Two-dimensional time-resolved scintillating sheet monitoring of proton pencil beam scanning FLASH mouse irradiations.

BACKGROUND: Dosimetry in pre-clinical FLASH studies is essential for understanding the beam delivery conditions that trigger the FLASH effect. Resolving the spatial and temporal characteristics of proton pencil beam scanning (PBS) irradiations with ultra-high dose rates (UHDR) requires a detector with high spatial and temporal resolution. PURPOSE: To implement a novel camera-based system for time-resolved two-dimensional (2D) monitoring and apply it in vivo during pre-clinical proton PBS mouse irradiations. METHODS: Time-resolved 2D beam monitoring was performed with a scintillation imaging system consisting of a 1 mm thick transparent scintillating sheet, imaged by a CMOS camera. The sheet was placed in a water bath perpendicular to a horizontal PBS proton beam axis. The scintillation light was reflected through a system of mirrors and captured by the camera with 500 frames per second (fps) for UHDR and 4 fps for conventional dose rates. The raw images were background subtracted, geometrically transformed, flat field corrected, and spatially filtered. The system was used for 2D spot and field profile measurements and compared to radiochromic films. Furthermore, spot positions were measured for UHDR irradiations. The measured spot positions were compared to the planned positions and the relative instantaneous dose rate to equivalent fiber-coupled point scintillator measurements. For in vivo application, the scintillating sheet was placed 1 cm upstream the right hind leg of non-anaesthetized mice submerged in the water bath. The mouse leg and sheet were both placed in a 5 cm wide spread-out Bragg peak formed from the mono-energetic proton beam by a 2D range modulator. The mouse leg position within the field was identified for both conventional and FLASH irradiations. For the conventional irradiations, the mouse foot position was tracked throughout the beam delivery, which took place through repainting. For FLASH irradiations, the delivered spot positions and relative instantaneous dose rate were measured. RESULTS: The pixel size was 0.1 mm for all measurements. The spot and field profiles measured with the scintillating sheet agreed with radiochromic films within 0.4 mm. The standard deviation between measured and planned spot positions was 0.26 mm and 0.35 mm in the horizontal and vertical direction, respectively. The measured relative instantaneous dose rate showed a linear relation with the fiber-coupled scintillator measurements. For in vivo use, the leg position within the field varied between mice, and leg movement up to 3 mm was detected during the prolonged conventional irradiations. CONCLUSIONS: The scintillation imaging system allowed for monitoring of UHDR proton PBS delivery in vivo with 0.1 mm pixel size and 2 ms temporal resolution. The feasibility of instantaneous dose rate measurements was demonstrated, and the system was used for validation of the mouse leg position within the field.

Oxygen Enhancement Ratio-Weighted Dose Quantitatively Describes Acute Skin Toxicity Variations in Mice After Pencil Beam Scanning Proton FLASH Irradiation With Changing Doses and Time Structures.

PURPOSE: The aim of this work was to investigate the ability of a biological oxygen enhancement ratio-weighted dose, DOER, to describe acute skin toxicity variations observed in mice after proton pencil beam scanning irradiations with changing doses and beam time structures. METHODS AND MATERIALS: In five independent experiments, the right hind leg of a total of 621 CDF1 mice was irradiated previously in the entrance plateau of a pencil beam scanning proton beam. The incidence of acute skin toxicity (of level 1.5-2.0-2.5-3.0-3.5) was scored for 47 different mouse groups that mapped toxicity as function of dose for conventional and FLASH dose rate, toxicity as function of field dose rate with and without repainting, and toxicity when splitting the treatment into 1 to 6 identical deliveries separated by 2 minutes. DOER was calculated for all mouse groups using a simple oxygen kinetics model to describe oxygen depletion. The three independent model parameters (oxygen-depletion rate, oxygen-recovery rate, oxygen level without irradiation) were fitted to the experimental data. The ability of DOER to describe the toxicity variations across all experiments was investigated by comparing DOER-response curves across the five independent experiments. RESULTS: After conversion from the independent variable tested in each experiment to DOER, all five experiments had similar MDDOER50 (DOER giving 50% toxicity incidence) with standard deviations of 0.45 - 1.6 Gy for the five toxicity levels. DOER could thus describe the observed toxicity variations across all experiments. CONCLUSIONS: DOER described the varying FLASH-sparing effect observed for a wide range of conditions. Calculation of DOER for other irradiation conditions can quantitatively estimate the FLASH-sparing effect for arbitrary irradiations for the investigated murine model. With appropriate fitting parameters DOER also may be able to describe FLASH effect variations with dose and dose rate for other assays and endpoints.

