System and methods for acoustic monitoring of electron radiotherapy

Abstract

The present embodiments relate generally to enabling an end user - e.g. medical physicists - to monitor radiation therapy and, with integration to the LINAC, adaptive radiotherapy. Embodiments record signals already released during radiotherapy, requiring no new irradiation of the patient for in vivo, in line, dose monitoring. Furthermore, as the transducers will be coupled to the patient with ultrasound gel, the present embodiments are not invasive to patients and will not introduce new discomfort during therapeutic procedures. The addition of the RiAD system provides the end user with additional information during the treatment of the patient, allowing for real-time beam tracking and dosimetry, enabling the end user to practice adaptive radiotherapy. The RiAD system enables the end user to ensure that proper dose delivery is occurring with each new beamlet and dose deposition, empowering them to adapt the medical treatment as it is performed and increase its precision in conventional electron beam radiotherapy, electron FLASH radiotherapy, and intraoperative electron beam radiotherapy.

Description

SYSTEM AND METHODS FOR ACOUSTIC MONITORING OF ELECTRON RADIOTHERAPYCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims priority to United States Provisional Patent Application No. 63 / 640,698, filed April 30, 2024, the contents of which are incorporated herein by reference in their entirety.TECHNICAL FIELD

[0002] The present embodiments relate generally to health technology, and more particularly to medical precision and application of radiotherapy by providing medical physicists and the LINAC with dose distribution maps and beam localization within the patient in 4D (volumetric real time imaging).BACKGROUND

[0003] Over 1.9 million novel cancer diagnosis are predicted to be delivered to Americans in 2023 and more than one third will undergo radiation therapy as part of their treatment plan (R. L. Siegel, K. D. Miller, N. S. Wagle, and A. Jemal, “Cancer statistics, 2023,” CA A Cancer J Clinicians, vol. 73, no. 1, pp. 17-48, Jan. 2023, doi: 10.3322 / caac.21763). Nearly 20% of these patients will experience severe radiation toxicity while others will experience acute radiation exposure symptoms (R. Baskar, K. A. Lee, R. Yeo, and K.-W. Yeoh, “Cancer and Radiation Therapy: Current Advances and Future Directions,” Int. J. Med. Sci., vol. 9, no. 3, pp. 193-199, 2012, doi: 10.7150 / ijms.3635). This can be mitigated with real time monitoring of dose deposition, increasing the precision of radiotherapy, among other things.

[0004] In a clinic, the main modalities utilized to determine dose prior to patient irradiation are radiochromic film, ion chambers, and electronic portal imaging devices (EPIDs). Radiochromic film, when exposed to ionizing radiation, experiences a color change in response to energy deposition, allowing for 2D dosimetry (D. F. Lewis and M. F. Chan, “Technical Note: On GAFChromic EBT-XD film and the lateral response artifact: Lateral response corrections forGAFChromic EBT-XD film,” Med. Phys., vol. 43, no. 2, pp. 643-649, Jan. 2016, doi: 10.1118 / 1.4939226). This results in surface measurements from in the beam path. Film is utilized prior to irradiation by placing it in water tank or solid water phantom at a set distance from the gantry head. This film is then irradiated with a set number of Monitor Units, the dose output of the x-ray or electron beam irradiating linear accelerator (LINAC). The film is digitized after irradiation and the intensity of the region of interest is correlated to the dose deposited into the film. This yields a 2D relative dose map of beam shape and intensity at that specific location, a surface level measurement that can determine the skin surface dose. Due to the time-intensive processing protocol for film, this method is not a real time method and is situated in the beam path.

[0005] Ion chambers can also be used to passively collect ions at a specific distance, displaying the total number of ions delivered to that surface (M. McManus et al., “The challenge of ionisation chamber dosimetry in ultra-short pulsed high dose-rate Very High Energy Electron beams,” Sci Rep, vol. 10, no. 1, p. 9089, Jun. 2020, doi: 10.1038 / s41598-020-65819-y). They provide a single 1 -dimensional surface measurement from in the beam path, determining the total dose deposited by the beam. For 2D measurements, an ion-chamber array can be used, allowing for the spatial characteristics of the beam to be captured. However, the dose here is only surface level, providing no information regarding dose deposition within the patient in the z-axis.

[0006] The third most commonly used method of dosimetry during clinical radiotherapy is Electronic Portal Imaging Devices (EPID) (A. E. Dragun et al., “Electronic Portal Imaging Devices (EPID),” in Encyclopedia of Radiation Oncology, L. W. Brady and T. E. Yaeger, Eds., Berlin, Heidelberg: Springer Berlin Heidelberg, 2013, pp. 207-213. doi: 10.1007 / 978-3-540- 85516-3 33). This differential dosimeter places a screen behind the patient and compares the radiation that passes through the patient to the radiation that exited the gantry head, thus determining the dose that was retained in the patient. Because of the shallow penetration of electron beams, no radiation passes through the body and thus EPID cannot be used to monitor electron based radiotherapy.

[0007] The use of acoustic waves for computed tomography was first proposed in 2013 as X-ray-induced Acoustic Computed Tomography (XACT) where a point transducer was immersed in water and rotated around the beam, allowing for a 2D reconstruction of the beamshape. The amplitude of measured acoustic waves was demonstrated to be proportional to the deposited dose (XIANG 2012). This proportionality makes XACT and other radiation induced acoustic measurements a good candidate for real-time, in-line dosimetry. Real time imaging and dosimetry can be achieved with the use of a multiple transducer element matrix, wherein signals are reconstructed into two or three dimensions depending on element configuration (Pandey). Electron radiotherapy monitoring has been demonstrated in vivo with averaging, which has thus far not allowed for individual pulse monitoring and thus not real-time monitoring, of radiotherapy (Isham).

[0008] It is against this technological backdrop that a technological solution to these and other problems rooted in this technology was sought.SUMMARY

[0009] The present embodiments relate generally to enabling an end user - e.g. medical physicists - to monitor radiation therapy and, with integration to the LINAC, adaptive radiotherapy. Embodiments record signals already released during radiotherapy, requiring no new irradiation of the patient for in vivo, in line, dose monitoring. Furthermore, as the transducers can be coupled to the patient with ultrasound gel, the present embodiments are not invasive to patients and will not introduce new discomfort during therapeutic procedures. The addition of a system according to embodiments provides the end user with additional information during the treatment of the patient, allowing for real-time beam tracking and dosimetry, enabling the end user to practice adaptive radiotherapy.

[0010] A system according to embodiments enables the end user to ensure that proper dose delivery is occurring with each new beamlet and dose deposition, empowering them to adapt the medical treatment as it is performed and increase its precision in conventional electron beam radiotherapy, electron FLASH radiotherapy, and intraoperative electron beam radiotherapy. Some aspects of the present embodiments include:

[0011] Individual Pulse Monitoring: Ability to extract dose information from a single electron beam pulse and reconstruct a volumetric dose deposition map with no averaging.

[0012] Matrix Array based system: Use of a matrix array, allowing for 3D imaging to occur with single pulse irradiations. The use of additional probes can be added to reduce the limited angle problem and this avenue is currently being explored.

[0013] Real-time Dosimetry in vivo: Reconstruction of volumetric imaging of dose deposition from individual pulses in highly heterogenous animal tissue. Combining of prior CT information with our reconstruction algorithm will improve the fidelity of the dose deposition map, allowing for real time dosimetry in vivo.BRIEF DESCRIPTION OF THE DRAWINGS

[0014] These and other aspects and features of the present embodiments will become apparent to those ordinarily skilled in the art upon review of the following description of specific embodiments in conjunction with the accompanying figures, wherein:

[0015] Figures 1 A to 1C illustrate a representative RiAD system and representative signals in accordance with embodiments.

[0016] Figures 2A to 2C illustrate aspects of raw RiA signals captured by a system in accordance with embodiments.

[0017] Figure 3 illustrates aspects of 3D reconstruction of RiA signals captured and processed by a system in accordance with embodiments.

[0018] Figure 4 illustrates further aspects of 3D reconstruction of signals from individual consecutive pulses in accordance with embodiments.

