time t n (ns) where the density of each data point indicates the number of neutrons per primary particle, calibrated by the scale to the right of each spectrogram.

[0128] Figures 8A-8F do not use NCI. 12 C ion beam, no NCI 4 He ion beam, 10 B. Using NCI 12 C ion beam, 10 B. Using NCI 4He ion beam, 157 Gd NCI was used 12 C ion beam and 157 Gd NCI was used 4 Gamma ray energy E for each He ion beam γ Photon arrival time t of the detector volume as a function of (MeV) γ Figure 1 shows spectrograms of the ion beam at 1000 Hz (ns) for 100 Hz (all ion beams were polychromatic energies). The density of each data point indicates the number of photons per primary particle, calibrated by the scale on the right side of each spectrogram.

[0129] The band of gamma rays (arriving between 1 ns and 10-12 ns) across the bottom of each of Figures 8A-8F (labeled "γ") corresponds to prompt photons (non-neutron capture photons). A delayed 511 keV annihilation photon is shown (see Figures 8A-8D), as well as a 2.23 MeV photon from hydrogen neutron capture (see Figures 8A and 8B), a 478 keV photon from boron neutron capture (see Figures 8C and 8D), and a 7.94 MeV photon from gadolinium neutron capture (see Figures 8E and 8F).

[0130] Figures 9A-9F do not use NCI. 12 C ion beam, no NCI 4 He ion beam, 10 B. Using NCI 12 C ion beam, 10 B. Using NCI 4 He ion beam, 157 Gd NCI was used 12 C ion beam and 157 Gd NCI was used 4 Neutron energy E for each He ion beam n Neutron arrival time t of the detector volume as a function of (MeV) n Figure 1 shows spectrograms of neutrons emitted from a neutron-emitting ion beam at 1000 keV (ns) (all ion beams were polychromatic energies). The density of each data point indicates the number of neutrons per primary particle, calibrated by the scale on the right side of each spectrogram.

[0131] Optimization of detector materials, exposure duration and shielding A study was conducted for the best temporal mask and detector. For carbon ion beams, the ratio of true positives to false positives (R TF A 1 μs exposure time window (i.e., beam duration) and a CdTe detector were determined to be the optimal combination for the boron neutron capture insert because they yielded the highest R TF A beam duration of 1 ms and an LSO:Ce detector were the optimal combination because they gave the highest values ​​of

[0132] For the helium ion beam, the optimum beam duration was determined to be the same as for the carbon ion beam (i.e., 1 μs) for the boron neutron capture insert, but for the gadolinium neutron capture insert, the optimum beam duration was determined to be 10 μs instead of 1 ms.

[0133] Various results of carbon ion irradiation are shown in Figures 10A-13B, each of which plots the sensitivity S (normalized to the number of photons incident on the detector) in the upper row and R TF In the upper row, square markers (□) indicate true positives (T+), and cross markers (×) indicate false positives (F+).

[0134] 10A and 10B show the results for all detected events. 12 as a function of the duration of the time mask Π(t) (ns) for a realistic detector model after irradiation with a C ion beam. 10 B and 157 Sensitivity of different detector materials for Gd NCI, S (top) and R TF(Lower panel) shows a comparison plot. The total illumination time window was 1 μs (FIG. 10A) and 100 ms (FIG. 10B).

[0135] 11A and 11B show the results for photons only, i.e., excluding other particles interacting with the detector (which can be done in the simulation), over the entire illumination time window (1 μs to 100 ms, as labeled). 12 as a function of time mask duration after irradiation with a C ion beam. 10 B and 157 Sensitivity S (top row) and R for the two best detector materials for Gd NCI TF The plot in the lower part is shown.

[0136] 12A and 12B show the results for all detected events, spanning the entire illumination time window (1 μs to 100 ms, as labeled). 12 as a function of the duration of the time mask Π(t) (ns) after target irradiation with a C ion beam. 10 B and 157 Sensitivity S (top row) and R for the two best detector materials for Gd NCI TF (Lower) plot is shown. Note that in the lower part of FIG. 12A, the curves for 1 ms and 100 ms are nearly identical.

