Proton Range Research Articles

Analysis of characteristics of images acquired with a prototype clinical proton radiography system.

Verification of patient-specific proton stopping powers obtained in the patient's treatment position can be used to reduce the distal and proximal margins needed in particle beam planning. Proton radiography can be used as a pretreatment instrument to verify integrated stopping power consistency with the treatment planning CT. Although a proton radiograph is a pixel by pixel representation of integrated stopping powers, the image may also be of high enough quality and contrast to be used for patient alignment. This investigation quantifies the accuracy and image quality of a prototype proton radiography system on a clinical proton delivery system. We have developed a clinical prototype proton radiography system designed for integration into efficient clinical workflows. We tested the images obtained by this system for water-equivalent thickness (WET) accuracy, image noise, and spatial resolution. We evaluated the WET accuracy by comparing the average WET and rms error in several regions of interest (ROI) on a proton radiograph of a custom peg phantom. We measured the spatial resolution on a CATPHAN Line Pair phantom and a custom edge phantom by measuring the 10% value of the modulation transfer function (MTF). In addition, we tested the ability to detect proton range errors due to anatomical changes in a patient with a customized CIRS pediatric head phantom and inserts of varying WET placed in the posterior fossae of the brain. We took proton radiographs of the phantom with each insert in place and created difference maps between the resulting images. Integrated proton range was measured from an ROI in the difference maps. We measured the WET accuracy of the proton radiographic images to be ±0.2mm (0.33%) from known values. The spatial resolution of the images was 0.6lp/mm on the line pair phantom and 1.13lp/mm on the edge phantom. We were able to detect anatomical changes producing changes in WET as low as 0.6mm. The proton radiography system produces images with image quality sufficient for pretreatment range consistency verification.

Analog Filters Design for Improving Precision in Proton Sound Detectors

This paper analyzes how to improve the precision of ionoacoustic proton range verification by optimizing the analog signal processing stages with particular emphasis on analog filters. The ionoacoustic technique allows one to spatially detect the proton beam penetration depth/range in a water absorber, with interesting possible applications in real-time beam monitoring during hadron therapy treatments. The state of the art uses nonoptimized detectors that have low signal quality and thus require a higher total dose, which is not compatible with clinical applications. For these reasons, a comprehensive analysis of acoustic signal bandwidth, signal-to-noise-ratio and noise power/bandwidth will be presented. The correlation between these signal-quality parameters with maximum achievable proton range measurement precision will be discussed. In particular, the use of an optimized analog filter allows one to decrease the dose required to achieve a given precision by as much as 98.4% compared to a nonoptimized filter approach.

Modulating ultrasound contrast generation from injectable nanodroplets for proton range verification by varying the degree of superheat.