[0019] Figure 5 illustrates aspects of an example 3D reconstruction of a 1 .8 ps pulse width beam depositing in a rabbit chest using a system according to embodiments.

[0020] Figure 6 illustrates aspects of in vivo real-time monitoring and the ability to see variation in dose deposition from pulse to pulse using a system according to embodiments.

[0021] Figure 7 illustrates an example RiAD system diagram of point transducer experiments according to embodiments.

[0022] Figures 8A to 8D illustrate another example system and signals in accordance with embodiments.

[0023] Figures 9A to 9G illustrate another example system and setup in accordance with embodiments.DETAILED DESCRIPTION

[0024] The present embodiments will now be described in detail with reference to the drawings, which are provided as illustrative examples of the embodiments so as to enable those skilled in the art to practice the embodiments and alternatives apparent to those skilled in the art. Notably, the figures and examples below are not meant to limit the scope of the present embodiments to a single embodiment, but other embodiments are possible by way of interchange of some or all of the described or illustrated elements. Moreover, where certain elements of the present embodiments can be partially or fully implemented using known components, only those portions of such known components that are necessary for an understanding of the present embodiments will be described, and detailed descriptions of other portions of such known components will be omitted so as not to obscure the present embodiments. Embodiments described as being implemented in software should not be limited thereto, but can include embodiments implemented in hardware, or combinations of software and hardware, and vice- versa, as will be apparent to those skilled in the art, unless otherwise specified herein. In the present specification, an embodiment showing a singular component should not be considered limiting; rather, the present disclosure is intended to encompass other embodiments including a plurality of the same component, and vice-versa, unless explicitly stated otherwise herein. Moreover, applicants do not intend for any term in the specification or claims to be ascribed an uncommon or special meaning unless explicitly set forth as such. Further, the present embodiments encompass present and future known equivalents to the known components referred to herein by way of illustration.

[0025] The present embodiments relate generally to a radiation-induced acoustic dosimetry (RiAD) system that is capable of real-time acquisition of dose deposition during electron beam line radiotherapy, allowing for real time tracking of the beam location and adaptive radiotherapy, ensuring proper dose delivery. Embodiments include the use of a matrix array for electron radiotherapy monitoring, allowing for 3D monitoring of individual pulses and 3D imaging of dose deposition from electron beam lines. Embodiments further include single pulse monitoring for radiotherapy with a RiAD system.

[0026] Currently, no real-time method exists for monitoring electron beam line radiation therapy in the clinic. A RiAD system according to embodiments allows for in vivo in situ monitoring of the beam during radiotherapy. Not only is the beam spatially monitored, ensuring that dose is deposited in target tissue, the dose can also be mapped in 4D, allowing for continuous dose monitoring of every individual pulse.

[0027] The present embodiments can be utilized during radiation therapy, making use of the acoustic waves generated during radiotherapy, thus ensuring no new radiation need be deposited. Due to the 3D propagation of acoustic waves, transducers do not need to be placed in the beam line as required by other dosimetry methods. Moreover, because of the 3D propagation of acoustic waves, 3D dose mapping can be done from a single pulse, requiring no scanning.

[0028] An aspect of the present disclosure is a recognition that, among other things, the acoustic signals generated during radiation therapy with electron based beam lines, during both conventional and FLASH radiotherapy (RT), can be utilized to monitor and adapt therapies. Since the energy deposition is proportional to the strength of the acoustic waves, reconstruction of the captured acoustic signals can be used to image the beam location, the spatial distribution of beam in the tissue, and the dose deposited into the tissue with individual pulses.

[0029] For signal acquisition, using a matrix array of transducer elements and combining it with planning computed tomography (CT) information, reconstructions of single pulse irradiations can be done. Dose information can be extracted from the peak to peak voltages of the captured acoustic waves, allowing for real time, in vivo dosimetry. Reconstruction overlayed on prior CT can create 3D dose distribution mapping from single irradiations, ensuring that the dose is delivered to the target region. This temporal and spatial monitoring of beam dose deposition allows for adaptive radiotherapy in which the dose delivered to the target will be determined after every pulse and inform the dose still to be delivered to the target region.

[0030] Translation of ultra-high dose rate FLASH radiotherapy (FLASH-RT) stands to improve patient outcomes due to the benefits of sparing normal tissue toxicities, where real time dosimetry can enhance safety by accurately measuring dose delivery to the tumor site. Current clinical trends implementing hypofractionation (i.e. fewer pulses) at higher dose per pulse compared to conventional radiotherapy, substantiates further the need for in vivo, real-time, volumetric (4D) dosimetric monitoring.

[0031] The present Applicant demonstrated the feasibility of a RiAD system according to embodiments as a real-time beam tracking method for FLASH-RT, allowing for spatial and dosimetric monitoring of each individual pulse. The present embodiments allow for individual pulse, volumetric beam imaging and demonstrates dose rate linearity across a wide range including those used in FLASH-RT.

[0032] In the feasibility study, a FLASH-capable eRT6 LINAC was used to deliver electron beams under a variety of beam parameters. The beam was imaged in water and in ex vivo rabbit tissue with coupled ultrasound transducers. The dose per pulse was varied to explore dose linearity. A custom 256-element matrix ultrasound array was used for real-time volumetric beam imaging from individual pulses. Signal processing and image reconstruction was performed in MATLAB.

[0033] The dose per pulse was varied by changes to source-to-surface distance (SSD). Radiochromic film dose measurements were compared to the peak-to-peak amplitudes of resulting pressure waves captured by the RiAD system to establish dose per pulse linearity, dose rate linearity, and instantaneous dose linearity in the FLASH regime. No saturation was recorded even at the highest doses per pulse achievable with the Oriatron eRT6. The 2D matrix array used allowed for 3D reconstructions of beam dose distributions in water and animal tissue in realtime.

[0034] The feasibility of real-time volumetric (4D) dosimetry during FLASH-RT with a RiAD system was demonstrated, allowing for spatial and temporal beam monitoring of individual FLASH beamlets during beam delivery. The present detector system can facilitate clinical translation of FLASH-RT by ensuring accurate dose delivery to the target volume, thereby improving the safety and efficacy of radiotherapeutic procedures.

[0035] INTRODUCTION

[0036] One of the leading causes of death globally and a major public health concern, cancer is mainly treated by a combination of surgery, chemotherapy, and radiotherapy (Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA Cancer J Clin. 2023;73(l):17- 48. doi: 10.3322 / caac.21763; Baskar R, Lee KA, Yeo R, Yeoh KW. Cancer and Radiation Therapy: Current Advances and Future Directions. Int J Med Sci. 2012;9(3): 193-199.doi : 10.7150 / ij ms.3635). Radiotherapy is prescribed to over a third of cancer patients, yet, despite its prevalence in the clinical treatment course, radiation therapy still has no real-time in vivo method for monitoring dose delivery (Id ). Currently, around 20% of patients experience severe radiation toxicity and are hospitalized following treatments (Waddle MR, Chen RC, Arastu NH, et al. Unanticipated hospital admissions during or soon after radiation therapy: Incidence and predictive factors. Pract Radiat Oncol. 2015;5(3):e245-e253. doi: 10.1016 / j.prro.2014.08.004; Tonse R, Ramamoorthy V, Rubens M, et al. Hospitalization rates from radiotherapy complications in the United States. Sci Rep. 2022;12(l):4371. doi: 10.1038 / s41598-022-08491- 8). Many more will experience short term conditions, ranging from hearing loss to gastroenteritis, and long term toxicities such as cardiovascular disease, cognitive impairment, and infertility (Palumbo MO, Kavan P, Miller WH, et al. Systemic cancer therapy: achievements and challenges that lie ahead. Front Pharmacol. 2013;4. doi: 10.3389 / fphar.2013.00057). Despite improved capabilities in conformal beam delivery, as the beam travels through the body, irradiating the tumor region and damaging DNA in tumor cells, normal tissue in the beam path is also exposed and damaged. As the tumor shrinks over the course of treatment and respiratory tumor motion occurs during individual irradiation fractions, normal tissue is invariably irradiated, leading to undesirable complications. Lung cancer patients experience the highest levels of hospitalizations due to complications post-radiation therapy. Respiratory motion by itself can cause off-target effects with gamma passing rates falling to 40% and beam conformity with tumor region reducing to 80% (Yang Y, Kang M, Huang S, et al. Impact of respiratory motion on proton pencil beam scanning FLASH radiotherapy: an in silico and phantom measurement study. Phys Med Biol. 2023;68(8):085008. doi:10.1088 / 1361-6560 / acc632). This unintended dose deposition in normal tissue confounds patient outcomes in multifaceted ways, precipitating a cascade of early and late toxicities and even secondary cancers that compromise quality of life in cancer survivors (Id.).

