Range verification of a clinical proton beam in an abdominal phantom by co-registration of ionoacoustics and ultrasound.

Objective.The range uncertainty in proton radiotherapy is a limiting factor to achieve optimum dose conformity to the tumour volume. Ionoacoustics is a promising approach forin siturange verification, which would allow to reduce the size of the irradiated volume relative to the tumour volume. The energy deposition of a pulsed proton beam leads to an acoustic pressure wave (ionoacoustics), the detection of which allows conclusion about the distance between the Bragg peak and the acoustic detector. This information can be transferred into a co-registered ultrasound image, marking the Bragg peak position relative to the surrounding anatomy.Approach.A CIRS 3D abdominal phantom was irradiated with 126 MeV protons at a clinical proton therapy centre. Acoustic signals were recorded on the beam axis distal to the Bragg peak with a Cetacean C305X hydrophone. The ionoacoustic measurements were processed with a correlation filter using simulated filter templates. The hydrophone was rigidly attached to an ultrasound device (Interson GP-C01) recording ultrasound images of the irradiated region.Main results.The time of flight obtained from ionoacoustic measurements were transferred to an ultrasound image by means of an optoacoustic calibration measurement. The Bragg peak position was marked in the ultrasound image with a statistical uncertainty ofσ= 0.5 mm of 24 individual measurements depositing 1.2 Gy at the Bragg peak. The difference between the evaluated Bragg peak position and the one obtained from irradiation planning (1.0 mm) is smaller than the typical range uncertainty (≈4 mm) at the given penetration depth (10 cm).Significance.The measurements show that it is possible to determine the Bragg peak position of a clinical proton beam with submillimetre precision and transfer the information to an ultrasound image of the irradiated region. The dose required for this is smaller than that used for a typical irradiation fraction.

On the robustness of multilateration of ionoacoustic signals for localization of the Bragg peak at pre-clinical proton beam energies in water.

Objectives.The energy deposited in a medium by a pulsed proton beam results in the emission of thermoacoustic waves, also called ionoacoustics (IA). The proton beam stopping position (Bragg peak) can be retrieved from a time-of-flight analysis (ToF) of IA signals acquired at different sensor locations (multilateration). This work aimed to assess the robustness of multilateration methods in proton beams at pre-clinical energies for the development of a small animal irradiator.Approach.The accuracy of multilateration performed using different algorithms; namely, time of arrival and time difference of arrival, was investigatedin-silicofor ideal point sources in the presence of realistic uncertainties on the ToF estimation and ionoacoustic signals generated by a 20 MeV pulsed proton beam stopped in a homogeneous water phantom. The localisation accuracy was further investigated experimentally based on two different measurements with pulsed monoenergetic proton beams at energies of 20 and 22 MeV.Main results.It was found that the localisation accuracy mainly depends on the position of the acoustic detectors relative to the proton beam due to spatial variation of the error on the ToF estimation. By optimally positioning the sensors to reduce the ToF error, the Bragg peak could be locatedin-silicowith an accuracy better than 90µm (2% error). Localisation errors going up to 1 mm were observed experimentally due to inaccurate knowledge of the sensor positions and noisy ionoacoustic signals.Significance.This study gives a first overview of the implementation of different multilateration methods for ionoacoustics-based Bragg peak localisation in two- and three-dimensions at pre-clinical energies. Different sources of uncertainty were investigated, and their impact on the localisation accuracy was quantifiedin-silicoand experimentally.

On the potential biological impact of radiation-induced acoustic emissions during ultra-high dose rate electron radiotherapy: a preliminary study.

Ionizing radiation pulses delivered at ultra-high dose rates in emerging FLASH radiotherapy can result in high-intensity low-frequency thermoacoustic emissions that may have a biological impact. This study aims at providing insights into the thermoacoustic emissions expected during FLASH radiotherapy and their likelihood of inducing acoustic cavitation. The characteristics of acoustic waves induced by the energy deposition of a pulsed electron beam similar to previous pre-clinical FLASH radiotherapy studies and their propagation in murine head-like phantoms are investigated in-silico. The results show that the generated pressures are sufficient to produce acoustic cavitation due to resonance in the irradiated object. It suggests that thermoacoustics may, in some irradiation scenarios, contribute to the widely misunderstood FLASH effect or cause adverse effects if not taken into account at the treatment planning stage.