Despite the physical benefits of protons over conventional photon radiation in cancer treatment, range uncertainties impede the ability to harness the full potential of proton therapy. While monitoring the proton range in vivo could reduce the currently adopted safety margins, a routinely applicable range verification technique is still lacking. Recently, phase-change nanodroplets were proposed for proton range verification, demonstrating a reproducible relationship between the proton range and generated ultrasound contrast after radiation-induced vaporization at 25°C. In this study, previous findings are extended with proton irradiations at different temperatures, including the physiological temperature of 37°C, for a novel nanodroplet formulation. Moreover, the potential to modulate the linear energy transfer (LET) threshold for vaporization by varying the degree of superheat is investigated, where the aim is to demonstrate vaporization of nanodroplets directly by primary protons. Perfluorobutane nanodroplets with a shell made of polyvinyl alcohol (PVA-PFB) or 10,12-pentacosadyinoic acid (PCDA-PFB) were dispersed in polyacrylamide hydrogels and irradiated with 62MeV passively scattered protons at temperatures of 37°C and 50°C. Nanodroplet transition into echogenic microbubbles was assessed using ultrasound imaging (gray value and attenuation analysis) and optical images. The proton range was measured independently and compared to the generated contrast. Nanodroplet design proved crucial to ensure thermal stability, as PVA-shelled nanodroplets dramatically outperformed their PCDA-shelled counterpart. At body temperature, a uniform radiation response proximal to the Bragg peak is attributed to nuclear reaction products interacting with PVA-PFB nanodroplets, with the 50% drop in ultrasound contrast being 0.17mm±0.20mm (mean±standard deviation) in front of the proton range. Also at 50°C, highly reproducible ultrasound contrast profiles were obtained with shifts of -0.74mm±0.09mm (gray value analysis), -0.86mm±0.04mm (attenuation analysis) and -0.64mm±0.29mm (optical analysis). Moreover, a strong contrast enhancement was observed near the Bragg peak, suggesting that nanodroplets were sensitive to primary protons. By varying the degree of superheat of the nanodroplets' core, one can modulate the intensity of the generated ultrasound contrast. Moreover, a submillimeter reproducible relationship between the ultrasound contrast and the proton range was obtained, either indirectly via the visualization of secondary reaction products or directly through the detection of primary protons, depending on the degree of superheat. The potential of PVA-PFB nanodroplets for in vivo proton range verification was confirmed by observing a reproducible radiation response at physiological temperature, and further studies aim to assess the nanodroplets' performance in a physiological environment. Ultimately, cost-effective online or offline ultrasound imaging of radiation-induced nanodroplet vaporization could facilitate the reduction of safety margins in treatment planning and enable adaptive proton therapy.

Fluence-modulated proton CT optimized with patient-specific dose and variance objectives for proton dose calculation

Particle therapy treatment planning requires accurate volumetric maps of the relative stopping power, which can directly be acquired using proton computed tomography (pCT). With fluence-modulated pCT (FMpCT) imaging fluence is concentrated in a region-of-interest (ROI), which can be the vicinity of the treatment beam path, and imaging dose is reduced elsewhere. In this work we present a novel optimization algorithm for FMpCT which, for the first time, calculates modulated imaging fluences for joint imaging dose and image variance objectives. Thereby, image quality is maintained in the ROI to ensure accurate calculations of the treatment dose, and imaging dose is minimized outside the ROI with stronger minimization penalties given to imaging organs-at-risk. The optimization requires an initial scan at uniform fluence or a previous x-ray CT scan. We simulated and optimized FMpCT images for three pediatric patients with tumors in the head region. We verified that the target image variance inside the ROI was achieved and demonstrated imaging dose reductions outside of the ROI of 74% on average, reducing the imaging dose from 1.2 to 0.3 mGy. Such dose savings are expected to be relevant compared to the therapeutic dose outside of the treatment field. Treatment doses were re-calculated on the FMpCT images and compared to treatment doses re-recalculated on uniform fluence pCT scans using a 1% criterion. Passing rates were above 98.3% for all patients. Passing rates comparing FMpCT treatment doses to the ground truth treatment dose were above 88.5% for all patients. Evaluation of the proton range with a 1 mm criterion resulted in passing rates above 97.5% (FMpCT/pCT) and 95.3% (FMpCT/ground truth). Jointly optimized fluence-modulated pCT images can be used for proton dose calculation maintaining the full dosimetric accuracy of pCT but reducing the required imaging dose considerably by three quarters. This may allow for daily imaging during particle therapy ensuring a safe and accurate delivery of the therapeutic dose and avoiding excess dose from imaging.

Investigating high-energy proton-induced reactions on spherical nuclei: Implications for the preequilibrium exciton model