[0037] The foregoing provides the backdrop for the excitement surrounding FLASH-RT, where the sparing of normal tissue toxicity that occurs at dose rates >40Gy / s and can be achieved without compromising the efficacy of tumor kill defines the FLASH effect (Favaudon V, Caplier L, Monceau V, et al. Ultrahigh dose-rate FLASH irradiation increases the differential response between normal and tumor tissue in mice. Sci Transl Med. 2014;6(245).doi: 10.1126 / scitranslmed.3008973; Montay-Gruel P, Acharya MM, Goncalves Jorge P, et al. Hypofractionated FLASH-RT as an Effective Treatment against Glioblastoma that Reduces Neurocognitive Side Effects in Mice. Clin Cancer Res. 2021;27(3):775-784. doi: 10.1158 / 1078- 0432.CCR-20-0894; Soto LA, Casey KM, Wang J, et al. FLASH Irradiation Results in Reduced Severe Skin Toxicity Compared to Conventional-Dose-Rate Irradiation. Radiat Res. 2020;194(6):618-624. doi: 10.1667 / RADE-20-00090). The FLASH effect observed by several preclinical models covering a range of tumor types and normal tissue and clinical translation would improve the quality of life of cancer patients. While preclinical data has been promising, certain obstacles remain before FLASH-RT can be implemented routinely in the clinic such as the lack of real time, in vivo dosimetry. Unlike conventional radiotherapy, which utilizes hundreds of low dose pulses per patient session, clinical FLASH radiotherapy will likely deliver larger doses per pulse, reducing overall treatment times and requiring only a few pulses of the ionizing beam (Ashraf MR, Rahman M, Zhang R, et al. Dosimetry for FLASH Radiotherapy: A Review of Tools and the Role of Radioluminescence and Cherenkov Emission. Front Phys. 2020;8:328. doi: 10.3389 / fphy.2020.00328; Rahman M, Ashraf MR, Zhang R, et al. Spatial and temporal dosimetry of individual electron FLASH beam pulses using radioluminescence imaging. Phys Med Biol. 2021;66(13): 135009. doi: 10.1088 / 1361-6560 / ac0390). While higher dose rates can minimize motion management issues of tumor targeting, the risk of exposing normal tissue to higher doses and reducing dose delivery to the tumor site is greater if the dosimetry or beam positioning of any individual beam is incorrect.

[0038] In conventional radiotherapy, the machine output is measured in clinics daily during calibration with radiochromic film and ion chambers (Miften M, Oleh A, Mihailidis D, et al. Tolerance limits and methodologies for IMRT measurement-based verification QA : Recommendations of AAPM Task Group No. 218 . Med Phys. 2018;45(4). doi: 10.1002 / mp.12810; Klein EE, Hanley J, Bayouth J, et al. Task Group 142 report: Quality assurance of medical acceleratorsa): Task Group 142 Report: QA of Medical Accelerators. Med Phys. 2009;36(9Partl):4197-4212. doi: 10.1118 / 1.3190392). Radiochromic film is placed in solid water phantom and irradiated with preplanned treatment courses, giving a 2D relative dose map of the beam at a certain distance. When read by a digitizer immediately following acquisition, one can get the dose deposition map in one plane (Pai S, Das IJ, Dempsey JF, et al. TG-69:Radiographic film for megavoltage beam dosimetry: TG-69: Radiographic film. Med Phys. 2007;34(6Partl):2228-2258. doi: 10.1118 / 1.2736779). Film only allows for surface dose measurements if used during radiotherapy. Ion chambers passively collect ions at a specific distance, displaying the total number of ions delivered to that location (Id.). While this method gives an absolute measurement, the measurement is a single number and gives no information on the dose distribution in space unless an ion chamber array is used. Importantly, neither of the two gold standard methods are real time methods that would provide feedback to the doctors administering the therapy or to the LINAC itself, allowing for adjustments to be made to optimize patient treatments.

[0039] Furthermore, there is currently no 3D real time beam tracking which could be used to ensure proper dose delivery to the targeted treatment volume (Mijnheer B, Beddar S, Izewska J, Reft C. In vivo dosimetry in external beam radiotherapy: In vivo dosimetry in external beam radiotherapy. Med Phys. 2013;40(7):070903. doi:10.1118 / 1.4811216). Currently, in clinic, patients are aligned with LINAC lasers and physical casts that limit movement. The beam is conformed to the tumor shape as best as possible using a planning CT scan, Monte Carlo simulation, and the multi-leaf collimator in the LINAC head in both volumetric modulated arc radiotherapy and intensity modulated radiotherapy (Ezzell GA, Galvin JM, Low D, et al.Guidance document on delivery, treatment planning, and clinical implementation of IMRT: Report of the IMRT subcommittee of the AAPM radiation therapy committee. Med Phys. 2003;30(8):2089-2115. doi: l 0.1118 / 1.1591194; Teoh M, Clark CH, Wood K, Whitaker S, Nisbet A. Volumetric modulated arc therapy: a review of current literature and clinical use in practice. Br J Radiol. 2011;84(1007):967-996. doi: 10.1259 / bjr / 22373346). However, as the patient breathes or consumes more food or water in contrast to the first visit, causing organ positioning to change slightly, the beam may still irradiate additional tissues (Cusumano D, Dhont J, Boldrini L, et al. Predicting tumour motion during the whole radiotherapy treatment: a systematic approach for thoracic and abdominal lesions based on real time MR. Radiother Oncol. 2018;129(3):456-462. doi: 10.1016 / j.radonc.2018.07.025; Grim A, Kawgan-Kagan M, Kaul D, et al. Impact of bladder volume on acute genitourinary toxicity in intensity modulated radiotherapy for localized and locally advanced prostate cancer. Strahlenther Onkol. 2019; 195(6): 517-525. doi:10.1007 / s00066-018-1398-8; Corradini S, Alongi F, Andratschke N, et al. MR-guidance inclinical reality: current treatment challenges and future perspectives. Radiat Oncol. 2019;14(l):92. doi: 10.1186 / sl3014-019-l 308-y). Although this is less of a concern for healthy tissue due to the FLASH effect, it is still a concern. Thus, utilizing a real-time, in-situ capable monitoring system is critical to the translation of FLASH RT into the clinic.

[0040] One method that is not commonly used is placing an electronic portal imaging device (EPID) underneath the patient and capturing the dose that has passed through the patient, thus determining the dose deposited in the patient via differential (Jeong S, Yoon M, Chung K, Ahn SH, Lee B, Seo J. Clinical application of a gantry-attachable plastic scintillating plate dosimetry system in pencil beam scanning proton therapy beam monitoring. Phys Med.2020;77: 181-186. doi: 10.1016 / j.ejmp.2020.08.019; Dragun AE, Schilling PJ, Speer TW, et al. Electronic Portal Imaging Devices (EPID). In: Brady LW, Yaeger TE, eds. Encyclopedia of Radiation Oncology. Springer Berlin Heidelberg; 2013:207-213. doi: 10.1007 / 978-3-540-85516- 3 33). This allows for real-time dosimetry in 2D (Phillips TL, Hoppe R, Roach M, Leibel SA, eds. Leibel and Phillips Textbook of Radiation Oncology. 3rd ed. Elsevier / Saunders; 2010). However, this method can only be used for photon based therapy where the radiation beam passes through the body to the portal. Furthermore, most portals are liquid ion chamber based or scintillator screen based, both methods which show saturation at high doses per pulse and thus in the FLASH regime (McManus M, Romano F, Lee ND, et al. The challenge of ionisation chamber dosimetry in ultra-short pulsed high dose-rate Very High Energy Electron beams. Sci Rep. 2020;10(l):9089. doi:10.1038 / s41598-020-65819-y; Morrocchi M, Pensavalle JH, Ciarrocchi E, et al. Experimental characterization and Monte Carlo simulation of scintillator detectors in online electron FLASH radiotherapy dosimetry. J Instrum. 2022;17(09):P09005. doi: 10.1088 / 1748-0221 / 17 / 09 / P09005; Vanreusel V, Gasparini A, Galante F, et al. Point scintillator dosimetry in ultra-high dose rate electron “FLASH” radiation therapy: A first characterization. Phys Med. 2022; 103: 127-137. doi: 10.1016 / j.ejmp.2022.10.005).