Determination of intrinsic energy dependence of point-like inorganic scintillation detector in brachytherapy.

BACKGROUND: Inorganic scintillation detectors (ISDs) are promising for in vivo dosimetry in brachytherapy (BT). ISDs have fast response, providing time resolved dose rate information, and high sensitivity, attributed to high atomic numbers. However, the conversion of the detector signal to absorbed dose-to-water is highly dependent on the energy spectrum of the incident radiation. This dependence is comprised of absorbed dose energy dependence, obtainable with Monte Carlo (MC) simulation, and the absorbed dose-to-signal conversion efficiency or intrinsic energy dependence requiring measurements. Studies have indicated negligible intrinsic energy dependence of ZnSe:O-based ISDs in Ir-192 BT. A full characterization has not been performed earlier. PURPOSE: This study characterizes the intrinsic energy dependence of ZnSe:O-based ISDs for kV X-ray radiation qualities, with energies relevant for BT. METHODS: Three point-like ISDs made from fiber-coupled cuboid ZnSe:O-based scintillators were calibrated at the Swedish National Metrology Laboratory for ionizing radiation. The calibration was done in terms of air kerma free-in-air, Kair , in 13 X-ray radiation qualities, Q, from 25 to 300 kVp (CCRI 25-250 kV and ISO 4037 N-series), and in terms of absorbed dose to water, Dw , in a Co-60 beam, Q0 . The mean absorbed dose to the ISDs, relative to Kair and Dw , were obtained with the MC code TOPAS (Geant4) using X-ray spectra obtained with SpekPy software and laboratory filtration data and a generic Co-60 source. The intrinsic energy dependence was determined as a function of effective photon energy, E e f f ${E}_{eff}$ , (relative to Co-60). The angular dependence of the ISD signal was measured in a 25 kVp (0.20 mm Al HVL) and 135 kVp beam (0.48 mm Cu HVL), by rotating the ISDs 180° around the fiber's longitudinal axis (perpendicular to the beam). A full 360° was not performed due to setup limitations. The impact of detector design was quantified with MC simulation. RESULTS: Above 30 keV E e f f ${E}_{eff}$ the intrinsic energy dependence varied with less than 5 ± 4% from unity for all detectors (with the uncertainty expressed as the mean of all expanded measurement uncertainties for individual E e f f ${E}_{eff}$ above 30 keV, k = 2). Below 30 keV, it decreased with up to 17% and inter-detector variations of 13% were observed, likely due to differences in detector geometry not captured by the simulations using nominal geometry. In the 25 kVp radiation quality, the ISD signal varied with 24% over a ∼45° rotation. For 135 kVp, the corresponding variation was below 3%. Assuming a 0.05 mm thicker layer of reflective paint around the sensitive volume changed the absorbed dose with 6.3% at the lowest E e f f ${E}_{eff}$ , and with less than 2% at higher energies. CONCLUSION: The study suggests that the ISDs have an intrinsic energy dependence relative to Co-60 lower than 5 ± 4% in radiation qualities with E e f f ${E}_{eff}\ $ > 30 keV. Therefore, they could in principle be calibrated in a Co-60 beam quality and transferred to such radiation qualities with correction factors determined only by the absorbed dose energy dependence obtained from MC simulations. This encourages exploration of the ISDs' applications in intensity modulated BT with Yb-169 or other novel intermediate energy isotopes.

Tissue-specific range uncertainty estimation in proton therapy.

Background and Purpose: Proton therapy is sensitive to range uncertainties, which typically are accounted for by margins or robust optimization, based on tissue-independent uncertainties. However, range uncertainties have been shown to depend on the specific tissues traversed. The aim of this study was to investigate the differences between range margins based on stopping power ratio (SPR) uncertainties which were tissue-specific (applied voxel-wise) or fixed (tissue-independent or composite). Materials and Methods: Uncertainties originating from imaging, computed tomography (CT) number estimation, and SPR estimation were calculated for low-, medium-, and high-density tissues to quantify the tissue-specific SPR uncertainties. Four clinical treatment plans (four different tumor sites) were created and recomputed after applying either tissue-specific or fixed SPR uncertainties. Plans with tissue-specific and fixed uncertainties were compared, based on dose-volume-histogram parameters for both targets and organs-at-risk. Results: The total SPR uncertainties were 7.0% for low-, 1.0% for medium-, and 1.3% for high-density tissues. Differences between the proton plans with tissue-specific and fixed uncertainties were mainly found in the vicinity of the target. Composite uncertainties were found to capture the tissue-specific uncertainties more accurately than the tissue-independent uncertainties. Conclusion: Different SPR uncertainties were found for low-, medium-, and high-density tissues indicating that range margins based on tissue-specific uncertainties may be more exact than the standard approach of using tissue-independent uncertainties. Differences between applying tissue-specific and fixed uncertainties were found, however, a fixed uncertainty might still be sufficient, but with a magnitude that depends on the body region.

