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Objective. Proton therapy is highly sensitive to range uncertainties due to the nature of the dose deposition of charged particles. To ensure treatment quality, range verification methods can be used to verify that the individual spots in a pencil beam scanning treatment fraction match the treatment plan. This study introduces a novel metric for proton therapy quality control based on uncertainties in range verification of individual spots. Approach. We employ uncertainty-aware deep neural networks to predict the Bragg peak depth in an anthropomorphic phantom based on secondary charged particle detection in a silicon pixel telescope designed for proton computed tomography. The subsequently predicted Bragg peak positions, along with their uncertainties, are compared to the treatment plan, rejecting spots which are predicted to be outside the 95% confidence interval. The such-produced spot rejection rate presents a metric for the quality of the treatment fraction. Main results. The introduced spot rejection rate metric is shown to be well-defined for range predictors with well-calibrated uncertainties. Using this method, treatment errors in the form of lateral shifts can be detected down to 1 mm after around 1400 treated spots with spot intensities of 1 × 107 protons. The range verification model used in this metric predicts the Bragg peak depth to a mean absolute error of 1.107 ± 0.015 mm. Significance. Uncertainty-aware machine learning has potential applications in proton therapy quality control. This work presents the foundation for future developments in this area. [ABSTRACT FROM AUTHOR]

Objective. The results of a follow-up experiment investigating a novel method for sub-milimetre range verification (RV) in proton therapy (PT) are presented. Approach. The method consists of implanting a hadron tumour marker (HTM) near the planned treatment volume, and measuring the γ -ray signals emitted as a result of activation by the proton beam. These signals are highly correlated with the energy of the beam impinging on the HTM and can provide an absolute measurement of the range of the beam relative to the position of the HTM, which is independent of any uncertainties in beam delivery. Main results. Three candidate HTM materials were identified and combined into a single composite HTM, which makes use of the strongest reaction in each material. The setup of the previous experiment was improved on by using high-purity germanium detectors to measure the γ -ray signal with a higher resolution than was previously achieved. A PMMA phantom was also used to simulate the γ -ray background from tissue activation. HTM RV using the data collected in this study yielded range measurements whose average deviation from the expected value was 0.13(22)mm. Significance. Range uncertainty in PT limits the prescribed treatment plan for cancer patients with large safety margins and constrains the direction of the proton beam in relation to any organ at risk. The sub-milimetre range uncertainty achieved in this study using HTM RV, if implemented clinically, would allow for a reduction in the size of safety margins, increasing the therapeutic window for PT. [ABSTRACT FROM AUTHOR]

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 for in situ range 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 of σ = 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. [ABSTRACT FROM AUTHOR]