[0041] The use of acoustic waves for computed tomography was first proposed in 2012 as X-ray -induced Acoustic Computed Tomography (XACT) where a point transducer was immersed in water and rotated around the beam, allowing for a 2D reconstruction of the beam shape (Xiang L, Han B, Carpenter C, Pratx G, Kuang Y, Xing L. X-ray acoustic computed tomography with pulsed x-ray beam from a medical linear accelerator. Med Phys.2012;40(l):010701. doi: 10.1118 / 1.4771935). The amplitude of measured acoustic waves was demonstrated to be proportional to the deposited dose (Sun L, Gonzalez G, Pandey PK, et al. Towards quantitative in vivo dosimetry using x-ray acoustic computed tomography. Med Phys. Published online May 18, 2023:mp.16476. doi: 10.1002 / mp.16476). This proportionality makes XACT and other radiation induced acoustic measurements a good candidate for real-time, in-line dosimetry (Xiang L, Tang S, Ahmad M, Xing L. High Resolution X-ray-Induced Acoustic Tomography. Sci Rep. 2016;6( 1):26118. doi: 10.1038 / srep26118; Hickling S, Hobson M, El Naqa I. Characterization of X-Ray Acoustic Computed Tomography for Applications in Radiotherapy Dosimetry. IEEE Trans Radiat Plasma Med Sci. 2018;2(4):337-344. doi : 10.1109 / TRPMS.2018.2801724). Real time imaging and dosimetry can be achieved with the use of a multiple transducer element matrix, wherein signals are reconstructed into two or three dimensions depending on element configuration (Zhang W, Oraiqat I, Lei H, Carson PL, El Naqa I, Wang X. Dual-Modality X-Ray-Induced Radiation Acoustic and Ultrasound Imaging for Real-Time Monitoring of Radiotherapy. BME Front. 2020;2020: 1-10. doi: 10.34133 / 2020 / 9853609; Zhang W, Oraiqat I, Litzenberg D, et al. Real-time, volumetric imaging of radiation dose delivery deep into the liver during cancer treatment. Nat Biotechnol. Published online January 2, 2023. doi: 10.1038 / s41587-022-01593-8; Jiang Z, Sun L, Yao W, Wu QJ, Xiang L, Ren L. 3D in vivo dose verification in prostate proton therapy with deep learningbased proton-acoustic imaging. Phys Med Biol. 2022;67(21):215012. doi: 10.1088 / 1361- 6560 / ac9881; Pandey PK, Wang S, Aggrawal HO, Bjegovic K, Boucher S, Xiang L. Model- Based X-Ray-Induced Acoustic Computed Tomography. IEEE Trans Ultrason Ferroelectr Freq Control. 2021;68(12):3560-3569. doi: 10.1109 / TUFFC.2021.3098501).

[0042] Because each individual pulse can be utilized for imaging and dose measuring, real-time tracking is possible. Furthermore, the transducers are not placed in the beam path; they are coupled to the irradiated sample. This allows for dosimetry without interfering with treatment beams that can thus be used for real time monitoring during radiotherapy. With a well characterized and calibrated system, an aspect of this disclosure is a recognition that RiAD would allow for quantitative intra-tumoral dosimetry and dosimetry-modulated precision radiotherapy. Multiple groups have used transducers of varying center frequencies and configurations to demonstrate the capabilities of spatial beam tracking (Hickling S, Lei H,Hobson M, Leger P, Wang X, El Naqa I. Experimental evaluation of x-ray acoustic computed tomography for radiotherapy dosimetry applications. Med Phys. 2017;44(2):608-617. doi: 10.1002 / mp.12039; Xianfen Diao, Jing Zhu, Weihao Li, et al. Broadband detection of dynamic acoustic emission process induced by 6 MV therapeutic X-ray beam from a clinical linear accelerator. In: 2015 IEEE International Ultrasonics Symposium (IUS). IEEE; 2015: 1-4. doi: 10.1109 / ULTSYM.2015.0241; Hickling S, Leger P, El Naqa I. On the Detectability of Acoustic Waves Induced Following Irradiation by a Radiotherapy Linear Accelerator. IEEE Trans Ultrason Ferroelectr Freq Control. 2016;63(5):683-690. doi: 10.1109 / TUFFC.2016.2528960; Forghani F, Mahl A, Patton TJ, et al. Simulation of x-ray- induced acoustic imaging for absolute dosimetry: Accuracy of image reconstruction methods. Med Phys. 2020;47(3): 1280-1290. doi: 10.1002 / mp,13961; Lei H, Zhang W, Oraiqat I, et al. Toward in vivo dosimetry in external beam radiotherapy using x-ray acoustic computed tomography: A soft-tissue phantom study validation. Med Phys. 2018;45(9):4191-4200. doi: 10.1002 / mp.13070; Kim J, Park EY, Jung Y, et al. X-Ray Acoustic-Based Dosimetry Using a Focused Ultrasound Transducer and a Medical Linear Accelerator. IEEE Trans Radiat Plasma Med Sci. 2017;l(6):534-540. doi: 10.1109 / TRPMS.2017.2757484); for example, irregular beam collimation was verified in water, imaging of biological tissue was demonstrated, and the use of simultaneous XACT and ultrasound for beam localization was demonstrated ex vivo. Little work has been done towards achieving in situ dosimetry with most research focusing on the use of radiation induced acoustics for relative water tank dosimetry.

[0043] Most recently, Zhang et al. demonstrated the feasibility of radiation induced systems to track the beam in situ, imaging the radiation in the tumor region of a patient’s liver with 100 averages at a 3.3Hz frame rate, allowing for real time monitoring of conventional radiotherapy fractions (Id.). Some exploration of radiation induced acoustic signals has been done with FLASH irradiation, showing linearity at up to 25cGy per pulse with electron beams and 2D beam edge tracking has been shown (Oraiqat I, Zhang W, Litzenberg D, et al. An ionizing radiation acoustic imaging (iRAI) technique for real-time dosimetric measurements for FLASH radiotherapy. Med Phys. 2020;47(10):5090-5101. doi:10.1002 / mp.14358). Explorations of higher dose per pulse are needed to ensure linearity across the entire FLASH regime and thefeasibility of imaging dose deposition in real-time volumetric space with radiation induced 3D acoustics must be shown.