[0137] 13A and 13B show the thermal neutron cross section (Tc) as a function of the duration of the time mask Δt (ns) after target irradiation with a carbon ion beam for events recorded with a realistic detector both without a front shield material with high thermal neutron cross section and with various front shield materials (i.e., Cd, Gd, B, Hf). 10 B and 157 Sensitivity S (upper row) and R TF (Lower) plots are shown. The total illumination time window was 1 μs (FIG. 13A) and 100 ms (FIG. 13B).

[0138] In the top row of Figure 13A, the false positive cadmium shielded detector curve is mostly hidden by the gadolinium and hafnium shielded detector curves. The unlabeled curve corresponds to the detector without shielding. In the top row of Figure 13A, this true positive curve is just above the gadolinium shielded detector curve. In the top row of Figure 13B, this curve is hidden by the boron shielded detector curve.

[0139] Also, the gamma ray energy signature is 10 It has also been found to be strong enough to detect the change in the magnitude of the 478 keV gamma ray line resulting from B thermal neutron capture. This indicates that the thermal neutron flux generated internally (i.e., within the phantom or subject) is greater than predicted by the simulations. Figure 14A shows the relationship between counts (N) and 12 Plot of C ion beam energy (keV). This figure shows the results for the same experimental conditions. 10 B Empirical data collected without NCI (Figure 14B) and 10 B. Empirical data collected using NCI (see FIG. 14C) are plotted overlaid. 10 It included B plates.

[0140] It should be noted that the two data sets generally have little difference over the energy range of the beam, but the 478 keV gamma line is clearly larger with NCI than without it.

[0141] 4 Similar results were obtained with a He ion beam. Figure 15A shows the counts (N) and 4 This figure also plots the energy (keV) of the He ion beam under the same experimental conditions. 10 B Empirical data collected without NCI (Figure 15B) and 10 B. Empirical data collected using NCI (see FIG. 15C) are plotted overlaid. 10 B plate and one 10B cube. Again, the two data sets generally show little difference over the energy range of the beam, although the 478 keV gamma line is noticeably larger with NCI than without.

[0142] Essay From the energy and timing distributions of neutrons entering the NCI region (see Figures 7A and 7B), it is clear that the neutron arrival time depends on the neutron energy. Neutrons generated with high initial kinetic energy must be scattered many times to reach thermal equilibrium, which takes time. Neutron spectrograms for both carbon and helium ion beams show that thermal neutrons are scattered approximately 12 ns to 10 ns after generation. 6 As a result of the time delay between the arrival of the primary particles and the arrival of the thermal neutrons at the NCI, gamma radiation due to the thermal neutron capture process in the NCI occurs 12 ns to 10 ns after the start of the beam pulse. 6 It is expected that observations will begin within ns.

[0143] In the phantoms without NCI (see Figure 8A for the carbon ion beam and Figure 8B for the helium ion beam), all prompt (non-neutron capture) photons reached the detector within the first 11 ns after the primary particle was generated. As discussed above, thermal neutrons are mainly generated between 12 ns and 10 ns because thermalization takes time. 6 neutron capture line at 2.23 MeV), and almost nothing outside that window. 6 The use of a timing window of ns is justified. In both the NCI and non-NCI phantoms, the 511 keV annihilation line is approximately 10 4 ns and its intensity increases as time increases and the positron-emitting fragmentation products decay (note that the binning is logarithmic in time).

[0144] 10 B. In the phantom using NCI (see FIG. 8C for carbon ion beam and FIG. 8D for helium ion beam), 10 The 478 keV line from B thermal neutron capture corresponds to the time window during which thermal neutrons are present in the phantom, from approximately 12 ns to 10 6 The 2.23 MeV hydrogen neutron capture leads to a broad range of lower energy background due to Compton scattering.

[0145] 157 In the phantoms using Gd NCI (see Figure 8E for carbon ion beam and Figure 8F for helium ion beam), 157 The 7.94 MeV photon line due to Gd neutron capture is 10 B Within the same time window as the NCI line (i.e., about 12 ns to 10 6 ns), whereas for carbon ion beams, it is mainly 12ns to 10 6 ns, whereas for helium ion beams, it is 750ns to 10 5.8 ns. However, 10 Unlike in case B, there is no significant scattering background due to the absence of nearby attenuation or capture peaks.

