A framework for defining FLASH dose rate for pencil beam scanning

The dynamic collimation system (DCS) provides energy layer-specific collimation for pencil beam scanning (PBS) proton therapy using two pairs of orthogonal nickel trimmer blades. While excellent measurement-to-calculation agreement has been demonstrated for simple cube-shaped DCS-trimmed dose distributions, no comparison of measurement and dose calculation has been made for patient-specific treatment plans. To validate a patient-specific quality assurance (PSQA) process for DCS-trimmed PBS treatment plans and evaluate the agreement between measured and calculated dose distributions. Three intracranial patient cases were considered. Standard uncollimated PBS and DCS-collimated treatment plans were generated for each patient using the Astroid treatment planning system (TPS). Plans were recalculated in a water phantom and delivered at the Miami Cancer Institute (MCI) using an Ion Beam Applications (IBA) dedicated nozzle system and prototype DCS. Planar dose measurements were acquired at two depths within low-gradient regions of the target volume using an IBA MatriXX ion chamber array. Measured and calculated dose distributions were compared using 2D gamma analysis with 3%/3mm criteria and low dose threshold of 10% of the maximum dose. Median gamma pass rates across all plans and measurement depths were 99.0% (PBS) and 98.3% (DCS), with a minimum gamma pass rate of 88.5% (PBS) and 91.2% (DCS). The PSQA process has been validated and experimentally verified for DCS-collimated PBS. Dosimetric agreement between the measured and calculated doses was demonstrated to be similar for DCS-collimated PBS to that achievable with noncollimated PBS.

The FLASH effect has been investigated experimentally using beam modalities with different time structures such as pulsed electron beams and pencil beam scanning (PBS) proton fields. The different beam time structures make direct comparisons between experiments difficult. A biologically founded dose rate concept that is applicable across all beam time structures is highly needed. For any dose delivery with a time-varying dose rate, we define the equivalent constant dose rate ( eq,const) as the dose rate that would give the same FLASH sparing effect if the same dose had been delivered with a constant dose rate. This study develops a mathematical framework for eq,const and uses this to investigate eq,const for a range of beam time structures. Calculation of eq,const requires a model of the FLASH sparing effect. Here, eq,const was investigated using a phenomenological oxygen enhancement ratio (OER) weighted dose model that has previously been used for successful quantification of the acute skin toxicity variations observed in mice across various proton PBS irradiations. Analytical equations were developed to calculate eq,const for any piece-wise constant dose rate irradiation and used to determine eq,const for several pulsed beams and PBS fields. eq,const was characterized systematically for pulsed beams and PBS fields, and the ability of eq,const to describe acute skin toxicity occurrence in previous mice experiments was investigated. For pulsed beams with mean dose rate mean, n pulses, pulse doses up to 5 Gy and pulse repetition times up to 100 ms, eq,const was approximately given by n/(n+1)⋅ mean. eq,const for a 40 Gy PBS transmission proton field with mean=60 Gy/s previously used for mouse irradiations was 155 Gy/s without repainting, 64 Gy/s with four repaintings, and 7.7 Gy/s when splitting the field into two deliveries separated by 2 minutes. eq,const was 98 Gy/s for spread-out Bragg peak irradiation without repainting. The occurrence of acute skin toxicity in mice after ∼40 Gy irradiations with various beam time structures, including pulsed electron beams and proton PBS, followed the same trend as function of eq,const, demonstrating its radiobiological relevance. eq,const only depended slightly on the phenomenological OER-model parameters. The generally applicable biologically founded dose rate concept eq,const allows direct comparison of FLASH dose rates across all beam time structures.

