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.

Multi-stage image registration based on list-mode proton radiographies for small animal proton irradiation: A simulation study.

We present a multi-stage and multi-resolution deformable image registration framework for image-guidance at a small animal proton irradiation platform. The framework is based on list-mode proton radiographies acquired at different angles, which are used to deform a 3D treatment planning CT relying on normalized mutual information (NMI) or root mean square error (RMSE) in the projection domain. We utilized a mouse X-ray micro-CT expressed in relative stopping power (RSP), and obtained Monte Carlo simulations of proton images in list-mode for three different treatment sites (brain, head and neck, lung). Rigid transformations and controlled artificial deformation were applied to mimic position misalignments, weight loss and breathing changes. Results were evaluated based on the residual RMSE of RSP in the image domain including the comparison of extracted local features, i.e. between the reference micro-CT and the one transformed taking into account the calculated deformation. The residual RMSE of the RSP showed that the accuracy of the registration framework is promising for compensating rigid (>97% accuracy) and non-rigid (∼95% accuracy) transformations with respect to a conventional 3D-3D registration. Results showed that the registration accuracy is degraded when considering the realistic detector performance and NMI as a metric, whereas the RMSE in projection domain is rather insensitive. This work demonstrates the pre-clinical feasibility of the registration framework on different treatment sites and its use for small animal imaging with a realistic detector. Further computational optimization of the framework is required to enable the use of this tool for online estimation of the deformation.

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.

A Monte Carlo feasibility study on quantitative laser-driven proton radiography.

Laser-accelerated proton bunches with kinetic energies up to several tens of MeV and at repetition rates in the order of Hz are nowadays achievable at several research centres housing high-power laser system. The unique features of such ultra-short bunches are also arousing interest in the field of radiological and biomedical applications. For many of these applications, accurate positioning of the biological target is crucial, raising the need for on-site imaging. One convenient option is proton radiography, which can exploit the polyenergetic spectrum of laser-accelerated proton bunches. We present a Monte Carlo (MC) feasibility study to assess the applicability and potential of laser-driven proton radiography of millimetre to centimetre sized objects. Our radiography setup consists of a thin time-of-flight spectrometer operated in transmission prior to the object and a pixelated silicon detector for imaging. Proton bunches with kinetic energies up to 20MeV and up to 100MeV were investigated. The water equivalent thickness (WET) of the traversed material is calculated from the energy deposition inside an imaging detector, using an online generated calibration curve that is based on a MC generated look-up table and the reconstructed proton energy distribution. With a dose of 43mGy for a 1mm thin object imaged with protons up to 20MeV, the reconstructed WET of defined regions-of-interest was within 1.5% of the ground truth values. The spatial resolution, which strongly depends on the gap between object and imaging detector, was 2.5lpmm-1 for a realistic distance of 5mm. Due to this relatively high imaging dose, our proposed setup for laser-driven proton radiography is currently limited to objects with low radio-sensitivity, but possibilities for further dose reduction are presented and discussed.

Assessment of quantitative information for radiation therapy at a first-generation clinical photon-counting computed tomography scanner.

As one of the latest developments in X-ray computed tomography (CT), photon-counting technology allows spectral detection, demonstrating considerable advantages as compared to conventional CT. In this study, we investigated the use of a first-generation clinical photon-counting computed tomography (PCCT) scanner and estimated proton relative (to water) stopping power (RSP) of tissue-equivalent materials from virtual monoenergetic reconstructions provided by the scanner. A set of calibration and evaluation tissue-equivalent inserts were scanned at 120 kVp. Maps of relative electron density (RED) and effective atomic number (EAN) were estimated from the reconstructed virtual monoenergetic images (VMI) using an approach previously applied to a spectral CT scanner with dual-layer detector technology, which allows direct calculation of RSP using the Bethe-Bloch formula. The accuracy of RED, EAN, and RSP was evaluated by root-mean-square errors (RMSE) averaged over the phantom inserts. The reference RSP values were obtained experimentally using a water column in an ion beam. For RED and EAN, the reference values were calculated based on the mass density and the chemical composition of the inserts. Different combinations of low- and high-energy VMIs were investigated in this study, ranging from 40 to 190 keV. The overall lowest error was achieved using VMIs at 60 and 180 keV, with an RSP accuracy of 1.27% and 0.71% for the calibration and the evaluation phantom, respectively.

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.

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.

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.

Optimization and performance study of a proton CT system for pre-clinical small animal imaging.