Background: A number of accelerator-based isotope production facilities utilize 100- to 200-MeV proton beams due to the high production rates enabled by high-intensity beam capabilities and the greater diversity of isotope production brought on by the long range of high-energy protons. However, nuclear reaction modeling at these energies can be challenging because of the interplay between different reaction modes and a lack of existing guiding cross-section data.Purpose: A Tri-lab collaboration has been formed among the Lawrence Berkeley, Los Alamos, and Brookhaven National Laboratories to address these complexities by characterizing charged-particle nuclear reactions relevant to the production of established and novel radioisotopes.Method: In the inaugural collaboration experiments, stacked-targets of niobium foils were irradiated at the Brookhaven Linac Isotope Producer (${E}_{p}=200\phantom{\rule{0.28em}{0ex}}\mathrm{MeV}$) and the Los Alamos Isotope Production Facility (${E}_{p}=100\phantom{\rule{0.28em}{0ex}}\mathrm{MeV}$) to measure $^{93}\mathrm{Nb}(p,x)$ cross sections between 50 and 200 MeV. First measurements of the $^{93}\mathrm{Nb}(p,4n)^{90}\mathrm{Mo}$ beam monitor reaction beyond 100 MeV are reported in this work, as part of the broadest energy-spanning dataset for the reaction to date. $^{93}\mathrm{Nb}(p,x)$ production cross sections are additionally reported for 22 other measured residual products. The measured cross-section results were compared with literature data as well as the default calculations of the nuclear model codes TALYS, CoH, EMPIRE, and ALICE.Results: The default code predictions largely failed to reproduce the measurements, with consistent underestimation of the preequilibrium emission. Therefore, we developed a standardized procedure that determines the reaction model parameters that best reproduce the most prominent reaction channels in a physically justifiable manner. The primary focus of the procedure was to determine the best parametrization for the preequilibrium two-component exciton model via a comparison to the energy-dependent $^{93}\mathrm{Nb}(p,x)$ data, as well as previously published $^{139}\mathrm{La}(p,x)$ cross sections.Conclusions: This modeling study revealed a trend toward a relative decrease for internal transition rates at intermediate proton energies (${E}_{p}=20$--60 MeV) in the current exciton model as compared to the default values. The results of this work are instrumental for the planning, execution, and analysis essential to isotope production.

CBCT-Based Adaptive Assessment Workflow for Intensity Modulated Proton Therapy for Head and Neck Cancer.

PurposeAnatomical changes and patient setup uncertainties during intensity modulated proton therapy (IMPT) of head and neck (HN) cancers demand frequent evaluation of delivered dose. This work investigated a cone-beam computed tomography (CBCT) and deformable image registration based therapy workflow to demonstrate the feasibility of proton dose calculation on synthetic computed tomography (sCT) for adaptive IMPT treatment of HN cancer.Materials and MethodsTwenty-one patients with HN cancer were enrolled in this study, a retrospective institutional review board protocol. They had previously been treated with volumetric modulated arc therapy and had daily iterative CBCT. For each patient, robust optimization (RO) IMPT plans were generated using ±3 mm patient setup and ±3% proton range uncertainties. The sCTs were created and the weekly delivered dose was recalculated using an adaptive dose accumulation workflow in which the planning computed tomography (CT) was deformably registered to CBCTs and Hounsfield units transferred from the planning CT. Accumulated doses from ±3 mm/±3% RO-IMPT plans were evaluated using clinical dose-volume constraints for targets (clinical target volume, or CTV) and organs at risk.ResultsEvaluation of weekly recalculated dose on sCTs showed that most of the patient plans maintained target dose coverage. The primary CTV remained covered by the V95 > 95% (95% of the volume receiving more than 95% of the prescription dose) worst-case scenario for 84.5% of the weekly fractions. The oral cavity accumulated mean dose remained lower than the worst-case scenario for all patients. Parotid accumulated mean dose remained within the uncertainty bands for 18 of the 21 patients, and all were kept lower than RO-IMPT worst-case scenario for 88.7% and 84.5% for left and right parotids, respectively.ConclusionThis study demonstrated that RO-IMPT plans account for most setup and anatomical uncertainties, except for large weight-loss changes that need to be tracked throughout the treatment course. We showed that sCTs could be a powerful decision tool for adaptation of these cases in order to reduce workload when using repeat CTs.

Feasibility of using megavoltage computed tomography to reduce proton range uncertainty: A simulation study.