Objective. Beams of stable ions have been a well-established tool for radiotherapy for many decades. In the case of ion beam therapy with stable 12C ions, the positron emitters 10,11C are produced via projectile and target fragmentation, and their decays enable visualization of the beam via positron emission tomography (PET). However, the PET activity peak matches the Bragg peak only roughly and PET counting statistics is low. These issues can be mitigated by using a short-lived positron emitter as a therapeutic beam. Approach. An experiment studying the precision of the measurement of ranges of positron-emitting carbon isotopes by means of PET has been performed at the FRS fragment-separator facility of GSI Helmholtzzentrum für Schwerionenforschung GmbH, Germany. The PET scanner used in the experiment is a dual-panel version of a Siemens Biograph mCT PET scanner. Main results. High-quality in-beam PET images and activity distributions have been measured from the in-flight produced positron emitting isotopes 11C and 10C implanted into homogeneous PMMA phantoms. Taking advantage of the high statistics obtained in this experiment, we investigated the time evolution of the uncertainty of the range determined by means of PET during the course of irradiation, and show that the uncertainty improves with the inverse square root of the number of PET counts. The uncertainty is thus fully determined by the PET counting statistics. During the delivery of 1.6 × 107 ions in 4 spills for a total duration of 19.2 s, the PET activity range uncertainty for 10C, 11C and 12C is 0.04 mm, 0.7 mm and 1.3 mm, respectively. The gain in precision related to the PET counting statistics is thus much larger when going from 11C to 10C than when going from 12C to 11C. The much better precision for 10C is due to its much shorter half-life, which, contrary to the case of 11C, also enables to include the in-spill data in the image formation. Significance. Our results can be used to estimate the contribution from PET counting statistics to the precision of range determination in a particular carbon therapy situation, taking into account the irradiation scenario, the required dose and the PET scanner characteristics. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective. In carbon ion therapy, the visualization of the range of incident particles in a patient body is important for treatment verification. In-beam positron emission tomography (PET) imaging is one of the methods to verify the treatment in ion therapy due to the high quality of PET images. We have shown the feasibility of in-beam PET imaging of radioactive 15O and 11C ion beams for range verification using our OpenPET system. Recently, we developed a whole gamma imager (WGI) that can simultaneously work as PET, single gamma ray and triple gamma ray imaging. The WGI has high potential to detect the location of 10C, which emits positrons with a simultaneous gamma ray of 718 keV, within the patient’s body during ion therapy. Approach. In this work, we focus on investigating the performance of WGI for 10C imaging and its feasibility for range verification in carbon ion therapy. First, the performance of the WGI was studied to image a 10C point source using the Geant4 toolkit. Then, the feasibility of WGI was investigated for an irradiated polymethyl methacrylate (PMMA) phantom with a 10C ion beam at the carbon therapy facility of the Heavy Ion Medical Accelerator in Chiba. Main results. The average spatial resolution and sensitivity for the simulated 10C point source at the centre of the field of view were 5.5 mm FWHM and 0.010%, respectively. The depth dose of the 10C ion beam was measured, and the triple gamma image of 10C nuclides for an irradiated PMMA phantom was obtained by applying a simple back projection to the detected triple gammas. Significance. The shift between Bragg peak position and position of the peak of the triple gamma image in an irradiated PMMA phantom was 2.8 ± 0.8 mm, which demonstrates the capability of triple gamma imaging using WGI for range verification of 10C ion beams. [ABSTRACT FROM AUTHOR]

Objective : To present a long short-term memory (LSTM)-based prompt gamma (PG) emission prediction method for proton therapy. Approach : Computed tomography (CT) scans of 33 patients with a prostate tumor were included in the dataset. A set of 10 7 histories proton pencil beam (PB)s was generated for Monte Carlo (MC) dose and PG simulation. For training (20 patients) and validation (3 patients), over 6000 PBs at 150, 175 and 200 MeV were simulated. 3D relative stopping power (RSP), PG and dose cuboids that included the PB were extracted. Three models were trained, validated and tested based on an LSTM-based network: (1) input RSP and output PG, (2) input RSP with dose and output PG (single-energy), and (3) input RSP/dose and output PG (multi-energy). 540 PBs at each of the four energy levels (150, 175, 200, and 125-210 MeV) were simulated across 10 patients to test the three models. The gamma passing rate (2%/2 mm) and PG range shift were evaluated and compared among the three models. Results : The model with input RSP/dose and output PG (multi-energy) showed the best performance in terms of gamma passing rate and range shift metrics. Its mean gamma passing rate of testing PBs of 125-210 MeV was 98.5% and the worst case was 92.8%. Its mean absolute range shift between predicted and MC PGs was 0.15 mm, where the maximum shift was 1.1 mm. The prediction time of our models was within 130 ms per PB. Significance : We developed a sub-second LSTM-based PG emission prediction method. Its accuracy in prostate patients has been confirmed across an extensive range of proton energies., (Creative Commons Attribution license.)