[0146] In all phantoms, the arrival time of the neutrons at the detector was dependent on the neutron energy (see Figures 9A-9F). In this study, we consider three energy and timing bands of neutrons arriving at the detector, which for the present purposes are defined as follows: Fast neutrons: have energies greater than 1 MeV, with the majority of neutrons arriving before 50 ns; Intermediate energy neutrons: They have energies between 0.4 eV and 1 MeV. Most neutrons have energies between 50 ns and 10 4ns; and Thermal neutrons: have energies below 0.4 eV. The majority of neutrons (>99.9%) have energies below 10 4 ~2×10 6 (Thermal neutrons are generally defined as having an average kinetic energy of about 0.025 eV based on the Boltzmann temperature. Neutron energies below 0.4 eV include what are commonly referred to as cold, thermal and epithermal neutrons. However, as will be appreciated by those skilled in the art, it is known that for therapeutic neutron capture applications, the cadmium edge of about 0.5 eV is accepted as a more appropriate threshold, and 0.4 eV is selected as the upper limit of this energy band.)

[0147] As discussed above, fast and intermediate energy neutrons could potentially deposit enough energy in the detector to fill the energy window for neutron capture prompt gamma detection, which could result in a false positive. Shielding against these high energy neutrons is impractical because of the large amount of shielding material required to stop them, which would attenuate the gamma photons emitted during the neutron capture process at the target. Fast neutrons that reach the detector do so within approximately 50 ns of the end of the beam pulse (provided that the detector itself is not activated with long-lived radioisotopes), so detection of fast neutrons can be significantly reduced by using a 50 ns time mask after irradiation. While intermediate energy neutrons reach the detector at lower fluences and over longer timescales than fast and thermal neutrons, they could potentially deposit enough energy to trigger a false positive. Intermediate energy neutrons are much less abundant than fast neutrons and, in any case, cannot be effectively blocked by shielding without impairing the sensitivity of the detector.

[0148] In all ideal photon detectors, the target 10 B. When NCI is included (see Figure 11A), the R TFincreases, and then the rate starts to decrease. This is because the non-neutron capture prompt gamma emission occurs only until 11 ns after the beam injection (after the end of the beam injection), so a time mask of 22 ns is sufficient to suppress the detection of the non-neutron capture prompt gamma emission. As the beam duration increases, R TF decreases. 157 In the case of Gd NCI (see Figure 11B), as the time mask expands, R TF increases and reaches a maximum value at a mask interval of 40 ns. However, the absolute counts of true and false positives are very low (i.e., the sensitivity is low) within this mask, so a time mask of 22 ns provides the best overall balance of selectivity and sensitivity for an ideal photon detector. Moreover, as the beam duration increases, R TF increases and reaches a maximum value at a beam duration of 1 ms, due to the absence of a high-energy emission peak above 7.94 MeV. By increasing the beam duration and therefore the acquisition time, a higher proportion of photons from the neutron capture insert (true positives) can be detected without increasing the false positive rate.

[0149] In all physical detector materials evaluated, as well as 10 B and 157 In both Gd neutron capture inserts, as the time mask duration increases up to about 60 ns, R TF R increases to its maximum value, after which the rate levels off (see Figures 12A and 12B). Fast neutrons cannot be effectively shielded, and those that deposit energy in the detector do so within the first 60 ns, resulting in an increase in false negative counts and R TF decreases. 10 For the phantoms with B neutron capture inserts, the RTF decreases. 157 In the case of Gd NCI, the number of high-energy photons is insufficient, and the number of fast neutrons and intermediate energy neutrons that can deposit energy in the energy window is small, so the R TF continues to increase.

[0150] For a carbon ion beam with a 60 ns time mask (see FIG. 10A), 10 B Highest R using NCI TF The detector material that achieved this is CdTe(R TF =2.07±0.01), followed by CZT (R TF = 1.645 ± 0.009), and finally, LaBr3 (R TF =1.402±0.007).

[0151] For a carbon ion beam with a 60 ns time mask (see FIG. 10B), 157 Highest R using Gd NCI TF The detector material that achieved this is LSO(R TF =5.52±0.06), followed by BGO (R TF = 1.454 ± 0.008), and finally, PbWO4 (R TF =0.442±0.002). 10 Unlike the case of B NCI, there is no scattering from high energy photons, which means that all false positives are the result of neutron interactions within the detector. The PbWO4 detector had the highest absolute sensitivity to true positives, but the false positive rate was higher than the true positive rate at all time masks. This suggests that if the detector shielding against intermediate energy neutrons is sufficient and the rate of false positives can be reduced, it may become a more competitive detector material choice. In addition, the R TF The detector with the highest was the LSO detector, even though it had the lowest sensitivity to true positives because neutrons caused the lowest rate of false positives compared to the other detectors.