PurposeTo demonstrate that variation in chemical composition has a negligible effect on the mapping curve from relative electron density (RED) to proton stopping power ratio (SPR), and to establish the theoretical framework of using Megavoltage (MV) computed tomography (CT), instead of kilovoltage (kV) dual energy CT, to accurately estimate proton SPR.MethodsA simulation study was performed to evaluate the effect of chemical composition variation on kVCT number and proton SPR. The simulation study involved both reference and simulated human tissues. The reference human tissues, together with their physical densities and chemical compositions, came from the ICRP publication 23. The simulated human tissues were created from the reference human tissues assuming that elemental percentage weight followed a Gaussian distribution. For all tissues, kVCT number and proton SPR were obtained through (a) theoretical calculation from tissue’s physical density and chemical composition which served as the ground truth, and (b) estimation from RED using the calibration curves established from the stoichiometric method. Deviations of the estimated values from the calculated values were quantified as errors in using RED to estimate kVCT number and proton SPR.ResultsGiven a chemical composition variation of 5% (1σ) of the nominal percentage weights, the total estimation error of using RED to estimate kVCT number was 0.34%, 0.62%, and 0.77% and the total estimation error of using RED to estimate proton SPR was 0.30%, 0.22%, and 0.16% for fat tissues, non‐fat soft tissues and bone tissues, respectively.ConclusionChemical composition had a negligible effect on the method of using RED to determine proton SPR. RED itself is sufficient to accurately determine proton SPR. MVCT number maintains a superb linear relationship with RED because it is highly dominated by Compton scattering. Therefore, MVCT has great potential in reducing the proton range uncertainty.

Accounting for prompt gamma emission and detection for range verification in proton therapy treatment planning

Prompt gamma (PG) imaging is widely investigated as one of the most promising methods for proton range verification in proton therapy. The performance of this technique is affected by several factors like tissue heterogeneity, number of protons in the considered pencil beam and the detection device. Our previous work proposed a new treatment planning concept which boosts the number of protons of a few PG monitoring-friendly pencil beams (PBs), selected on the basis of two proposed indicators quantifying the conformity between the dose and PG at the emission level, above the desired detectability threshold. To further explore this method at the detection level, in this work we investigated the response of a knife-edge slit PG camera which was deployed in the first clinical application of PG to proton therapy monitoring. The REGistration Graphical User Interface (REGGUI) is employed to simulate the PG emission, PG detection as well as the corresponding dose distribution. As the PG signal detected by this kind of PG camera is sensitive to the relative position of the camera and PG signal falloff, we optimized our PB selection method for this camera by introducing a new camera position indicator identifying whether the expected falloff of the PG signal is centered in the field of view of the camera or not. Our camera-adapted PB selection method is investigated using computed tomography (CT) scans at two different treatment time points of a head and neck, and a prostate cancer patient under scenarios considering different statistics level. The results show that a precision of 0.8 mm for PG falloff identification can be achieved when a PB has more than 2 × 108 primary protons. Except for one case due to unpredictable and comparably large anatomical changes, the PG signals of most of the PBs recommended by all our indicators are observed to be reliable for proton range verification with deviations between the inter-fractional shift of proton range (as deduced from the PB dose distribution) and the detected PG signal within 2.0 mm. In contrast, a shift difference up to 9.6 mm has been observed for the rejected PBs. The magnitude of the proton range shift due to the inter-fractional anatomical changes is observed to be up to 23 mm. The proposed indicators are shown to be valuable for identifying and recommending reliable PBs to create new PG monitoring-friendly TPs. Comparison between our PB boosting method and the alternative PB aggregation, which combines the signal of nearby PBs to reach the desired counting statistics, is also discussed.