Objective . To compare in reproducible and equalized conditions the performance of two independent proton range verification systems based on prompt gamma-ray detectors from two different proton therapy centers. Approach . An anthropomorphic head phantom with calibrated stopping power, serving as ground truth, was irradiated with comparable treatment plans, spot positions and energies in both facilities. Clinical beam current, tumor contour and dose were used. The absolute range measurement was compared to the expected value according to the ground truth. The statistical precision was assessed by repeating each measurement ten times. Sensitivity to relative range shifts was evaluated by introducing 2 mm and 5 mm plastic slabs on half of the field. Main results . The resulting absolute range accuracy was within 2.4 mm in all cases. Relative range shifts were detected with deviations lower than 14%. Significance . The performance of both systems was deemed worthy of clinical application for the detection of range deviations. This study represents the first comparison of independent prompt gamma-ray-based proton range verification systems under equalized conditions with realistic treatment fields and beam currents., (Creative Commons Attribution license.)

Objective. Compton camera imaging shows promise as a range verification technique in proton therapy. This work aims to assess the performance of a machine learning model in Compton camera imaging for proton beam range verification improvement. Approach. The presented approach was used to recognize Compton events and estimate more accurately the prompt gamma (PG) energy in the Compton camera to reconstruct the PGs emission profile during proton therapy. This work reports the results obtained from the Geant4 simulation for a proton beam impinging on a polymethyl methacrylate (PMMA) target. To validate the versatility of such an approach, the produced PG emissions interact with a scintillating fiber-based Compton camera. Main results. A trained multilayer perceptron (MLP) neural network shows that it was possible to achieve a notable three-fold increase in the signal-to-total ratio. Furthermore, after event selection by the trained MLP, the loss of full-energy PGs was compensated by means of fitting an MLP energy regression model to the available data from true Compton (signal) events, predicting more precisely the total deposited energy for Compton events with incomplete energy deposition. Significance. A considerable improvement in the Compton camera's performance was demonstrated in determining the distal falloff and identifying a few millimeters of target displacements. This approach has shown great potential for enhancing online proton range monitoring with Compton cameras in future clinical applications., (Creative Commons Attribution license.)

Objective. Prompt-gamma imaging encompasses several approaches to the online monitoring of the beam range or deposited dose distribution in proton therapy. We test one of the imaging techniques - a coded mask approach - both experimentally and via simulations. Approach. Two imaging setups have been investigated experimentally. Each of them comprised a structured tungsten collimator in the form of a modified uniformly redundant array mask and a LYSO:Ce scintillation detector of fine granularity. The setups differed in detector dimensions and operation mode (1D or 2D imaging). A series of measurements with radioactive sources have been conducted, testing the performance of the setups for near-field gamma imaging. Additionally, Monte Carlo simulations of a larger setup of the same type were conducted, investigating its performance with a realistic gamma source distribution occurring during proton therapy. Main results. The images of point-like sources reconstructed from two small-scale prototypes' data using the maximum-likelihood expectation maximisation algorithm constitute the experimental proof of principle for the near-field coded-mask imaging modality, both in the 1D and the 2D mode. Their precision allowed us to calibrate out certain systematic offsets appearing due to the limited alignment accuracy of setup elements. The simulation of the full-scale setup yielded a mean distal falloff retrieval precision of 0.72 mm in the studies for beam energy range 89.5-107.9 MeV and with 1 × 10 8 protons (a typical number for distal spots). The implemented algorithm of image reconstruction is relatively fast-a typical procedure needs several seconds. Significance. Coded-mask imaging appears a valid option for proton therapy monitoring. The results of simulations let us conclude that the proposed full-scale setup is competitive with the knife-edge-shaped and the multi-parallel slit cameras investigated by other groups., (Creative Commons Attribution license.)