[0152] Thermal neutrons, a significant number of which are 10 4 Thermal neutrons begin to reach the detector after 1 ns. Thermal neutrons have low kinetic energy and therefore do not directly cause false positives. However, they do activate the detector itself, which leads to an increase in background radiation and therefore false positives (depending on the wavelength of the emitted gamma radiation). As detectors age, this problem is expected to become increasingly greater, so it is desirable to block thermal neutrons from the detector.

[0153] Adding a thin layer of any of the evaluated shielding materials in front of the detector: 10 When using a phantom with a B neutron capture insert, R TF (see FIG. 13A) is a result of slightly increased attenuation and scattering of the neutron-captured gamma photons before they reach the sensitive volume of the detector, with only a minimal effect on the background levels of scattered photons, fast neutrons, and intermediate neutrons.

[0154] 157 In the case of Gd neutron capture inserts, adding a hafnium or boron front shield to the detector reduces the false positives, as they are mainly caused by neutron interactions within the detector, and the hafnium (R TF =6.65±0.08) and boron (R TF = 9.3 ± 0.1), R TF (See Figure 13B). However, in the target 157 Adding cadmium shielding with Gd NCI 113 In the Cd neutron capture reaction, high-energy photons of 8.48 MeV and 9.04 MeV are emitted, which causes the single and double escape peaks to fall into the energy allowable band of 7.94 MeV. TF is very significantly reduced (R TF =0.00667±0.00003) [Reference 31].

[0155] The effect of the thermal neutron shield is to almost completely eliminate the problem of thermal neutron activation of the detector while minimizing the adverse effect on the sensitivity and specificity of the prompt gamma detector system ( 157 With the exception of cadmium shielding in the case of Gd-containing targets, the use of thermal neutron shielding to extend detector lifetime is justified.

[0156] Finally, it is noted that these simulations (and the preceding discussion) focus on carbon ion and helium ion beams. However, the simulations also support the use of dose quantification system 20 with other beam types (whether by simple trial or simulation) with only minor adjustments to the timing windows. This is because system 20 relies on principles common to all beam types: detection of gamma rays of known energy by thermal neutron capture, and rejection of detection events due to prompt gamma rays and thermal neutrons.

[0157] Similarly, these simulations (and the preceding discussion) 10 B and / or 157 The focus is on neutron capture agents in the form of Gd, since this is currently the best agent in terms of getting the agent to the tumor or lesion site without harming the subject. However, since the system 20 employs an adjustable energy window corresponding in each case to the energy (or energies) of the neutron capturing gamma ray, the system 20 is also suitable for other neutron capture agents. Similarly, it is a simple matter to select the type of gamma ray detector 22 depending on the gamma ray to be detected, and the shielding material (if employed) to distinguish it from the neutron capture agent.

[0158] Moreover, the examples and simulations shown above are based on a beam-on time window of 11 ns because this is the beam-on time window provided by many synchrotrons. This time window may be different for other synchrotrons or beam delivery devices, but the duration of the time mask Δt (ns) only needs to be adjusted accordingly to maintain the time coverage of the mask after the end of each beam-on time window.

[0159] In addition, in the simulation, R TF A number of parameter combinations were identified that optimize R TF Values ​​as low as 1.4 or 1.5 gave acceptable results, although not optimal doses or dose distributions.

[0160] conclusion These simulations allow for the estimation of the beam pulse arrival time during particle therapy through energy windows and time masks. 10 B or 157 The feasibility of the method to distinguish Gd neutron capture events from other sources of prompt gamma radiation from the target volume is demonstrated.

[0161] Overall, 10 B For targets containing NCI, the highest R TF The detector that obtained the R was a CdTe detector with a time mask of 60 ns and an exposure duration of 1 μs. TF Tolerance values ​​of were obtained with shorter time masks (eg, down to 50 ns).