A simple method to measure the gating latencies in photon and proton based radiotherapy using a scintillating crystal.

BACKGROUND: In respiratory gated radiotherapy, low latency between target motion into and out of the gating window and actual beam-on and beam-off is crucial for the treatment accuracy. However, there is presently a lack of guidelines and accurate methods for gating latency measurements. PURPOSE: To develop a simple and reliable method for gating latency measurements that work across different radiotherapy platforms. METHODS: Gating latencies were measured at a Varian ProBeam (protons, RPM gating system) and TrueBeam (photons, TrueBeam gating system) accelerator. A motion-stage performed 1 cm vertical sinusoidal motion of a marker block that was optically tracked by the gating system. An amplitude gating window was set to cover the posterior half of the motion (0-0.5 cm). Gated beams were delivered to a 5 mm cubic scintillating ZnSe:O crystal that emitted visible light when irradiated, thereby directly showing when the beam was on. During gated beam delivery, a video camera acquired images at 120 Hz of the moving marker block and light-emitting crystal. After treatment, the block position and crystal light intensity were determined in all video frames. Two methods were used to determine the gate-on (τon ) and gate-off (τoff ) latencies. By method 1, the video was synchronized with gating log files by temporal alignment of the same block motion recorded in both the video and the log files. τon was defined as the time from the block entered the gating window (from gating log files) to the actual beam-on as detected by the crystal light. Similarly, τoff was the time from the block exited the gating window to beam-off. By method 2, τon and τoff were found from the videos alone using motion of different sine periods (1-10 s). In each video, a sinusoidal fit of the block motion provided the times Tmin of the lowest block position. The mid-time, Tmid-light , of each beam-on period was determined as the time halfway between crystal light signal start and end. It can be shown that the directly measurable quantity Tmid-light - Tmin  = (τoff +τon )/2, which provided the sum (τoff +τon ) of the two latencies. It can also be shown that the beam-on (i.e., crystal light) duration ΔTlight increases linearly with the sine period and depends on τoff - τon : ΔTlight  = constant•period+(τoff - τon ). Hence, a linear fit of ΔTlight as a function of the period provided the difference of the two latencies. From the sum (τoff +τon ) and difference (τoff - τon ), the individual latencies were determined. RESULTS: Method 1 resulted in mean (±SD) latencies of τon  = 255 ± 33 ms, τoff  = 82 ± 15 ms for the ProBeam and τon  = 84 ± 13 ms, τoff  = 44 ± 11 ms for the TrueBeam. Method 2 resulted in latencies of τon  = 255 ± 23 ms, τoff  = 95 ± 23 ms for the ProBeam and τon  = 83 ± 8 ms, τoff  = 46 ± 8 ms for the TrueBeam. Hence, the mean latencies determined by the two methods agreed within 13 ms for the ProBeam and within 2 ms for the TrueBeam. CONCLUSIONS: A novel, simple and low-cost method for gating latency measurements that work across different radiotherapy platforms was demonstrated. Only the TrueBeam fully fulfilled the AAPM TG-142 recommendation of maximum 100 ms latencies.

Time-resolved dose rate measurements in pencil beam scanning proton FLASH therapy with a fiber-coupled scintillator detector system.