Objective. We designed a geometrical solution for a small animal in-beam positron emission tomography (PET) scanner to be used in the project SIRMIO (Small animal proton irradiator for research in molecular image-guided radiation-oncology). The system is based on 56 scintillator blocks of pixelated LYSO crystals. The crystals are arranged providing a pyramidal-step shape to optimize the geometrical coverage in a spherical configuration. Approach. Different arrangements have been simulated and compared in terms of spatial resolution and sensitivity. The chosen setup enables us to reach a good trade-off between a solid angle coverage and sufficient available space for the integration of additional components of the first design prototype of the SIRMIO platform. The possibility of moving the mouse holder inside the PET scanner furthermore allows for achieving the optimum placement of the irradiation area for all the possible tumor positions in the body of the mouse. The work also includes a study of the scintillator material where LYSO and GAGG are compared with a focus on the random coincidence noise due to the natural radioactivity of Lutetium in LYSO, justifying the choice of LYSO for the development of the final system. Main results. The best imaging performance can be achieved with a sub-millimeter spatial resolution and sensitivity of 10% in the center of the scanner, as verified in thorough simulations of point sources. The simulation of realistic irradiation scenarios of proton beams in PMMA targets with/without air gaps indicates the ability of the proposed PET system to detect range shifts down to 0.2 mm. Significance. The presented results support the choice of the identified optimal design for a novel spherical in-beam PET scanner which is currently under commissioning for application to small animal proton and light ion irradiation, and which might find also application, e.g. for biological image-guidance in x-ray irradiation., (Creative Commons Attribution license.)

Objective. A new method to estimate the range of an ion beam in a patient during heavy-ion therapy was investigated, which was previously verified for application in proton therapy. Approach. The method consists of placing a hadron tumour marker (HTM) close to the tumour. As the treatment beam impinges on the HTM, the marker undergoes nuclear reactions. When the HTM material is carefully chosen, the activation results in the emission of several delayed, characteristic γ rays, whose intensities are correlated with the remaining range inside the patient. When not just one but two reaction channels are investigated, the ratio between these two γ ray emissions can be measured, and the ratio is independent of any beam delivery uncertainties. Main results. A proof-of-principle experiment with an 16 O ion beam and Ag foils as HTM was successfully executed. The 107 Ag( 16 O, x ) 112 Sb and the 107 Ag( 16 O, x ) 114 Sb reaction channels were identified as suitable for the HTM technique. When only one γ -ray emission is measured, the resulting range-uncertainty estimation is at the 0.5 mm scale. When both channels are considered, a theoretical limit on the range uncertainty of a clinical fiducal marker was found to be ±290 μ m. Significance. Range uncertainty of a heavy-ion beam limits the prescribed treatment plan for cancer patients, especially the direction of the ion beam in relation to any organ at risk. An easy to implement range-verification technique which can be utilized during clinical treatment would allow treatment plans to take full advantage of the sharp fall-off of the Bragg peak without the risk of depositing excessive dose into healthy tissue., (Creative Commons Attribution license.)

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 investigated in-silico for 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 located in-silico with an accuracy better than 90 μ m (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 quantified in-silico and experimentally., (Creative Commons Attribution license.)

Objective. Proton therapy as the next generation radiation-based cancer therapy offers dominant advantages over conventional radiation therapy due to the utilization of the Bragg peak; however, range uncertainty in beam delivery substantially mitigates the advantages of proton therapy. This work reports using protoacoustic measurements to determine the location of proton Bragg peak deposition within a water phantom in real time during beam delivery. Approach. In protoacoustics, proton beams have a definitive range, depositing a majority of the dose at the Bragg peak; this dose is then converted to heat. The resulting thermoelastic expansion generates a 3D acoustic wave, which can be detected by acoustic detectors to localize the Bragg peak. Main results. Protoacoustic measurements were performed with a synchrocyclotron proton machine over the exhaustive energy range from 45.5 to 227.15 MeV in clinic. It was found that the amplitude of the acoustic waves is proportional to proton dose deposition, and therefore encodes dosimetric information. With the guidance of protoacoustics, each individual proton beam (7 pC/pulse) can be directly visualized with sub-millimeter (<0.7 mm) resolution using single beam pulse for the first time. Significance. The ability to localize the Bragg peak in real-time and obtain acoustic signals proportional to dose within tumors could enable precision proton therapy and hope to progress towards in vivo measurements., (© 2023 Institute of Physics and Engineering in Medicine.)