[0044] EXAMPLE MATERIALS AND METHODS

[0045] A, RiA Signal Generation

[0046] Radiation induced Acoustic Dosimetry is based on an effect similar to the photoacoustic effect, where energy that is deposited in tissue causes a local temperature rise. As the temperature increases, the tissue expands (Id.). When the beam pulse ends, the temperature decreases as no new energy is deposited and the tissue contracts. This thermoelastic expansion and contraction generates 3D acoustic waves, governed by following the wave equation when thermal confinement is met:

[0047] where vsis the speed of sound in the target medium, (r, t) is the acoustic pressure rise at time t and location f , p is the target volume thermal coefficient, Cpis the specific heat capacity of the target medium at a constant pressure, and H(r, t) is the heating function (Id.).The heating function H(r, t) can be written as:H(r, t) = r)thD(f, t)p (Eq. 2)

[0048] as a function of D, the deposited dose per unit time, where r|this the percentage of the absorbed energy or dose that converts into heat, and p is the density of the target tissue (Khan FM, Gibbons JP. Khan’s the Physics of Radiation Therapy. Sixth edition.; 2020). Thus, Equation 1 can be rewritten, describing the generated pressure waves as a function of the dose deposited into the tissue: )

[0049] This relationship between the generated pressure waves and the deposited dose over time allows for the use of radiation-induced acoustic waves as a method of determining the dose delivered into the tissue. When stress confinement is also met, the local rise in pressure can be described as:Po = FrithPD Eq. 4)

[0050] where p0is the local pressure rise and T is the material specific Gruneisen parameter (Samant P, Trevisi L, Ji X, Xiang L. X-ray induced acoustic computed tomography. Photoacoustics. 2020;19: 100177. doi: 10.1016 / j.pacs.2020.100177). This correlates the amplitude of the initial pressure with the dose deposited into the tissue, allowing for dosimetry information to be extracted from radiation-induced acoustic (RiA) signals.

[0051] RiA signals can be collected with ultrasound transducers coupled to the medium through which the resultant 3D acoustic waves are propagating. By utilizing multiple transducers in different geometries, 2D and 3D images can be reconstructed from the recorded RiA signals, allowing for dose deposition mapping in situ. Dose linearity of RiAD systems has been demonstrated by the present Applicant in conventional dose rate regimes. As many current dosimetry tools demonstrate instantaneous dose rate dependence and dose per pulse dependence in the FLASH regime, dose linearity of RiAD systems must be demonstrated in the FLASH regime. The present Applicant has further demonstrated the linearity of RiA signals and dose per pulse, as well as instantaneous dose rate, in the FLASH regime and the feasibility of RiAD for dose mapping.

[0052] B, RiA Dosimetry

[0053] Figures 1 A to 1C illustrate aspects of an example RiAD system and signals according to embodiments. For example, Figure 1A depicts a system 100 comprising a clinical LINAC 102 with electron beam for patient treatment according to embodiments. In this illustration, beam 104 deposition in water is monitored via a water-coupled matrix array 106. For in vivo studies, ultrasound gel coupling is sufficient for individual pulse monitoring of dosedeposition. In one example, array 106 consists of a matrix array of 16 x 16 ultrasound transducers whose acoustic signals 108 are acquired in parallel. As further shown, signals 108 are provided to a 256-channel preamplifier and ADC combo 110. The acquired signal is processed and reconstructed in MATLAB via processor 112.

[0054] More particularly, different source LINACs can be made FLASH capable for use in the present embodiments. In one non-limiting example, a prototype electron beam LINAC (Oriatron eRT6, PMB-Alcen, France) can be utilized for LINAC 102. This LINAC is conventional RT and FLASH RT capable with variable dose per pulse (less than 15 cGy - 20 Gy), variable pulse width (500 ns - 4 ps), variable repetition frequency (5-250 Hz), and variable electron gun voltage (0-300 V). A beam current transformer (BCT, Bergoz Instrumentation, Saint-Genis-Pouilly, France, not shown), modified for ultra-high dose rate capability, is attached to the beam exit for monitoring beam output during usage. The BCT signal is split to two outputs - a beam monitoring system used during FLASH-RT experiments for beam counting and a trigger pathway for synchronized RiAD acquisition, allowing for capture of RiA signals generated by a single irradiation pulse. Before the beam enters the acquisition area, it can be collimated with graphite collimators 114; a rectangular collimator can be utilized for linearity data.

[0055] Array 106 can be implemented with a point transducer (500 kHz, A389S-SU, Olympus INS, Japan) and a custom matrix array of 256 transducer elements (Photosound, USA). The point transducer can be immersed in a water tank and used for linearity studies as shown in Figure 1A. The 256-element matrix array allows for synchronized simultaneous capture of resultant acoustic waves, enabling single pulse volumetric reconstructions of dose deposition. Preamplifier 110 for amplifying individual pulse RiA signals can be implemented by a 40 dB preamplifier (5660B Ultrasonic Preamplifier Panametrics-NDT, Olympus, Japan). Raw RiA signals 108 from each transducer element can be amplified and acquired in parallel with a custom 256-channel data acquisition system (Legion ADC, Photosound, USA). This allows for 3D reconstructions to be completed from individual pulses with no need for mechanical scanning, with all imaging speed limitations depending on the speed of sound of the medium and the speed of the universal back projection algorithm used. All data processing and reconstructioncan be done by processor 112 in MATLAB (e.g. R2021b, MathWorks Inc, USA), for example utilizing a universal back-projection (UBP) approach as known to those skilled in the art.

[0056] C. Film Dosimetry for Dose Linearity Study

[0057] For gold standard comparison, radiochromic film (Gafchromic EBT3 film, Ashland Advanced Materials, USA) was irradiated in the same plane as the point transducer, allowing for accurate comparisons. The whole plane was irradiated, capturing the whole beam shape and dose deposition. For each distance, film was irradiated with an individual pulse of electron beam and repeated on a new film, allowing for averaging as well as individual dose per pulse measurement comparisons. These measurements were compared to the point transducer measurements of the same beam collimation and strength at the same depth in the water tank.

[0058] D, Data processing and 3D reconstruction

[0059] Universal back-projection is one of the most widely used 3D acoustic image reconstruction methods (Xu M, Wang LV. Universal back-projection algorithm for photoacoustic computed tomography. Phys Rev E. 2005;71(l):016706. doi: 10.1103 / PhysRevE.71.016706). In the feasibility study, employed was the UBP algorithm by using the following equation:

[0060] where pQ(f) is the reconstructed initial pressure at position r, p(rd, t) is the measured pressure signal at detector position rdand time t = \r^ — r \vs, and fl0is the solid angle that the transducer surface S covers.

[0061] Before reconstruction, averaging can be applied to increase signal-to-noise-ratio (SNR). 25 frames were acquired and used for averaging although single pulse reconstructions were completed as well. The size of the 256-element matrix array was 4.8 cm x 4 8 cm and a reconstruction grid of 4.8 cm x 4 8 cm x 6 cm above the transducer was created with a voxel resolution of 400 pm. All reconstruction was run in MATLAB.

[0062] EXAMPLE RESULTS

[0063] A, Dose Linearity Study

[0064] Due to the ultra-high dose rate of FLASH-RT, overall treatments can be hypo- fractionated compared to conventional radiotherapy plans, with each pulse delivering a much higher dose that must be accurately evaluated. In order to realize the translational promise of FLASH-RT, individual pulses must be monitored as natural variation will be compounded. To study the linearity of RiA signal amplitude and the delivered dose, the coupled point transducer system was utilized as shown in Figure 7 (similar to the system of Figure 1, but including an oscilloscope (DSOX2024A, Keysight Technologies, USA). During FLASH RT experiments on mice, pulses at a pulse width of 1.8 ps and a repetition rate of 100 Hz are utilized and the source to surface distance (SSD) is changed to achieve different doses. This method of varying dose by varying the SSD is also utilized in the clinic. The distance between the beam source, where the BCT is located, and the water tank edge was measured with a laser, allowing for highly precise SSD changes. To characterize the FLASH beam and the resulting RiA signals, the translational stage with the water tank and submerged transducer was moved to 5 different Source-to-Surface Distances (SSD), varying the dose per pulse. At each distance, the 1.8 ps FLASH electron beam was pulsed 5 times. Radiochromic film was also irradiated at each distance for comparison between the RiA signal amplitude and the gold standard dose measurement. In looking at the IA signals generated by the same electron beam profile at different distances, dose linearity can be established in the manner that it would be used in a clinical setting, as described in more detail below in connection with Figures 2A to 2C. For this, the peak-to-peak voltage of each measured IA wave was extracted within the signal relating to the beam.