FLASH proton therapy has the potential to reduce side effects of conventional proton therapy by delivering a high dose of radiation in a very short period of time. However, significant progress is needed in the development of FLASH proton therapy. Increasing the dose rate while maintaining dose conformality may involve the use of advanced beam-shaping technologies and specialized equipment such as 3D patient-specific range modulators, to take advantage of the higher transmission efficiency at the highest energy available. The dose rate is an important factor in FLASH proton therapy, but its definition can vary because of the uneven distribution of the dose over time in pencil-beam scanning (PBS). Highlight the distinctions, both in terms of concept and numerical values, of the various definitions that can be established for the dose rate in PBS protontherapy. In an insilico study, five definitions of the dose rate, namely the PBS dose rate, the percentile dose rate, the maximum percentile dose rate, the average dose rate, and the dose averaged dose rate (DADR) were analyzed first through theoretical comparison, and then applied to a head and neck case. To carry out this study, a treatment plan utilizing a single energy level and requiring the use of a patient-specific range modulator was employed. The dose rate values were compared both locally and by means of dose rate volume histograms (DRVHs). The PBS dose rate, the percentile dose rate, and the maximum percentile dose are definitions that are specifically designed to take into account the time structure of the delivery of a PBS treatment plan. Although they may appear similar, our study shows that they can vary locally by up to 10%. On the other hand, the DADR values were approximately twice as high as those of the PBS, percentile, and maximum percentile dose rates, since the DADR disregards the periods when a voxel does not receive any dose. Finally, the average dose rate can be defined in various ways, as discussed in this paper. The average dose rate is found to be lower by a factor of approximately 1/2 than the PBS, percentile, and maximum percentile doserates. We have shown that using different definitions for the dose rate in FLASH proton therapy can lead to variations in calculated values ranging from a few percent to a factor of two. Since the dose rate is a critical parameter in FLASH radiation therapy, it is essential to carefully consider the choice of definition. However, to make an informed decision, additional biological data and models areneeded.

Ion therapy guideline (Version 2020)

The literature is controversial about the scan direction dependency of interplay effects in pencil beam scanning (PBS) treatment of moving targets. A directional effect is supported by many simulation studies, whereas the experimental data are mostly limited to simple geometries, not reflecting realistically clinical treatment plans. We have compared increasingly complex treatment fields, from a homogeneous single energy layer to a more modulated lung plan, under identical experimental settings, seeking evidence for differences in motion mitigation due to the selection of primary scanning direction. In total, 120 experimental samples were taken, combining two primary scan directions and three rescanning regimes with different motion scenarios. 4D dose distributions were measured in water with a moving ionisation chamber array and compared to those of a stationary delivery using 2D gamma analysis. Each plan has been verified twice for the same rescanning regime and motion scenario, changing the meandering direction in between to scan perpendicularly to, or along, the target motion. Additionally, machine log files of the lung plan, together with 4DCT data, were used to calculate the dose distribution that such deliveries would have produced in the patient. The primary meandering direction has a clear influence on measured dose distributions when considering a single energy layer. Introducing spot weight modulation and multiple energy layers however, makes the dynamic of interplay more complex and difficult to predict. Overall, gamma (3%/3 mm) differences between scanning along or orthogonal to the target motion follow a normal distribution when considering multiple motion scenarios and rescanning regimes. Nevertheless, data spread is significant enough such that, for individual experiments and set-ups, a dependency may be observed even if this is not a general result. Patient reconstructed doses follow the same trend, the two primary scan directions producing statistically insignificant differences in dose distributions in terms of conformity or homogeneity. Except for extremely simplified cases of mono-energetic and homogeneous treatment fields, the interplay effect has been found to be only marginally influenced by the choice of the primary scanning direction.

Purpose:To determine the neutron contamination from the aperture in pencil beam scanning during proton therapy.Methods:A Monte Carlo based proton therapy research platform TOPAS and the UF‐series hybrid pediatric phantoms were used to perform this study. First, pencil beam scanning (PBS) treatment pediatric plans with average spot size of 10 mm at iso‐center were created and optimized for three patients with and without apertures. Then, the plans were imported into TOPAS. A scripting method was developed to automatically replace the patient CT with a whole body phantom positioned according to the original plan iso‐center. The neutron dose equivalent was calculated using organ specific quality factors for two phantoms resembling a 4‐ and 14‐years old patient.Results:The neutron dose equivalent generated by the apertures in PBS is 4–10% of the total neutron dose equivalent for organs near the target, while roughly 40% for organs far from the target. Compared to the neutron dose equivalent caused by PBS without aperture, the results show that the neutron dose equivalent with aperture is reduced in the organs near the target, and moderately increased for those organs located further from the target. This is due to the reduction of the proton dose around the edge of the CTV, which causes fewer neutrons generated in the patient.Conclusion:Clinically, for pediatric patients, one might consider adding an aperture to get a more conformal treatment plan if the spot size is too large. This work shows the somewhat surprising fact that adding an aperture for beam scanning for facilities with large spot sizes reduces instead of increases a potential neutron background in regions near target.Changran Geng is supported by the Chinese Scholarship Council (CSC) and the National Natural Science Foundation of China (Grant No. 11475087).