Denoising PET images for proton therapy using a residual U-net

The use of proton therapy has the advantage of high dose concentration as it is possible to concentrate the dose on the tumor while suppressing damage to the surrounding normal organs. However, the range uncertainty significantly affects the actual dose distribution in the vicinity of the proton range, limiting the benefit of proton therapy for reducing the dose to normal organs. By measuring the annihilation gamma rays from the produced positron emitters, it is possible to obtain a proton induced positron emission tomography (pPET) image according to the irradiation region of the proton beam. Smoothing with a Gaussian filter is generally used to denoise PET images; however, this approach lowers the spatial resolution. Furthermore, other conventional smoothing processing methods may deteriorate the steep region of the pPET images. In this study, we proposed a denoising method based on a Residual U-Net for pPET images. We conducted the Monte Carlo simulation and irradiation experiment on a human phantom to obtain pPET data. The accuracy of the range estimation and the image similarity were evaluated for pPET images using the Residual U-Net, a Gaussian filter, a median filter, the block-matching and 3D-filtering (BM3D), and a total variation (TV) filter. Usage of the Residual U-Net yielded effective results corresponding to the range estimation; however, the results of peak-signal-to-noise ratio were identical to those for the Gaussian filter, median filter, BM3D, and TV filter. The proposed method can contribute to improving the accuracy of treatment verification and shortening the PET measurement time.

Measuring prompt gamma-ray emissions from elements found in tissue during passive-beam proton therapy

Prompt gamma detection during proton radiotherapy for range verification purposes will need to operate in both active and passive treatment beam environments. This paper describes prompt gamma measurements using a high resolution 2″ × 2″ LaBr3 detector for a 200 MeV clinical passive-scatter proton beam. These measurements examine the most likely discrete prompt gamma rays emitted from tissue by detecting gammas produced in water, Perspex, carbon and liquid-nitrogen targets. Measurements were carried out at several positions around the depth corresponding to the location of the Bragg peak for water and Perspex targets in order to investigate prompt gamma emission as a function of depth along the beam path. This work also focused on validating the Geant4 Monte Carlo model of the passive-scatter proton beam line and LaBr3 detector by making a direct comparison between the simulated and experimental results. The initial prompt gamma measurements were overwhelmed by the high amount of scattered radiation when measuring at isocenter, shifting the target further downstream from the final collimator significantly reduced the background radiation. Prompt gamma peaks were then clearly identified for the water, Perspex and graphite targets. The developed Geant4 Monte Carlo model was able to replicate the measured prompt gamma ray energy spectra, including production for important photopeaks to within 10%, except for the 4.44 MeV peak from the water target, which had more than a 50% overestimation of the number of produced prompt gamma rays. The prompt gamma measurements at various depths correlated well with the proton dose deposition; the 4.44 and 6.13 MeV photopeak profiles peaked within 1 cm of the Bragg peak and the R50% value for the 3–7 MeV energy range predicted the proton range within 8 mm.

Direct proton range verification using oxygen-18 enriched water as a contrast agent

We propose the use of 18O-enriched water as a suitable contrast agent for potential in-vivo range verification in proton therapy. The low energy production threshold of 18F (2.6 MeV, proton range in water of 115 μm) leads to tissue activation in very close proximity to the maximum dose deposition, facilitating accurate range verification with off-line PET imaging.This idea has been explored in a phantom experiment. A 3D-printed phantom containing inserts with 18O-enriched water was irradiated with a 100-MeV, 8 × 8 cm2 proton beam, and the induced activity was measured with a small-animal PET-CT 30 min after irradiation. The images obtained were compared against Monte Carlo simulation using TOPAS.Good agreement was observed between reconstructed and simulated activity profiles (within 40% for specific 18F activity), with excellent spatial match to the simulated dose deposition. Because of the long half-life of 18F, the specific activity of the contrast agent could be separated and was clearly observed for more than 2 h after irradiation. Activity distribution maps were used to determine the position of the Bragg peak within 2 mm for three different regions of interest. These results show the potential of 18O-enriched water as a contrast agent in proton therapy.

An improved centroid localization algorithm based on acoustic for proton range verification

The proton beam generates a unique acoustic signal, which can be used for range verification. It is a crucial issue to use the acoustic signal for accurate positioning. The propagation of sound waves emitted by a proton pulse(20 MeV, 1 × 107protons) is simulated, and acoustic signals are recorded. The distance between sensors and Bragg Peak is calculated by the time of arrival and speed of sound. An improved centroid localization algorithm based on trilateration is presented to locate the Bragg Peak with the distance. After evaluating the verification accuracy of different methods, the results show that this algorithm significantly improves the verification accuracy.