[0065] Figure IB illustrates a representative raw IA signal (e.g. single transducer signal collected at 470 mm away from a 1.8 ps pulse) with dotted lines to represent the time of flight estimations of the RiA signal reaching the transducer surface. As shown, initially there is a headwave region, the signal that occurs the moment the beam is fired. This signal comes from irradiation of the transducer and occurs at time t=0. Knowing the distance between the collimated beam edges and the point transducer surface as well as the speed of sound in the medium, a time-of-flight calculation can be done to estimate when the acoustic waves from thebeam will reach the transducer. In Figure IB, the dotted lines denote the time when acoustic signals from the two beam edges will theoretically arrive at the transducer and all signal between the two lines is acoustic signal from beam deposition in the medium. The peak-to-peak amplitude of this portion of the acoustic signal was compared to the dose deposited at that same distance as measured by digitized eBT3 film. There are three main measurements of dose that were analyzed for linearity with IA signals in the FLASH regime: dose per pulse, dose rate, and instantaneous dose rate. The dose per pulse is defined as the dose delivered in a single pulse of the LINAC and is measured in Gy; this measurement is of high importance in FLASH radiotherapy as fractionated FLASH treatments will occur with only a few pulses as compared to the thousands of pulses of low dose per pulse delivered during conventional radiotherapy. Single pulses of high dose per pulse were studied in the linearity study. The dose rate, or average dose rate, is defined as the dose deposited in tissue over one second, and depends on both the dose per pulse and the repetition rate of the system and is measured in Gy / s. Finally, the instantaneous dose is defined as the dose per pulse delivered in the time of a single pulse and is also measured in Gy / s; this measurement is utilized in the characterization of FLASH and CONV radiotherapy by those in the medical field.

[0066] Figure 1C depicts a representative max projection in the XY plane showing dose deposition in water. The 256 element matrix array orientation used for 3D imaging is shown.

[0067] Figure 2A demonstrates single pulse RAW signals taken at varying SSD’s, resulting in different doses per pulse. Higher doses per pulse result in greater peak-to-peak amplitudes in RiA signals. Linear fitting was performed in MATLAB for the dose per pulse, dose rate, and instantaneous dose rate comparisons, achieving a R2value greater than 0.99 for all three, demonstrating high linearity. No saturation was observed across repetitions. In Figure 2A, single pulse raw IA signals are shown, demonstrating the increase in amplitude that occurs with the increase in dose per pulse.

[0068] Figures 2B and 2C depict the linearity observed for the dose per pulse and the instantaneous dose rate, with all 5 measurements depicted as open circles and averages as filled circles with two standard deviation error bars. At the SSD of 470 mm, pulse trains of 5-100 Hz repetition frequency were delivered but no change was observed in the RiA signal as no overlap occurred between the RiA signals. This was expected due to the time-of-flight calculationoutcomes predicting no overlap between RiA signals. At the highest (250 Hz) frequency possible, inter-pulse time would be 4 ms while RiA signals occurred in the first 100 ps, well before even the first millisecond after the pulse. Thus, even for the highest possible repetition frequency, no signal overlap would occur.

[0069] B, Volumetric Dosimetry for FLASH RT

[0070] To show the feasibility of dose mapping in 3D with RiA waves during FLASH RT, a 256-element matrix array such as array 106 described above was utilized. The array was placed in water facing upwards, parallel to the beam edges. A rectangular collimator 114 was utilized to shape the beam. The SSD was varied to 4 distances with 25 pulses acquired at each distance. When processing at the data collected across all 256 transducers, a 3D image can be reconstructed in MATLAB.

[0071] Figure 3 illustrates example results obtained with a 1.8 ps pulse width beam depositing in the water tank at a SSD of 450 mm. Here, the sliced volume planes are shown in 3D on the left. The middle panel shows the maximum intensity projection in each plane. The panel on the right depicts the TOPAS simulation of the same experimental setup as a comparison to the reconstructed experimental XY plane. As seen in Figure 3, the 3D reconstructions and the maximum intensity projections in different planes give a visual representation of the beam deposition in water. Here, the distance of 470 mm is examined. Utilizing a single pulse, a volumetric representation of the dose deposition in water is shown, demonstrating the potential for RiAD to be utilized for 3D radiotherapy monitoring.

[0072] Figure 4 illustrates signals that were generated by the 1.8 ps pulse width beam depositing in the water tank at a SSD of 450 mm. 3D reconstruction of signals from individual consecutive pulses are shown, demonstrating the feasibility of real-time monitoring and the ability to see variation in dose deposition from pulse to pulse. More particularly, in the XY- plane shown in Figure 4, the dose deposition of the electron beam is shown to be a shallow penetrating Gaussian beam, as is expected of a 5.4MeV electron beam. Utilizing planning software (TOPAS), Monte Carlo simulation of the expected dose deposition was performed by a medical physicist (Faddegon B, Ramos-Mendez J, Schuemann J, et al. The TOPAS tool for particle simulation, a Monte Carlo simulation tool for physics, biology and clinical research.Phys Med. 2020;72: 114-121. doi: 10.1016 / j.ejmp.2020.03.019). The comparisons of the XY- plane are highly congruous as shown in Figure 3. In the XZ-plane, the collimated beam profile is depicted with some distortion due to the limited angle problem of reconstruction from a matrix array geometry.

[0073] Another issue for the translation of FLASH into the clinic concerns the dose conformity of individual pulses, needing a method to ensure accurate dose delivery to the target volume. When examining the individual pulses from the same location, fired in succession at FLASH dose rates, variation between pulse output can be shown. Consecutive individual pulses were reconstructed into volumetric dose deposition maps. Figure 4 depicts the variability between pulses, as captured by the RiAD system, thus demonstrating the real time 3D (4D) capabilities as well as capturing the small differences between individual pulses.

[0074] C. Towards in vivo dosimetry on animals

[0075] To show the feasibility of dose mapping in 3D with RiA signals during clinical FLASH RT, the same 256-element matrix array was used, coupled to an ex vivo rabbit chest with ultrasound gel. Adhering to the FLASH animal irradiation protocol, a 1.8 ps pulse width was used at 7 different distances, with 25 pulses of each combination acquired. At the 600 mm distance, FLASH and conventional RT were compared by varying the electron gun grid voltage. Examining the same SSD as highlighted for beam in water experiments, volumetric reconstructions from an individual pulse are depicted in Figure 5.

[0076] More particularly, Figure 5 illustrates the placement of the transducer on the rabbit chest. A 3D reconstruction of the 1.8 ps pulse width beam depositing in the rabbit chest at a SSD of 450 mm is shown. The maximum intensity projection of the XY plane depicts a similar beam penetration into the rabbit tissue as in water but with hot spots due to the heterogeneity.

[0077] As shown, the initial beam deposition maintains a low penetrating Gaussian shape in the XY plane with some hot spots due to tissue inhomogeneity. Irradiation of the rabbit chest area included irradiation of soft tissues, bones, muscles, and an air filled cavity, causing differences in the r / tlland p of the tissue. Variation in individual pulse distributions was depicted in ex vivo tissue as in water.

[0078] Consecutive generated RiA signals were reconstructed and variation in the volumetric dose distribution was observed in rabbit chest at the same distance as in water,depicted in Figure 6. More particularly, Figure 6 illustrates signals that were generated by the 1.8 ps pulse width beam depositing in the rabbit chest at a SSD of 450 mm. 3D reconstruction of signals from individual consecutive pulses are shown, demonstrating the feasibility of in vivo real-time monitoring and the ability to see variation in dose deposition from pulse to pulse. As shown, the variability between pulses was again demonstrated, with even more incongruity in tissue than in water, demonstrating both the need for real time volumetric monitoring of RT and the capability of RiAD to monitor radiotherapy in 4D.