Proton computed tomography (pCT) promises to reduce or even eliminate range uncertainties inherent in the conversion of Hounsfield units into relative stopping power (RSP) for proton therapy treatment planning. This is of particular interest for proton irradiation studies in animal models due to the high precision required and uncertainties in tissue properties. We propose a dedicated single-particle tracking pCT system consisting of low material budget floating strip Micromegas detectors for tracking and a segmented time-projection-chamber with vertical Mylar absorbers, functioning as a range telescope. Based on Monte Carlo simulations of a realistic in silico beam and detector implementation, a geometrical optimization of the system components was conducted to safeguard an ideal operation close to intrinsic performance limits at 75 MeV. Moreover, the overall imaging capabilities relevant for pre-clinical proton therapy treatment planning were evaluated for a mouse model. In order to minimize extrinsic uncertainties in the estimated proton trajectories, a spacing of the two tracking planes of at least 7 cm is required in both tracking detectors. Additionally, novel in-house developed and produced aluminum-based readout electrodes promise superior performance with around 3 mm-1 spatial resolution due to the reduced material budget. Concerning the range telescope, an absorber thickness within 500 µm to 750 µm was found to yield the best compromise between water-equivalent path length resolution and complexity of the detector instrumentation, still providing sub-0.5% RSP accuracy. The optimized detector configuration enables better than 2% range accuracy for proton therapy treatment planning in pre-clinical data sets. This work outlines the potential of pCT for small animal imaging. The performance of the proposed and optimized system provides superior treatment planning accuracy compared to conventional x-ray CT. Thus, pCT can play an important role in translational and pre-clinical cancer research.

A feasibility study of zebrafish embryo irradiation with laser-accelerated protons.

The development from single shot basic laser plasma interaction research toward experiments in which repetition rated laser-driven ion sources can be applied requires technological improvements. For example, in the case of radio-biological experiments, irradiation duration and reproducible controlled conditions are important for performing studies with a large number of samples. We present important technological advancements of recent years at the ATLAS 300 laser in Garching near Munich since our last radiation biology experiment. Improvements range from target positioning over proton transport and diagnostics to specimen handling. Exemplarily, we show the current capabilities by performing an application oriented experiment employing the zebrafish embryo model as a living vertebrate organism for laser-driven proton irradiation. The size, intensity, and energy of the laser-driven proton bunches resulted in evaluable partial body changes in the small (<1 mm) embryos, confirming the feasibility of the experimental system. The outcomes of this first study show both the appropriateness of the current capabilities and the required improvements of our laser-driven proton source for in vivo biological experiments, in particular the need for accurate, spatially resolved single bunch dosimetry and image guidance.

Gel dosimetry for three dimensional proton range measurements in anthropomorphic geometries.

Proton beams used for radiotherapy have potential for superior sparing of normal tissue, although range uncertainties are among the main limiting factors in the accuracy of dose delivery. The aim of this study was to benchmark an N-vinylpyrrolidone based polymer gel to perform three-dimensional measurement of geometric proton beam characteristics and especially to test its suitability as a range probe in combination with an anthropomorphic phantom. For single proton pencil beams as well as for 3×3cm2 mono-energy layers depth dose profiles, lateral dose distribution at different depths and proton range were evaluated in simple cubic gel phantoms at different energies from 75 to 115MeV and different dose levels. In addition, a 90MeV mono-energetic beam was delivered to an anthropomorphic 3D printed head phantom, which was filled with gel. Subsequently, all phantoms underwent magnetic resonance imaging using an axial pixel size of 0.68-0.98mm and with slice thicknesses of 2 or 3mm to derive a 3-dimensional distribution of the T2 relaxation time, which correlates with radiation dose. Indices describing lateral dose distribution and proton range were compared against predictions from a treatment planning system (TPS, for cubic and head phantoms) and Monte Carlo simulations (MC, for the head phantom) after manual rigid co-registration with the T2 relaxation time datasets. For all pencil beams, the FWHM agreement with TPS was better than 1mm or 7%. For the mono-energetic layer, the agreement with TPS in this respect was even better than 0.3mm in each case. With respect to range, results from gel measurements differed no more than 0.9mm (1.6%) from values predicted by TPS. In case of the anthropomorphic phantom, deviations with respect to a nominal range of about 61mm as well as in FWHM were slightly higher, namely within 1.0mm and 1.1mm respectively. Average deviations between gel and TPS/MC were similar (-0.3mm±0.4mm/-0.2±0.5mm). In conclusion, polymer gel dosimetry was found to be a valuable tool to determine geometric proton beam properties three-dimensionally and with high spatial resolution in simple cubic as well as in a more complex anthropomorphic phantom. Post registration range errors of the order of 1mm could be achieved. The additional registration uncertainty (95%) was 1mm.