Dictionary-based protoacoustic dose map imaging for proton range verification

Proton radiotherapy has the potential to provide state-of-the-art dose conformality in the tumor area, reducing possible adverse effects on surrounding organs at risk. However, uncertainties in the exact location of the proton Bragg peak inside the patient prevent this technique from achieving full clinical potential. In this context, in vivo verification of the range of protons in patients is key to reduce uncertainty margins. Protoacoustic range verification employs acoustic pressure waves generated by protons due to the radio-induced thermoacoustic effect to reconstruct the dose deposited in a patient during proton therapy. In this paper, we propose to use the a priori knowledge of the shape of the proton dose distribution to create a dictionary with the expected ultrasonic signals at predetermined detector locations. Using this dictionary, the reconstruction of deposited dose is performed by matching pre-calculated dictionary acoustic signals with data acquired online during treatment.The dictionary method was evaluated on a single-field proton plan for a prostate cancer patient. Dose calculation was performed with the open-source treatment planning system matRad, while acoustic wave propagation was carried out with k-Wave. We studied the ability of the proposed dictionary method to detect range variations caused by anatomical changes in tissue density, and alterations of lateral and longitudinal beam position.Our results show that the dictionary-based protoacoustic method was able to identify the changes in range originated by all the alterations introduced, with an average accuracy of 1.4 mm. This procedure could be used for in vivo verification, comparing the measured signals with the precalculated dictionary.

Particle-Tracking Proton Computed Tomography-Data Acquisition, Preprocessing, and Preconditioning.

Proton CT (pCT) is a promising new imaging technique that can reconstruct relative stopping power (RSP) more accurately than x-ray CT in each cubic millimeter voxel of the patient. This, in turn, will result in better proton range accuracy and, therefore, smaller planned tumor volumes (PTV). The hardware description and some reconstructed images have previously been reported. In a series of two contributions, we focus on presenting the software algorithms that convert pCT detector data to the final reconstructed pCT images for application in proton treatment planning. There were several options on how to accomplish this, and we will describe our solutions at each stage of the data processing chain. In the first paper of this series, we present the data acquisition with the pCT tracking and energy-range detectors and how the data are preprocessed, including the conversion to the well-formatted track information from tracking data and water-equivalent path length from the data of a calibrated multi-stage energy-range detector. These preprocessed data are then used for the initial image formation with an FDK cone-beam CT algorithm. The output of data acquisition, preprocessing, and FDK reconstruction is presented along with illustrative imaging results for two phantoms, including a pediatric head phantom. The second paper in this series will demonstrate the use of iterative solvers in conjunction with the superiorization methodology to further improve the images resulting from the upfront FDK image reconstruction and the implementation of these algorithms on a hybrid CPU/GPU computer cluster.

A prototype of pCT scanner: first tests

Proton therapy technique for cancer treatment offers a high selectivity with respect to conventional radiotherapy with X- and γ-rays due to the properties of the interaction of protons with matter. Very accurate and precise treatment plans and a good control on the dose deposition are required to exploit the full potential of the technique. The substitution of the currently used X-ray Computed Tomography (xCT) by proton Computed Tomography (pCT) in the design of treatment plans would allow for a reduction in proton range uncertainties. This would make possible an important improvement in the accuracy and precision of treatment plans. With this aim, a prototype of pCT scanner is under study. It includes two tracking detectors which provide information on the proton trajectories and a residual energy detector to determine the energy loss while traversing the object scanned. A proof-of-concept experiment has been performed using low-energy protons and a simplified prototype with only the two tracking detectors. The results obtained in the measurement are presented and discussed.