[0079] DISCUSSIONS

[0080] A. Dose Linearity Study

[0081] Since RiAD shows promise as an in vivo radiation dosimeter, it is important to investigate whether it maintains linearity in the FLASH region, where most of the current radiation dosimeters become saturated. When examining the raw signals (e.g. Figure 2A), the proportional relationship between the dose and amplitude is prominent; when more dose is deposited, the RiA signal has a higher amplitude. This is in line with Equation 2 where the dose deposited is proportional to the generated initial pressure when thermal and stress confinement are met. As the distances decreases from 1 m to 470 mm, less electrons are lost to dispersion and thus more electrons are deposited in the water tank. More electrons deposited lead to a higher local temperature rise, and thus stronger RiA waves. In one experiment, the two extremes were utilized as well as values in between and in line with mouse experimental setups. The furthest SSD possible (1 m) and the closest (470 mm) SSD possible were characterized. FLASH-RT protocols performed on mice using the Oriatron LINAC typically implement a distance of 470 mm and a pulse width of 1.8 ps. The proportional relationship between the dose deposition and the peak to peak voltage of the resulting IA signal is also a linear one, as shown in Figures 2b, c. In Figure 2B, the peak-to-peak voltages of the IA signal are compared to the dose per pulse (Gy / pulse). The doses per pulse were varied from 0.28 Gy (28 cGy) to 4.95 Gy as measured by EBT3 film. To date, IA signal linearity in the FLASH regime has only been proven to the 25 cGy dose per pulse limit. In comparison, the present embodiments demonstrate linearity in the FLASH regime at higher doses per pulse that match the doses per pulse used in several biological experiments conducted with this linear accelerator. The linearity demonstrated by thepresent embodiments allows for real time, in vivo, volumetric dose deposition monitoring during in vivo FLASH experiments with the Oriatron eRT6 as well as clinical experiments where FLASH doses are delivered in single, high dose pulses.

[0082] In Figure 2B, as the distance and the dose rate decrease at the 1.8 pis pulse width, a linear relationship is observed with an R2value greater than 0.99. Similarly, in Figure 2C, the peak-to-peak voltages are compared to the instantaneous dose rate (Gy / s). Instantaneous dose rate independence is seen as the distance and a linear relationship is observed with R2values greater than 0.99. No saturation is expected as long as thermal and stress confinement are met within the tissue and the tunable gain ability of the hardware. Stress and thermal confinement will be met as long as the pulse width of the LINAC is shorter than the amount of time it takes for built up pressure to begin to dissipate or the characteristic length of heat heterogeneity in the sample to allow for heat dissipation; this has been shown to be less than the milliseconds scale and will thus be met for pre-clinical and clinical LINACs which utilize a pulse width on the microsecond. Furthermore, any possible signal saturation can be mitigated in the hardware; these measurements were amplified more than lOOx with a 40 dB preamplifier. The gain of the preamplifier could be reduced to minimize any saturation noticed, allowing for IA signals generated by higher doses per pulse to also be collected without any issue.

[0083] B, Volumetric Dosimetry for FLASH RT

[0084] Dosimetry for in vivo, in situ monitoring during FLASH RT is necessary for translation into the clinic. While 2D monitoring is possible with RiAD systems in real time using conventional irradiation and 2D imaging capabilities in FLASH RT, no single pulse 3D monitoring has been demonstrated in real time in situ. In Figure 3, 3D reconstructions from single pulses were completed, allowing for individual beam monitoring. As the beam deposits energy in the water tank, in the y-direction of the XY plane, the shallow penetration of the gaussian distributed low energy electron beam can be observed.

[0085] Utilizing TOPAS, the same experimental setup was modeled. When compared to the TOPAS-simulated beam penetration in the XY plane, we can see high congruity. However, when examining the dose deposition in the XZ plane, the collimated beam shape should be visible as shown by the dotted red line. Due to the orientation of the matrix array, as shown inFigure 1A, the XY plane, which is in a plane parallel to the array surface, has the only reconstruction that is not distorted. For the XY plane, due to the mechanism of the UBP reconstruction, there is a limited angle problem. For the beam edge closer to the transducer, located on the left side of the XZ plane in Figure 3, there is less distortion; a sharp bead edge is visible in the reconstruction. However, the second edge is highly distorted due to the orientation of the transducer.

[0086] Multiple matrix arrays can be utilized to minimize the limited view problem, with a second transducer matrix added in the XY plane for additional views for the reconstruction algorithm. The shallow penetration of dose deposition allows for transducers to be placed outside of the XY plane without fear of dose deposition occurring within the transducer itself and damaging it. Additionally, different reconstruction algorithms can be used to reduce the limited angle problem; utilizing deep learning, neural network based reconstruction algorithms can reduce distortion due to the limited angle problem in previous experiments in the lab (Id.). With this two-pronged approach to reduce the limited angle problem, accurate volumetric dose deposition monitoring is possible. Currently, single pulse volumetric beam monitoring with RiAD has been demonstrated in Figures 3-6. Figure 4 depicts the inhomogeneity in dose deposition between consecutive pulses, illustrating the natural variety between pulses, demonstrating the ability to perform individual pulse monitoring during FLASH RT with a RiAD system.

[0087] C. Towards in vivo dosimetry on animals

[0088] For clinical translation of RiAD monitoring and FLASH RT, dose monitoring must be possible in vivo, in heterogeneous tissue. In Figures 5 and 6, the capability of real time, individual pulse monitoring of dose deposition in 3D is demonstrated. In Figure 5, a rabbit chest was irradiated with the transducer in the XY plane again, coupled to the rabbit with ultrasound gel. In the XY maximum intensity projection shown, shallow deposition is seen, as expected. Differing from the gaussian distributed XY plane shown in Figure 3, the hot spots that exist in this reconstruction are due to the inhomogeneity of the medium - the area of the rabbit chest irradiated contained soft tissue, bone, air, and muscle. This change in medium changes the absorption factor, the electron stopping power, as well as the acoustic attenuation. This couldcreate areas with high deposition but also would change the speed of sound used for the reconstruction in different areas of the tissue. Toward this end, the 256-element matrix array can be used in conjunction with an ultrasound in a dual-modal system, allowing for the overlay of the beam deposition to explain the changes in dose deposition by understanding the underlying tissue being irradiated. Furthermore, prior CT imaging allows for different speeds of sound to be used in reconstruction, improving the accuracy of the dose deposition mapping. This is easily translatable to clinic as prior CT is done for treatment planning and would thus be readily available for input into the reconstruction algorithm geometry.

[0089] In Figure 6, variation between pulses is shown, with even more variation shown than in the water tank individual pulse reconstructions shown in Figure 4. Here, the ability of the RiAD system to be used for real time, in vivo, 3D pulse monitoring of consecutive FLASH RT pulses is demonstrated.

[0090] Figures 8 and 9 illustrate aspects of an alternative feasibility study of the present embodiments.

[0091] For example, as set forth above, the advantages of FLASH-RT are widely known but the lack of in vivo monitoring presents a challenge. In conventional radiotherapy, each individual pulse carries a tiny fraction of the overall prescribed dose. As long as the majority of pulses are the proper dose (mGy - cGy per pulse) and on target (occurring during the correct part of the respiratory cycle, with minimal tumor shrinkage and position change from the original planning CT), there is not much risk in one pulse straying from the ideal planned pulse. However, with hypo-fractionated delivery of FLASH pulses (Gy / pulse), precise delivery is necessary for each pulse.

[0092] As further set forth above, the present embodiments allow for in vivo monitoring of electron FLASH therapy with a RiAD system. In a study described in more detail in connection with Figures 8 and 9, the conformity of volumetric RiAD reconstructions is compared to the current golden standard - 2D film - and the localization of the dose map in vivo is demonstrated with 3 mice and their planning CTs. This demonstration enables clinical translation of FLASH radiotherapy as real-time, in situ 3D visualization of individual FLASH electron beam pulses in vivo.

[0093] Figure 8A demonstrates the setup of imaging FLASH electron beam (9MeV, IGy / pulse) in water with the 2 orientations of the matrix array (256-elements, 1MHz center frequency), imaging the dose deposition for 6 different collimators (1cm circle, 2cm circle, Ixlcm square, 2x2cm square, 1x3cm rectangle, and conformal shapes). Film measurements were taken from 0.2 to 1.4 cm into the water at 0.2 cm intervals for comparison to RiAD reconstructions. Figure 8B demonstrates the Icmxlcm square film at 1.2cm and the corresponding RiAD reconstruction, respectively. Gamma index analysis had a pass rate of 100% for 5mm / 5% and 97.22% for 3mm / 3% parameters. Figure 8C similarly demonstrates the 1cm diameter circle film measurement and the reconstruction at 1.2cm, respectively. Gamma index analysis had a pass rate of 99.58% for 5mm / 5% and 95.84% for 3mm / 3% parameters. Figure 8D demonstrates the lcmx3cm rectangle film at 1.2cm and the reconstruction, respectively. Gamma index analysis had a pass rate of 92.04% for 5mm / 5% and 70.49% for 3mm / 3% parameters.