I-BEAT: Ultrasonic method for online measurement of the energy distribution of a single ion bunch.

The shape of a wave carries all information about the spatial and temporal structure of its source, given that the medium and its properties are known. Most modern imaging methods seek to utilize this nature of waves originating from Huygens' principle. We discuss the retrieval of the complete kinetic energy distribution from the acoustic trace that is recorded when a short ion bunch deposits its energy in water. This novel method, which we refer to as Ion-Bunch Energy Acoustic Tracing (I-BEAT), is a refinement of the ionoacoustic approach. With its capability of completely monitoring a single, focused proton bunch with prompt readout and high repetition rate, I-BEAT is a promising approach to meet future requirements of experiments and applications in the field of laser-based ion acceleration. We demonstrate its functionality at two laser-driven ion sources for quantitative online determination of the kinetic energy distribution in the focus of single proton bunches.

AN ONLINE, RADIATION HARD PROTON ENERGY-RESOLVING SCINTILLATOR STACK FOR LASER-DRIVEN PROTON BUNCHES.

We report on a scintillator-based online detection system for the spectral characterization of polychromatic proton bunches. Using up to nine stacked layers of radiation hard polysiloxane scintillators, coupled to and readout edge-on by a large area pixelated CMOS detector, impinging polychromatic proton bunches were characterized. The energy spectra were reconstructed using calibration data and simulated using Monte-Carlo simulations. Despite the scintillator stack showed some problems like thickness inhomogeneities and unequal layer coupling, the prototype allows to obtain a first estimate of the energy spectrum of proton beams.

Time-of-flight spectrometry of ultra-short, polyenergetic proton bunches.

A common approach for spectrum determination of polyenergetic proton bunches from laser-ion acceleration experiments is based on the time-of-flight (TOF) method. However, spectra obtained using this method are typically given in relative units or are estimated based on some prior assumptions on the energy distribution of the accelerated ions. In this work, we present a new approach using the TOF method that allows for an absolute energy spectrum reconstruction from a current signal acquired with a sub-nanosecond fast and 10 µm thin silicon detector. The reconstruction is based on solving a linear least-squares problem, taking into account the response function of the detection system. The general principle of signal generation and spectrum reconstruction by setting up an appropriate system response matrix is presented. Proof-of-principle experiments at a 12 MV Tandem accelerator using different nanosecond-short (quasi-)monoenergetic and polyenergetic proton bunches at energies up to 20 MeV were successfully performed. Within the experimental uncertainties of 2.4% and 12.1% for energy and particle number, respectively, reconstructed energy distributions were found in excellent agreement with the spectra calculated using Monte Carlo simulations and measured by a magnetic spectrometer. This TOF method can hence be used for absolute online spectrometry of laser-accelerated particle bunches.

Application of single- and dual-energy CT brain tissue segmentation to PET monitoring of proton therapy.

The purpose of this work was to evaluate the ability of single and dual energy computed tomography (SECT, DECT) to estimate tissue composition and density for usage in Monte Carlo (MC) simulations of irradiation induced ß + activity distributions. This was done to assess the impact on positron emission tomography (PET) range verification in proton therapy. A DECT-based brain tissue segmentation method was developed for white matter (WM), grey matter (GM) and cerebrospinal fluid (CSF). The elemental composition of reference tissues was assigned to closest CT numbers in DECT space (DECTdist). The method was also applied to SECT data (SECTdist). In a validation experiment, the proton irradiation induced PET activity of three brain equivalent solutions (BES) was compared to simulations based on different tissue segmentations. Five patients scanned with a dual source DECT scanner were analyzed to compare the different segmentation methods. A single magnetic resonance (MR) scan was used for comparison with an established segmentation toolkit. Additionally, one patient with SECT and post-treatment PET scans was investigated. For BES, DECTdist and SECTdist reduced differences to the reference simulation by up to 62% when compared to the conventional stoichiometric segmentation (SECTSchneider). In comparison to MR brain segmentation, Dice similarity coefficients for WM, GM and CSF were 0.61, 0.67 and 0.66 for DECTdist and 0.54, 0.41 and 0.66 for SECTdist. MC simulations of PET treatment verification in patients showed important differences between DECTdist/SECTdist and SECTSchneider for patients with large CSF areas within the treatment field but not in WM and GM. Differences could be misinterpreted as PET derived range shifts of up to 4 mm. DECTdist and SECTdist yielded comparable activity distributions, and comparison of SECTdist to a measured patient PET scan showed improved agreement when compared to SECTSchneider. The agreement between predicted and measured PET activity distributions was improved by employing a brain specific segmentation applicable to both DECT and SECT data.