Towards the experimental validation of a small Time-Projection-Chamber for the quasi-absolute measurement of the fission cross section

To accurately measure neutron-induced fission cross sections, to characterize neutron-beam lines or to make dosimetric investigations, it is necessary to have high accuracy measurements of neutron fluence. It is possible to perform independent and precise neutron flux measurements with respect to the 1H(n,n)p elastic scattering cross section. The use of a silicon detector is recommended from 1 to 70 MeV neutron energy. However, it has been observed that a high electrons background forbids its use below 1 MeV. Hence, a new gaseous proton-recoil telescope is developed and characterized to overcome this limit. It should provide quasi-absolute neutron flux measurements with an accuracy around 3% and is not sensible to gamma and electrons background. It consists in two ionization chambers read by a segmented micromegas technology detection plane. The gas pressure inside is adjustable to the proton range in the detector and therefore to the neutron energy. This detector is described in details below and the newest results of its characterization are presented. A special attention is paid to detection efficiency measurements.

Assessment of daily dose accumulation for robustly optimized intensity modulated proton therapy treatment of prostate cancer.

To implement a daily CBCT based dose accumulation technique in order to assess ideal robust optimization (RO) parameters for IMPT treatment of prostate cancer. Ten prostate cancer patients previously treated with VMAT and having daily CBCT were included. First, RO-IMPT plans were created with±3mm and±5mm patient setup and±3% proton range uncertainties, respectively. Second, the planning CT (pCT) was deformably registered to the CBCT to create a synthetic CT (sCT). Both daily and weekly sampling strategies were employed to determine optimal dose accumulation frequency. Doses were recalculated on sCTs for both±3mm/±3% and±5mm/±3% uncertainties and were accumulated back to the pCT. Accumulated doses generated from±3mm/±3% and±5mm/±3% RO-IMPT plans were evaluated using the clinical dose volume constraints for CTV, bladder, and rectum. Daily accumulated dose based on both±3mm/±3% and±5mm/±3% uncertainties for RO-IMPT plans resulted in satisfactory CTV coverage (RO-IMPT3mm/3% CTVV95=99.01±0.87% vs. RO-IMPT5mm/3% CTVV95=99.81±0.2%, P=0.002). However, the accumulated dose based on±3mm/3% RO-IMPT plans consistently provided greater OAR sparing than±5mm/±3% RO-IMPT plans (RO-IMPT3mm/3% rectumV65Gy=2.93±2.39% vs. RO-IMPT5mm/3% rectumV65Gy=4.38±3%, P<0.01; RO-IMPT3mm/3% bladderV65Gy=5.2±7.12% vs. RO-IMPT5mm/3% bladderV65Gy=7.12±9.59%, P<0.01). The gamma analysis showed high dosimetric agreement between weekly and daily accumulated dose distributions. This study demonstrated that for RO-IMPT optimization, ±3mm/±3% uncertainty is sufficient to create plans that meet desired CTV coverage while achieving superior sparing to OARs when compared with±5mm/±3% uncertainty. Furthermore, weekly dose accumulation can accurately estimate the overall dose delivered to prostate cancer patients.

Variance-based sensitivity analysis for uncertainties in proton therapy: A framework to assess the effect of simultaneous uncertainties in range, positioning, and RBE model predictions on RBE-weighted dose distributions.

Treatment plans in proton therapy are more sensitive to uncertainties than in conventional photon therapy. In addition to setup uncertainties, proton therapy is affected by uncertainties in proton range and relative biological effectiveness (RBE). While to date a constant RBE of 1.1 is commonly assumed, the actual RBE is known to increase toward the distal end of the spread-out Bragg peak. Several models for variable RBE predictions exist. We present a framework to evaluate the combined impact and interactions of setup, range, and RBE uncertainties in a comprehensive, variance-based sensitivity analysis (SA). The variance-based SA requires a large number (104 -105 ) of RBE-weighted dose (RWD) calculations. Based on a particle therapy extension of the research treatment planning system CERR we implemented a fast, graphics processing unit (GPU) accelerated pencil beam modeling of patient and range shifts. For RBE predictions, two biological models were included: The mechanistic repair-misrepair-fixation (RMF) model and the phenomenological Wedenberg model. All input parameters (patient position, proton range, RBE model parameters) are sampled simultaneously within their assumed probability distributions. Statistical formalisms rank the input parameters according to their influence on the overall uncertainty of RBE-weighted dose-volume histogram (RW-DVH) quantiles and the RWD in every voxel, resulting in relative, normalized sensitivity indices (S=0: noninfluential input, S=1: only influential input). Results are visualized as RW-DVHs with error bars and sensitivity maps. The approach is demonstrated for two representative brain tumor cases and a prostate case. The full SA including RWD calculations took 39, 11, and 55min, respectively. Range uncertainty was an important contribution to overall uncertainty at the distal end of the target, while the relatively smaller uncertainty inside the target was governed by biological uncertainties. Consequently, the uncertainty of the RW-DVH quantile D98 for the target was governed by range uncertainty while the uncertainty of the mean target dose was dominated by the biological parameters. The SA framework is a powerful and flexible tool to evaluate uncertainty in RWD distributions and DVH quantiles, taking into account physical and RBE uncertainties and their interactions. The additional information might help to prioritize research efforts to reduce physical and RBE uncertainties and could also have implications for future approaches to biologically robust planning and optimization.