[0094] Figure 9A demonstrates the setup of imaging the spatial distribution of FLASH electron beam (9MeV, IGy / pulse) for different collimators in vivo with the perpendicular orientation the matrix array (256-elements, 1MHz center frequency). Figure 9B elaborates on the 3D printed holder for the mice, made to ensure the mouse placement would be highly repeatable and aligned with the isocenter of the electron beam. Additionally, to ensure no radiation was deposited inside the matrix array, a layer of tissue-mimicking agar phantom was coupled in between the mice and the transducer surface. Figures 9C to 9G are an example of one of the mice used in the study. For example, Figure 9C shows the preliminary CT scan taken of each mouse in the 3D printed holder. Figures 10D and 10E demonstrate the reconstruction of the dose deposited by a Icmxlcm square field and a lcmx3cm rectangle, respectively. Figures 10F and 10G overlay the in vivo reconstructed dose deposition maps with the CT, aligned properly due to the fixed geometry of the holder.

[0095] CONCLUSIONS

[0096] The present Applicant has successfully demonstrated the feasibility of real-time 3D volumetric (4D) dosimetry from single pulses using a RiAD system during FLASH RT. This breakthrough enables the monitoring of spatial and temporal distributions of each individualFLASH beamlet during radiotherapy. With the present example detector system, concerns regarding unrecorded improper fractionation can be alleviated, paving the way for the clinical translation of FLASH technology. This advancement has the potential to greatly enhance the treatment experience and improve patient outcomes.

[0097] The herein described subject matter sometimes illustrates different components contained within, or connected with, different other components. It is to be understood that such depicted architectures are illustrative, and that in fact many other architectures can be implemented which achieve the same functionality. In a conceptual sense, any arrangement of components to achieve the same functionality is effectively "associated" such that the desired functionality is achieved. Hence, any two components herein combined to achieve a particular functionality can be seen as "associated with" each other such that the desired functionality is achieved, irrespective of architectures or intermedial components. Likewise, any two components so associated can also be viewed as being "operably connected," or "operably coupled," to each other to achieve the desired functionality, and any two components capable of being so associated can also be viewed as being "operably coupleable," to each other to achieve the desired functionality. Specific examples of operably coupleable include but are not limited to physically mateable and / or physically interacting components and / or wirelessly interactable and / or wirelessly interacting components and / or logically interacting and / or logically interactable components.

[0098] With respect to the use of plural and / or singular terms herein, those having skill in the art can translate from the plural to the singular and / or from the singular to the plural as is appropriate to the context and / or application. The various singular / plural permutations may be expressly set forth herein for sake of clarity.

[0099] It will be understood by those within the art that, in general, terms used herein, and especially in the appended claims (e.g., bodies of the appended claims) are generally intended as "open" terms (e.g., the term "including" should be interpreted as "including but not limited to," the term "having" should be interpreted as "having at least," the term "includes" should be interpreted as "includes but is not limited to," etc.).

[0100] Although the figures and description may illustrate a specific order of method steps, the order of such steps may differ from what is depicted and described, unless specified differently above. Also, two or more steps may be performed concurrently or with partial concurrence, unless specified differently above. Such variation may depend, for example, on the software and hardware systems chosen and on designer choice. All such variations are within the scope of the disclosure. Likewise, software implementations of the described methods could be accomplished with standard programming techniques with rule-based logic and other logic to accomplish the various connection steps, processing steps, comparison steps, and decision steps.

[0101] It will be further understood by those within the art that if a specific number of an introduced claim recitation is intended, such an intent will be explicitly recited in the claim, and in the absence of such recitation, no such intent is present. For example, as an aid to understanding, the following appended claims may contain usage of the introductory phrases "at least one" and "one or more" to introduce claim recitations. However, the use of such phrases should not be construed to imply that the introduction of a claim recitation by the indefinite articles "a" or "an" limits any particular claim containing such introduced claim recitation to inventions containing only one such recitation, even when the same claim includes the introductory phrases "one or more" or "at least one" and indefinite articles such as "a" or "an" (e.g., "a" and / or "an" should typically be interpreted to mean "at least one" or "one or more"); the same holds true for the use of definite articles used to introduce claim recitations. In addition, even if a specific number of an introduced claim recitation is explicitly recited, those skilled in the art will recognize that such recitation should typically be interpreted to mean at least the recited number (e.g., the bare recitation of "two recitations," without other modifiers, typically means at least two recitations, or two or more recitations).

[0102] Furthermore, in those instances where a convention analogous to "at least one of A, B, and C, etc." is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (e.g., "a system having at least one of A, B, and C" would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and / or A, B, and C together, etc.). In those instances where a convention analogous to "at least one of A, B, or C, etc." is used, in general, such a construction is intended in the sense one having skill in the art would understand theconvention (e.g., "a system having at least one of A, B, or C" would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and / or A, B, and C together, etc.). It will be further understood by those within the art that virtually any disjunctive word and / or phrase presenting two or more alternative terms, whether in the description, claims, or drawings, should be understood to contemplate the possibilities of including one of the terms, either of the terms, or both terms. For example, the phrase "A or B" will be understood to include the possibilities of "A" or "B" or "A and B."

[0103] Further, unless otherwise noted, the use of the words “approximate,” “about,” “around,” “substantially,” etc., mean plus or minus ten percent.

[0104] Although the present embodiments have been particularly described with reference to preferred examples thereof, it should be readily apparent to those of ordinary skill in the art that changes and modifications in the form and details may be made without departing from the spirit and scope of the present disclosure. It is intended that the appended claims encompass such changes and modifications.

Claims

WHAT IS CLAIMED IS:

1. A system for radiation therapy, comprising: a linear accelerator (LINAC) configured for radiating an object with a dose; a transducer array configured to capture acoustic signals from the object concurrently with the output of the beam; and a processor configured to generate an output that characterizes the dose.

2. The system of claim 1, wherein the system is configured for in vivo, in line, dose monitoring.

3. The system of claims 1 or 2, wherein the transducer array is coupled to the object with ultrasound gel.

4. The system of any of claims 1 to 3, wherein the output is configured for real-time beam tracking and dosimetry, enabling an end user to practice adaptive radiotherapy.

5. The system of claim 4, wherein the output enables the end user to ensure that proper dose delivery is occurring with each new beamlet and dose deposition.

6. The system of claim 4, wherein the adaptive radiotherapy is one of electron beam radiotherapy, electron FLASH radiotherapy, and intraoperative electron beam radiotherapy.

7. The system of claim 1, wherein the linear accelerator is configured for FLASH radiotherapy.

8. A method for radiation therapy, comprising: radiating an object with a dose using a linear accelerator (LINAC);capturing, using a transducer array, acoustic signals from the object concurrently with the output of the beam; and generating, by processing the acoustic signals, an output that characterizes the dose.

9. The method of claim 8, wherein the generating is configured for in vivo, in line, dose monitoring.

10. The method of claims 8 or 9, wherein the transducer array is coupled to the object with ultrasound gel.

11. The method of any of claims 8 to 10, wherein the output is configured for real-time beam tracking and dosimetry, enabling an end user to practice adaptive radiotherapy.

12. The method of claim 11, wherein the output enables the end user to ensure that proper dose delivery is occurring with each new beamlet and dose deposition.

13. The method of claim 11, wherein the adaptive radiotherapy is one of electron beam radiotherapy, electron FLASH radiotherapy, and intraoperative electron beam radiotherapy.

14. The method of claim 8, wherein the linear accelerator is configured for FLASH radiotherapy.

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