Proton beam range verification by means of ionoacoustic measurements at clinically relevant doses using a correlation-based evaluation.

Purpose: The Bragg peak located at the end of the ion beam range is one of the main advantages of ion beam therapy compared to X-Ray radiotherapy. However, verifying the exact position of the Bragg peak within the patient online is a major challenge. The goal of this work was to achieve submillimeter proton beam range verification for pulsed proton beams of an energy of up to 220 MeV using ionoacoustics for a clinically relevant dose deposition of typically 2 Gy per fraction by i) using optimal proton beam characteristics for ionoacoustic signal generation and ii) improved signal detection by correlating the signal with simulated filter templates. Methods: A water tank was irradiated with a preclinical 20 MeV proton beam using different pulse durations ranging from 50 ns up to 1 µs in order to maximise the signal-to-noise ratio (SNR) of ionoacoustic signals. The ionoacoustic signals were measured using a piezo-electric ultrasound transducer in the MHz frequency range. The signals were filtered using a cross correlation-based signal processing algorithm utilizing simulated templates, which enhances the SNR of the recorded signals. The range of the protons is evaluated by extracting the time of flight (ToF) of the ionoacoustic signals and compared to simulations from a Monte Carlo dose engine (FLUKA). Results: Optimised SNR of 28.0 ± 10.6 is obtained at a beam current of 4.5 µA and a pulse duration of 130 ns at a total peak dose deposition of 0.5 Gy. Evaluated ranges coincide with Monte Carlo simulations better than 0.1 mm at an absolute range of 4.21 mm. Higher beam energies require longer proton pulse durations for optimised signal generation. Using the correlation-based post-processing filter a SNR of 17.8 ± 5.5 is obtained for 220 MeV protons at a total peak dose deposition of 1.3 Gy. For this clinically relevant dose deposition and proton beam energy, submillimeter range verification was achieved at an absolute range of 303 mm in water. Conclusion: Optimal proton pulse durations ensure an ideal trade-off between maximising the ionoacoustic amplitude and minimising dose deposition. In combination with a correlation-based post-processing evaluation algorithm, a reasonable SNR can be achieved at low dose levels putting clinical applications for online proton or ion beam range verification into reach.

Fabrication and characterization of a multimodal 3D printed mouse phantom for ionoacoustic quality assurance in image-guided pre-clinical proton radiation research.

Objective.Image guidance and precise irradiation are fundamental to ensure the reliability of small animal oncology studies. Accurate positioning of the animal and the in-beam monitoring of the delivered radio-therapeutic treatment necessitate several imaging modalities. In the particular context of proton therapy with a pulsed beam, information on the delivered dose can be retrieved by monitoring the thermoacoustic waves resulting from the brief and local energy deposition induced by a proton beam (ionoacoustics). The objective of this work was to fabricate a multimodal phantom (x-ray, proton, ultrasound, and ionoacoustics) allowing for sufficient imaging contrast for all the modalities.Approach.The phantom anatomical parts were extracted from mouse computed tomography scans and printed using polylactic acid (organs) and a granite/polylactic acid composite (skeleton). The anatomical pieces were encapsulated in silicone rubber to ensure long term stability. The phantom was imaged using x-ray cone-beam computed tomography, proton radiography, ultrasound imaging, and monitoring of a 20 MeV pulsed proton beam using ionoacoustics.Main results.The anatomical parts could be visualized in all the imaging modalities validating the phantom capability to be used for multimodal imaging. Ultrasound images were simulated from the x-ray cone-beam computed tomography and co-registered with ultrasound images obtained before the phantom irradiation and low-resolution ultrasound images of the mouse phantom in the irradiation position, co-registered with ionoacoustic measurements. The latter confirmed the irradiation of a tumor surrogate for which the reconstructed range was found to be in reasonable agreement with the expectation.Significance.This study reports on a realistic small animal phantom which can be used to investigate ionoacoustic range (or dose) verification together with ultrasound, x-ray, and proton imaging. The co-registration between ionoacoustic reconstructions of the impinging proton beam and x-ray imaging is assessed for the first time in a pre-clinical scenario.

Investigating the accuracy of co-registered ionoacoustic and ultrasound images in pulsed proton beams.