[0162] 157 For Gd NCI, the LSO detector with a 60ns time mask and 1ms beam duration has the highest R TF (However, R TFTolerance values ​​of R were obtained with shorter time masks (e.g., as low as 50 ns or 40 ns for carbon ion beams). Adding a thin thermal neutron shield to the front of the detector slightly reduces sensitivity and selectivity when using boron NCI, but it allows almost all thermal neutrons to be absorbed before they reach the detector, avoiding the problem of neutron activation. In the case of gadolinium NCI, the addition of a front shield reduces R since false positives arise from neutron interactions within the detector. TF increases.

[0163] Modifications within the scope of the present invention may be readily effected by those skilled in the art, and it is to be understood, therefore, that the invention is not limited to the specific embodiments described by way of example hereinabove.

[0164] In the following claims and in the preceding description of the invention, unless the context dictates otherwise, either by express language or by necessary implication, the term "comprise" or variations thereof (such as "comprises" or "comprising") are used in their inclusive sense, i.e., to specify the presence of stated features but not to exclude the presence or addition of further features in various embodiments of the invention.

[0165] Furthermore, the reference to prior art in this specification is not intended to imply that such prior art forms or formed part of the common general knowledge in any country.

[0166] References [1]M.Safavi-Naeini et al.Opportunistic dose amplification for proton and carbon ion therapy via capture of internally generated thermal neutrons.Sci.Reports 8(2018).URL https: / / doi.org / 10.1038%2Fs41598-018-34643-w.DOI 10.1038 / s41598-018-34643-w. [2]Sauerwein,W.,Wittig,A.,Moss,R.& Nakagawa,Y.(eds.).Neutron Capture Therapy,164-165(Springer Berlin Heidelberg,2012). [3]Goorley,T.& Nikjoo,H.Electron and photon spectra for three gadolinium-based cancer therapy approaches.Radiat.Res.154,556-563(2000).DOI 10.1667 / 0033-7587(2000)154[0556:eapsft]2.0.co;2. [4]Tanaka,T.et al.Gamma-ray spectra from thermal neutron capture on gadolinium-155 and natural gadolinium.Prog.Theor.Exp.Phys.2020(4)(2020)043D02.DOI 10.1093 / ptep / ptaa015. [5]Dymova,M.A.,Taskaev,S.Y.,Richter,V.A.& Kuligina,E.V.Boron neutron capture therapy:Current status and future perspectives.Cancer Commun.40(2020)406-421.DOI 10.1002 / cac2.12089. [6]Sakurai,Y.& Kobayashi,T.Experimental verification of the nuclear data of gadolinium for neutron capture therapy.J.Nucl.Sci.Technol.39(2002)1294-1297.DOI 10.1080 / 00223131.2002.10875341. [7]Kelleter,L.et al.Spectroscopic study of prompt-gamma emission for range verification in proton therapy.Phys.Medica 34(2017)7-17.DOI 10.1016 / j.ejmp.2017.01.003. [8]Foulher,F.L.et al.Monte carlo simulations of prompt-gamma emission during carbon ion irradiation.IEEE Transactions on Nucl.Sci.57(2010)2768-2772.DOI 10.1109 / tns.2010.2048042. [9]Testa,E.et al.Dose profile monitoring with carbon ions by means of prompt-gamma measurements.Nucl.Instruments Methods Phys.Res.Sect.B:Beam Interactions with Mater.Atoms 267(2009)993-996.DOI 10.1016 / j.nimb.2009.02.031.

[10] Min,C.-H.,Kim,C.H.,Youn,M.-Y.& Kim,J.-W.Prompt gamma measurements for locating the dose falloff region in the proton therapy.Appl.Phys.Lett.89(2006)183517.DOI 10.1063 / 1.2378561.

[11] Richter,C.et al.First clinical application of a prompt gamma based in vivo proton range verification system.Radiother.Oncol.118(2016)232-237.DOI 10.1016 / j.radonc.2016.01.004.

[12] Parodi,K.& Polf,J.C.In vivo range verification in particle therapy.Med.Phys.45(2018).DOI 10.1002 / mp.12960.

[13] Bello,R.D.,Martins,P.M.& Seco,J.CeBr3scintillators for 4 He prompt gamma spectroscopy:Results from a monte carlo optimization study.Med.Phys.45,1622-1630(2018).DOI 10.1002 / mp.12795.