Ultra-fast prompt gamma detection in single proton counting regime for range monitoring in particle therapy

In order to fully exploit the ballistic potential of particle therapy, we propose an online range monitoring concept based on time-of-flight (TOF)-resolved prompt gamma (PG) detection in a single proton counting regime. In a proof of principle experiment, different types of monolithic scintillating gamma detectors are read in time coincidence with a diamond-based beam hodoscope, in order to build TOF spectra of PG generated in a target presenting an air cavity of variable thickness. Since the measurement was carried out at low beam currents (< 1 proton/bunch) it was possible to reach excellent coincidence time resolutions, of the order of 100 ps (σ). Our goal is to detect possible deviations of the proton range with respect to treatment planning within a few intense irradiation spots at the beginning of the session and then carry on the treatment at standard beam currents. The measurements were limited to 10 mm proton range shift. A Monte Carlo simulation study reproducing the experiment has shown that a 3 mm shift can be detected at 2σ by a single detector of ∼1.4 × 10−3 absolute detection efficiency within a single irradiation spot (∼108 protons) and an optimised experimental set-up.

A proof-of-concept study of an in-situ partial-ring time-of-flight PET scanner for proton beam verification.

Development of a PET system capable of in-situ imaging requires a design that can accommodate the proton treatment beam nozzle. Among the several PET instrumentation approaches developed thus far, the dual-panel PET scanner is often used as it is simpler to develop and integrate within the proton therapy gantry. Partial-angle coverage of these systems can however lead to limited-angle artefacts in the reconstructed PET image. We have previously demonstrated via simulations that time-of-flight (TOF) reconstruction reduces the artifacts accompanying limited-angle data, and permits proton range measurement with 1-2 mm accuracy and precision. In this work we show measured results from a small proof-of-concept dual-panel PET system that uses TOF information to reconstruct PET data acquired after proton irradiation. The PET scanner comprises of two detector modules, each comprised of an array of 4×4×30 mm3 lanthanum bromide scintillator. Measurements are performed with an oxygen-rich gel-water, an adipose tissue equivalent material, and in vitro tissue phantoms. For each phantom measurement, 2 Gy dose was deposited using 54 - 100 MeV proton beams. For each phantom, a Monte Carlo simulation generating the expected distribution of PET isotope from the corresponding proton irradiation was also performed. Proton range was calculated by drawing multiple depth-profiles over a central region encompassing the proton dose deposition. For each profile, proton range was calculated using two techniques (a) 50% pick-off from the distal edge of the profile, and (b) comparing the measured and Monte Carlo profile to minimize the absolute sum of differences over the entire profile. A 10 min PET acquisition acquired with minimal delay post proton-irradiation is compared with a 10 min PET scan acquired after a 20 min delay. Measurements show that PET acquisition with minimal delay is necessary to collect 15O signal, and maximize 11C signal collection with a short PET acquisition. In comparison with the 50% pick-off technique, the shift technique is more robust and offers better precision in measuring the proton range for the different phantoms. Range measurements from PET images acquired with minimal delay, and the shift technique demonstrate the ability to achieve <1.5 mm accuracy and precision in estimating proton range.