BACKGROUND: The spatial and temporal dose rate distribution of pencil beam scanning (PBS) proton therapy is important in ultra-high dose rate (UHDR) or FLASH irradiations. Validation of the temporal structure of the dose rate is crucial for quality assurance and may be performed using detectors with high temporal resolution and large dynamic range. PURPOSE: To provide time-resolved in vivo dose rate measurements using a scintillator-based detector during proton PBS pre-clinical mouse experiments with dose rates ranging from conventional to UHDR. METHODS: All irradiations were performed at the entrance plateau of a 250 MeV PBS proton beam. A detector system with four fiber-coupled ZnSe:O inorganic scintillators and 20 µs temporal resolution was used for dose rate measurements. The system was first characterized in terms of precision and stem signal. The detector precision was determined through repeated irradiations with the same field. The stem signal contribution was quantified by irradiating two of the detector probes alongside a bare fiber (fiber without a coupled scintillator). Next, the detector system was calibrated against an ionization chamber (IC) with all four detector probes and the IC placed in a water bath at 2 cm depth. A scan pattern covering 9.6 × 9.6 cm was used. Multiple irradiations with different requested nozzle currents provided instantaneous dose rates at the detector positions in the range of 7-1270 Gy/s. The correspondence of the detector signal (in Volts) to the instantaneous dose rate (in Gy/s) was found. The instantaneous dose rate was calculated from the beam current and the spot-to-detector distance assuming a Gaussian beam profile at distances up to 8 mm from the spot. Afterwards, the calibrated system was used in vivo, in mouse experiments, where mouse legs were irradiated with a constant dose and varying field dose rates of 0.7-87.5 Gy/s. The instantaneous dose rate was measured for each delivered spot and the delivered dose was determined as the integrated instantaneous dose rate. The spot dose profile and PBS dose rate map were calculated. The dose contamination to neighbouring mice were measured together with the upper limit of the dose to the mouse body. RESULTS: The detectors showed high precision with ≤0.4% fluctuations in the measured dose. The stem signal exceeded 10% for spots <5 mm from the optical fiber and >18 mm from the scintillator. It contributed up to 0.2% to the total dose, which was considered negligible. All four detectors showed a non-linear relation between signal and instantaneous dose rate, which was modelled with a polynomial response function. In the mouse experiments, the measured scintillator dose showed 1.8% fluctuations, independent of the field dose rate. The in vivo measured spot dose profile had tails that deviated from a Gaussian profile with measurable dose contributions from spots up to 85 mm from the detector. Neighbour mouse irradiation contributed ∼1% of the total mouse dose. The upper limit of the mouse body dose was 6% of the mouse leg dose. CONCLUSIONS: A fiber-coupled inorganic scintillator-based detector system can provide high precision in vivo measurements of the instantaneous dose rate if correction for the non-linear dose rate dependency is applied.

Toward 3D dose verification of an electronic brachytherapy source with a plastic scintillation detector.

BACKGROUND: Electronic brachytherapy (eBT) is considered a safe treatment with good outcomes. However, eBT lacks standardized and independent dose verification, which could impede future use. PURPOSE: To validate the 3D dose-to-water distribution of an electronic brachytherapy (eBT) source using a small-volume plastic scintillation detector (PSD). METHODS: The relative dose distribution of a Papillon 50 (P50) (Ariane Medical Systems, UK) eBT source was measured in water with a PSD consisting of a cylindrical scintillating BCF-12 fiber (length: 0.5 mm, Ø: 1 mm) coupled to a photodetector via an optical fiber. The measurements were performed with the PSD mounted on a motorized stage in a water phantom (MP3) (PTW, Germany). This allowed the sensitive volume of the PSD to be moved to predetermined positions relative to the P50 applicator, which pointed vertically downward while just breaching the water surface. The percentage depth-dose (PDD) was measured from 0 to 50 mm source-to-detector distance (SDD) in 1-3 mm steps. Dose profiles were measured along two perpendicular axes at five different SDDs with step sizes down to 0.5 mm. Characterization of the PSD consisted of determining the energy correction through Monte Carlo (MC) simulation and by measuring the stability and dose rate linearity using a well-type ionization chamber as a reference. The measured PDD and profiles were validated with corresponding MC simulations. RESULTS: The measured and simulated PDD curves agreed within 2% (except at 0 mm and 43 mm depth) after the PSD measurements were corrected for energy dependency. The absorbed dose decreased by a factor of 2 at 7 mm depth and by a factor of 10 at 26 mm depth. The measured dose profiles showed dose gradients at the profile edges of more than 50%/mm at 5 mm depth and 15%/mm at 50 mm depth. The measured profile widths increased 0.66 mm per 1 mm depth, while the simulated profile widths increased 0.74 mm per 1 mm depth. An azimuthal dependency of > 10% was observed in the dose at 10 mm distance from the beam center. The total uncertainty of the measured relative dose is < 2.5% with a positional uncertainty of 0.4 mm. The measurements for a full 3D dose characterization (PDD and profiles) can be carried out within 8 h, the limiting factor being cooling of the P50. CONCLUSION: The PSD and MP3 water phantoms provided a method to independently verify the relative 3D dose distribution in water of an eBT source.