[14] Zarifi,M.et al.Characterization of prompt gamma ray emission for in vivo range verification in particle therapy:A simulation study.Phys.Medica 62(2019)20-32.DOI 10.1016 / j.ejmp.2019.04.023.

[15] Testa,M.et al.Real-time monitoring of the bragg-peak position in ion therapy by means of single photon detection.Radiat.Environ.Biophys.49(2010)337-343.DOI 10.1007 / s00411-010-0276-2.

[16] Hueso-Gonzalez,F.et al.Compton camera and prompt gamma ray timing:Two methods for in vivo range assessment in proton therapy.Front.Oncol.6(2016).DOI 10.3389 / fonc.2016.00080.

[17] Werner,T.et al.Processing of prompt gamma-ray timing data for proton range measurements at a clinical beam delivery.Phys.Medicine & Biol.64(2019)105023.DOI 10.1088 / 1361-6560 / ab176d.

[18] Agostinelli,S.et al.Geant4a simulation toolkit.Nucl.Instruments Methods Phys.Res.Sect.A:Accel.Spectrometers,Detect.Assoc.Equip.506(2003)250-303.DOI 10.1016 / s0168-9002(03)01368-8.

[19] Bolst,D.et al.Validation of geant4 fragmentation for heavy ion therapy.Phys.Medica 42(2017)4.DOI 10.1016 / j.ejmp.2017.09.010.

[20] Chacon,A.et al.Comparative study of alternative geant4 hadronic ion inelastic physics models for prediction of positron-emitting radionuclide production in carbon and oxygen ion therapy.Phys.Medicine & Biol.64(2019)155014.DOI 10.1088 / 1361-6560 / ab2752.

[21] Geant4 Collaboration.Geant4 material database.http: / / geant4-userdoc.web.cern.ch / geant4-userdoc / UsersGuides / ForApplicationDeveloper / html / Appendix / materialNames.html.

[22] Advatech.LSO(Ce)- Lutetium Oxyorthosciilicate(Ce)Scintillator Crystal.Available URL:https: / / www.advatech-uk.co.uk / lso_ce.html(2021).

[23] Crystals,S.-G.BGO Bismuth Germanate Bi4Ge3O12.Available URL:https: / / www.crystals.saint-gobain.com / products / bgo(2021).

[24] Crystals,S.-G.Lanthinum Bromide LaBr3(Ce).Available URL:https: / / www.crystals.saint-gobain.com / products / standard-and-enhanced-lanthanum-bromide(2021).

[25] Advatech.LaBr3(Ce)- Scintillator Crystal.Available URL:https: / / www.advatech-uk.co.uk / labr3_ce.html(2021).

[26] MSE Supplies LLC.Lead-Tungstate Crystals PbWO4.Available URL:https: / / www.msesupplies.com / products / pbwo4-crystals-lead-tungstate(2021).

[27] Danevich,F.et al.Application of PbWO4 crystal scintillators in experiment to search for decay of 116cd.Nucl.Instruments Methods Phys.Res.Sect.A:Accel.Spectrometers,Detect.Assoc.Equip.556(2006)259-265.DOI 10.1016 / j.nima.2005.09.049.

[28] Murata,I.,Nakamura,S.,Manabe,M.,Miyamaru,H.& Kato,I.Characterization measurement of a thick CdTe detector for BNCT-SPECT detection efficiency and energy resolution.Appl.Radiat.Isot.88(2014)129-133.DOI 10.1016 / j.apradiso.2014.01.023.

[29] Yamada,S.Commissioning and performance of the HIMAC medical accelerator.In Proceedings Particle Accelerator Conference(IEEE).DOI 10.1109 / pac.1995.504557.

[30] Fujimoto,T.et al.Acceleration of heavy ions with a new RF system at HIMAC synchrotron.Nucl.Instruments Methods Phys.Res.Sect.B:Beam Interactions with Matter.Atoms 269(2011)2886-2890.DOI 10.1016 / j.nimb.2011.04.029.

[31] Rusev,G.et al.Cascade gamma rays following capture of thermal neutrons on 113cd.Phys.Rev.C 88(2013).DOI 10.1103 / physrevc.88.057602.