The sharp spatial and temporal dose gradients of pulsed ion beams result in an acoustic emission (ionoacoustics), which can be used to reconstruct the dose distribution from measurements at different positions. The accuracy of range verification from ionoacoustic images measured with an ultrasound linear array configuration is investigated both theoretically and experimentally for monoenergetic proton beams at energies relevant for pre-clinical studies (20 and 22 MeV). The influence of the linear sensor array arrangement (length up to 4 cm and number of elements from 5 to 200) and medium properties on the range estimation accuracy are assessed using time-reversal reconstruction. We show that for an ideal homogeneous case, the ionoacoustic images enable a range verification with a relative error lower than 0.1%, however, with limited lateral dose accuracy. Similar results were obtained experimentally by irradiating a water phantom and taking into account the spatial impulse response (geometry) of the acoustic detector during the reconstruction of pressures obtained by moving laterally a single-element transducer to mimic a linear array configuration. Finally, co-registered ionoacoustic and ultrasound images were investigated using silicone inserts immersed in the water phantom across the proton beam axis. By accounting for the sensor response and speed of sound variations (deduced from co-registration with ultrasound images) the accuracy is improved to a few tens of micrometers (relative error less than to 0.5%), confirming the promise of ongoing developments for ionoacoustic range verification in pre-clinical and clinical proton therapy applications.

Enhancement of the ionoacoustic effect through ultrasound and photoacoustic contrast agents.

The characteristic depth dose deposition of ion beams, with a maximum at the end of their range (Bragg peak) allows for local treatment delivery, resulting in better sparing of the adjacent healthy tissues compared to other forms of external beam radiotherapy treatments. However, the optimal clinical exploitation of the favorable ion beam ballistic is hampered by uncertainties in the in vivo Bragg peak position. Ionoacoustics is based on the detection of thermoacoustic pressure waves induced by a properly pulsed ion beam (e.g., produced by modern compact accelerators) to image the irradiated volume. Co-registration between ionoacoustics and ultrasound imaging offers a promising opportunity to monitor the ion beam and patient anatomy during the treatment. Nevertheless, the detection of the ionoacoustic waves is challenging due to very low pressure amplitudes and frequencies (mPa/kHz) observed in clinical applications. We investigate contrast agents to enhance the acoustic emission. Ultrasound microbubbles are used to increase the ionoacoustic frequency around the microbubble resonance frequency. Moreover, India ink is investigated as a possible mean to enhance the signal amplitude by taking advantage of additional optical photon absorption along the ion beam and subsequent photoacoustic effect. We report amplitude increase of up to 200% of the ionoacoustic signal emission in the MHz frequency range by combining microbubbles and India ink contrast agents.

Towards a novel small animal proton irradiation platform: the SIRMIO project.

Background: Precision small animal radiotherapy research is a young emerging field aiming to provide new experimental insights into tumor and normal tissue models in different microenvironments, to unravel complex mechanisms of radiation damage in target and non-target tissues and assess efficacy of novel therapeutic strategies. For photon therapy, modern small animal radiotherapy research platforms have been developed over the last years and are meanwhile commercially available. Conversely, for proton therapy, which holds potential for an even superior outcome than photon therapy, no commercial system exists yet. Material and methods: The project SIRMIO (Small Animal Proton Irradiator for Research in Molecular Image-guided Radiation-Oncology) aims at realizing and demonstrating an innovative portable prototype system for precision image-guided small animal proton irradiation, suitable for installation at existing clinical treatment facilities. The proposed design combines precise dose application with in situ multi-modal anatomical image guidance and in vivo verification of the actual treatment delivery. Results and conclusions: This manuscript describes the status of the different components under development, featuring a dedicated beamline for degradation and focusing of clinical proton beams, along with novel detector systems for in situimaging and range verification. The foreseen workflow includes pre-treatment proton transmission imaging, complemented by ultrasonic tumor localization, for treatment planning and position verification, followed by image-guided delivery with on site range verification by means of ionoacoustics (for pulsed beams) and positron-emission-tomography (PET, for continuous beams). The proposed compact and cost-effective system promises to open a new era in small animal proton therapy research, contributing to the basic understanding of in vivo radiation action to identify areas of potential breakthroughs for future translation into innovative clinical strategies.