Time structure of pencil beam scanning proton FLASH beams measured with scintillator detectors and compared with log files.

PURPOSE: Key factors in FLASH treatments are the ultra-high dose rate (UHDR) and the time structure of the beam delivery. Measurement of the time structure in pencil beam scanning (PBS) proton FLASH treatments is challenging for many types of detectors since high temporal resolution is needed. In this study, a fast scintillator detector system was developed and used to measure the individual spot durations as well as the time when the beam moves between two positions (transition duration) during PBS proton FLASH and UHDR treatments. The spot durations were compared with machine log-file recordings. METHODS: A detector system based on inorganic scintillating crystals was developed. The system consisted of four detector probes made of a sub-millimeter ZnSe:O crystal that was coupled via an optical fiber to an optical reader with 50 kHz sampling rate. The detector system was used in two experiments, both performed with a PBS proton beam with 250 MeV beam energy and 215 nA requested nozzle beam current. The sampling rate enabled multiple measurements during each spot delivery and during the beam transition between spots. First, the detector was tested in a phantom experiment, where a total of 305 scan sequences were delivered to the four detectors. The number of spots delivered without beam interruption in a single scan sequence ranged from one to 35. The spot duration and transition duration were measured for each individual spot. Secondly, the detector system was used in vivo in preclinical experiments with FLASH irradiation of mouse legs placed in the entrance plateau of the beam. A single detector was placed 1 cm downstream of the irradiated mouse leg. The mouse dose ranged from 30.5 to 44.2 Gy and the field consisted of 35 spots. The spot durations as well as the mean dose rate (field dose divided by the measured field duration) for each mouse were determined using the detector and then compared with the corresponding log files. RESULTS: The phantom experiment showed that the logged total duration of an uninterrupted spot sequence was consistently shorter than the measured duration with a difference of -0.252 ms (95% confidence interval: [-0.255, -0.249 ms]). This corresponded to 0.05%-0.07% of the spot sequence duration in the mice experiments. For individual spots, the mean ± 1SD difference between logged and measured spot duration was -0.39 ± 0.05 ms for the first spot in a sequence, 0.13 ± 0.04 ms for the last spot in a sequence, and -0.0017 ± 0.09 ms for the intermediate spots in a sequence. The measured spot transition durations were 0.20 ± 0.04 ms (5.1 mm horizontal steps) and 0.50 ± 0.04 ms (5.0 mm vertical steps). For the mouse experiments, the mean dose rate calculated from the measured field duration was 84.1-92.5 Gy/s. It agreed with log files with a root mean square difference of 0.02 Gy/s. CONCLUSIONS: Fiber-coupled scintillator detectors were designed with sufficient temporal resolution to measure the spot and transition duration during PBS proton UHDR deliveries. Their small volume makes them feasible for in vivo use in preclinical FLASH studies. The logged spot durations were in excellent agreement with measurements but showed small systematic errors in the logged duration for the first and last spot in a sequence.

Time-resolved in vivo dosimetry for source tracking in brachytherapy.

PURPOSE: The purpose of this article is to demonstrate that brachytherapy source tracking can be realized with in vivo dosimetry. This concept could enable real-time treatment monitoring. METHODS: In vivo dosimetry was incorporated in the clinical routine during high-dose-rate prostate brachytherapy at Aarhus University Hospital. The dosimetry was performed with a radioluminescent crystal positioned in a dedicated brachytherapy needle in the prostate. The dose rate was recorded every 50-100 ms during treatment and analyzed retrospectively. The measured total delivered dose and dose rates for each dwell position with dwell times >0.7 s were compared with expected values. Furthermore, the distance between the source and dosimeter, which was derived from the measured dose rates, was compared with expected values. The measured dose rate pattern in each needle was used to determine the most likely position of the needle relative to the dosimeter. RESULTS: In total, 305 needles and 3239 dwell positions were analyzed based on 20 treatments. The measured total doses differed from the expected values by -4.7 ± 8.4% (1SD) with range (-17% to 12%). It was possible to determine needle shifts for 304 out of 305 needles. The mean radial needle shift between imaging and treatment was 0.2 ± 1.1 mm (1SD), and the mean longitudinal shift was 0.3 ± 2.0 mm (1SD). CONCLUSION: Time-resolved in vivo dosimetry can be used to provide geometric information about the treatment progression of afterloading brachytherapy. This information may provide a clear indication of errors and uncertainties during a treatment and, therefore, enables real-time treatment monitoring.