Claims

1. detecting, using one or more detectors each having a sensitive volume, gamma rays emitted as a result of neutron capture by a composition in a subject subjected to an irradiation program, wherein the composition comprises one or more thermal neutron capture agents, the neutrons are generated by inelastic collisions between a primary beam of charged particles and atomic nuclei in the subject, the charged particles consisting of one or more of protons, deuterons, tritons and heavy ions, and the irradiation program comprises at least one irradiation time slot having a beam duration including a beam-on time slot and a beam-off time slot; applying at least one predefined energy window or filter configured to accept only detection events at the one or more detectors resulting from gamma rays having energies indicative of selected gamma rays resulting from the capture of thermal neutrons by the one or more thermal neutron capture agents, wherein the thermal neutrons are neutrons having energies below approximately 0.4 eV; applying a timing window configured to reject or ignore detection events at the one or more detectors resulting from at least prompt gamma rays produced in non-neutron capture events; determining a radiation dose of neutron radiation received by the subject from at least the accepted detection events during the irradiation program, or determining a dose map of the radiation received by the subject from at least the accepted detection events; A method for quantifying radiation dose, comprising:

2. i) rejecting the prompt gamma rays by rejecting gamma rays that reach the respective sensitive volume from the beginning of each beam-on time window until about 11 ns, until about 12 ns, or until 10-12 ns after the end of the respective beam-on time window; ii) rejecting detection events in said respective sensitive volumes due to fast neutrons based on timing; iii) rejecting, based on timing, detection events in said respective sensitive volumes that are due to neutrons having energies between 0.4 eV and 1 MeV; and / or iv) rejecting detection events within a detection window where the ratio of true positive detection events to false positive detection events, as confirmed empirically or by simulation, is less than approximately 1.4 or less than approximately 1.5, wherein a true positive detection event is an event that meets the timing window and the energy window and results from a neutron capture event, and a false positive detection event is an event that meets the timing window and the energy window and results from something other than a neutron capture event.

2. The method of claim 1, comprising configuring the timing window to:

3. 3. The method of claim 1, comprising shielding the one or more detectors with a thermal neutron absorbing material, the material being different from the one or more neutron capture agents.

4. The material is i) selected to be thick enough to block most of the thermal neutrons, but thin enough not to absorb too high a proportion of the gamma rays due to neutron capture; and / or ii) cadmium, gadolinium, boron and / or hafnium.

5. the one or more neutron capture agents １０ B base and / or １５７ 3. The method of claim 1 or 2, which is Gd-based.

6. the one or more neutron capture agents are such that the gamma rays have an energy of 478 keV. １０ B base, and / or the gamma rays have energies of 79.5 keV, 182 keV, 6.75 MeV, 7.86 MeV and / or 7.94 MeV. １５７ 3. The method of claim 1 or 2, which is Gd-based.

7. 3. The method of claim 1 or 2, comprising planning a radiation therapy that involves the generation of thermal neutrons within the patient's body through beam-target nuclei interactions at and around the treatment site.

8. The neutron capture agent is １０ B-based, and the one or more detectors are CdTe, CZT, LYSO:Ce, and LaBr ３ 10. The method of claim 1, further comprising one or more of: a Ce detector;

9. The method of claim 8, wherein the beam duration is between 1 and 10 μs, or approximately 1 μs.

10. 10. The method of claim 8 or 9, comprising shielding the one or more detectors with a thermal neutron absorbing material comprising natural Cd, natural Gd and / or natural Hf.

11. The neutron capture agent is １５７ Gd-based and the one or more detectors are LSO:Ce, BGO and PbWO ４ The method of claim 1 , comprising any one or more of the detectors.

12. i) the beam duration is between 10 μs and 100 ms; ii) the primary beam is a carbon ion beam and the beam duration is approximately 1 ms; or 12. The method of claim 11, wherein iii) the primary beam is a helium ion beam and the beam duration is approximately 10 μs.

13. 13. The method of claim 11 or 12, comprising shielding the one or more detectors with a thermal neutron absorbing material comprising natural B and / or natural Hf.

14. one or more detectors, each having a sensitive volume, configured to detect gamma rays emitted as a result of neutron capture by a composition within a subject undergoing an irradiation program, wherein the composition comprises one or more thermal neutron capture agents, the neutrons are generated by inelastic collisions between a primary beam of particles and atomic nuclei within the subject, the particles consisting of one or more of protons, deuterons, tritons, and heavy ions, and the irradiation program comprises at least one irradiation time window having a beam duration comprising a beam-on time window and a beam-off time window; an energy gate configured to apply at least one predefined energy window or filter such that the system accepts only detection events at the one or more detectors resulting from gamma rays having energies indicative of selected gamma rays resulting from the capture of thermal neutrons by the one or more thermal neutron capture agents, wherein the thermal neutrons are neutrons having energies below approximately 0.4 eV; a timing gate configured to receive beam data indicating a start or an end of the respective beam-on time window, generate from the beam data a timing window that causes the system to reject or ignore detection events at the one or more detectors resulting from at least prompt gamma rays produced in non-neutron capture events, and apply the timing window; an output for outputting data indicative of the accepted detection event; A radiation dose quantification system, including:

15. 15. The system of claim 14, wherein the one or more detectors are capable of sensing the angle of arrival of gamma rays.

16. 16. The system of claim 14 or 15, comprising a data logger or data analysis device configured to determine the radiation dose of the radiation received by the subject during the irradiation program from the counted gamma rays or to determine a dose map of the radiation received by the subject from the counted gamma rays.

17. 16. The system of claim 14 or 15, comprising a pile-up rejector configured to reject pile-ups in the output signals from the one or more detectors.

18. The timing gate i) rejecting the prompt gamma rays by rejecting gamma rays that reach the respective sensitive volume from the start of each beam-on time window until about 11 ns, until about 12 ns, or until the end of 10-12 ns after the end of the respective beam-on time window; ii) rejecting detection events in said respective sensitive volumes due to fast neutrons based on timing; iii) rejecting, based on timing, detection events in said respective sensitive volumes that are due to neutrons having energies between 0.4 eV and 1 MeV; and / or iv) rejecting detection events within a detection window where the ratio of true positive detection events to false positive detection events, as confirmed empirically or by simulation, is less than approximately 1.4 or less than approximately 1.5, wherein a true positive detection event is an event that meets the timing window and the energy window and results from a neutron capture event, and a false positive detection event is an event that meets the timing window and the energy window and results from something other than a neutron capture event.

16. The system of claim 14 or 15, configured to apply a timing window for performing:

19. 16. The system of claim 14 or 15, comprising a thermal neutron shield positioned to shield some or all of the one or more detectors and comprising a thermal neutron absorbing material, the material being different from the one or more neutron capture agents.

20. The thermal neutron absorbing material is i) selected to be thick enough to block most of the thermal neutrons, but thin enough not to absorb too high a proportion of the gamma rays due to neutron capture; and / or 20. The system of claim 19, comprising ii) cadmium, gadolinium, boron and / or hafnium.

21. the one or more neutron capture agents １０ B base and / or １５７ 16. The system of claim 14 or 15, which is Gd-based.

22. the one or more neutron capture agents are such that the gamma rays have an energy of 478 keV. １０ B base, and / or the gamma rays have energies of 79.5 keV, 182 keV, 6.75 MeV, 7.86 MeV and / or 7.94 MeV. １５７ 16. The system of claim 14 or 15, which is Gd-based.

23. The neutron capture agent is １０ B-based, and the one or more detectors are CdTe, CZT, LYSO:Ce, and LaBr ３ 15. The system of claim 14, comprising one or more of: a Ce detector;

24. 24. The system of claim 23, wherein the beam duration is between 1 and 10 μs, or approximately 1 μs.

25. 25. The system of claim 23 or 24, comprising a thermal neutron shield of thermal neutron absorbing material comprising natural Cd, natural Gd and / or natural Hf arranged to shield some or all of the one or more detectors.

26. The neutron capture agent is １５７ Gd-based and the one or more detectors are LSO:Ce, BGO and PbWO ４ 15. The system of claim 14, comprising any one or more of the detectors.

27. i) the beam duration is between 10 μs and 100 ms; ii) the primary beam is a carbon ion beam and the beam duration is approximately 1 ms; or 30. The system of claim 26, wherein iii) the primary beam is a helium ion beam and the beam duration is approximately 10 μs.

28. 28. The system of claim 26 or 27, including a thermal neutron shield of thermal neutron absorbing material comprising natural Cd, natural Gd and / or natural Hf arranged to shield some or all of the one or more detectors.

Images