Radiation-Induced Acute Lung Pneumonitis After Pencil-Beam Scanning Proton Treatment for Breast Cancer: Correlation With Dose-Volume Parameters and Optimization Objectives to Reduce Lung Toxicities.

Purpose:To illustrate patient QA results for the first 10 patients treated at Scripps Proton Center by comparing point dose measurement using an ion chamber and in‐house developed secondary MU program, and the measurement of 2D dose distribution using an ion chamber array.Methods:At the time of writing, 10 patient plans were approved for treatment using Varian ProBeam pencil beam scanning system and Eclipse treatment planning software. We used the IBA CC04 0.04 cm3 ion chamber and PTW Unidos E electrometer for point dose measurement in a small water tank (Sun Nuclear 1D scanner). We developed independent MU check software based on measured pencil beam dose profiles for various energies. We used PTW Octavius 729 XDR array to evaluate 2D planar dose distribution. The 3D gamma at 3%/3 mm local dose was used to compare a 3D calculated dose plan with a 2D measured dose distribution using PTW Verisoft software. All fields were exported to a verification phantom plan and delivered at 0 degrees for simplicity.Results:Comparisons between the CC04 ion chamber measurement and calculated dose agree well within 1%. The PTW Octavius 729 XDR array exhibited some dose rate dependence in high dose rate pencil beam delivery. Nevertheless, the results, used as a relative measurement, passed the gamma criteria of 3%/3mm for greater than 90% of area in all patient fields. Visual inspection showed good agreement between ion chamber dose profile and the calculated plan. The in‐house secondary check for MU agreed very well with the plan dose and measurement. The results will be updated with more patients treated.Conclusion:The initial patient specific QA results are encouraging for a new pencil beam scanning only proton therapy system.

A Potential Cause for Unexplained Radiation Toxicity in Proton Therapy

Reassessment of the Necessity of the Proton Gantry: Analysis of Beam Orientations From 4332 Treatments at the Massachusetts General Hospital Proton Center Over the Past 10 Years

Deliverable proton conformal FLASH radiotherapy treatment planning for head and neck re-irradiation patients.

Purpose:Proton irradiation degrades solid state detectors, producing high recombination and leakage currents and ultimately rendering them unusable for dosimetry. In this work we evaluate the performance of a new p‐type silicon diode under proton beam irradiation.Methods:A novel p‐type silicon diode with improved radiation hardness has recently been developed (IBA Dosimetry, Schwarzenbruck, Germany). The dosimetric properties of the devices were assessed for application in pencil beam scanning (PBS) proton irradiation. Using PBS fields with 4 mm spaced, uniform intensity spots, dose and dose rate linearity were evaluated over a clinical range. Output factors were measured at energies of 100, 180, and 225 MeV and for field sizes ranging from 4×4 – 20×20 cm2. Measurements were performed at the center of the square fields at varying depths upstream from the Bragg peak and compared with previously published results.Results:At shallow depths, the diode exhibits linear behavior (0.1%) over the clinical range of doses and dose rates; the sensitivity of the diode in this region is ∼6.0 nC/Gy. As the depth of measurement approaches within 2 cm of each Bragg peak, the deviation from linearity becomes greater (±2–6%). The diode shows less response with small fields and ‐ over responds with large fields.ConclusionAt depths more than 2 cm upstream from the Bragg Peak, the diode shows very good agreement with ion chamber and calculated results for output factors. This demonstrates that diodes can be used for relative measurements at shallow depths, but should be used with caution at deeper depths and for higher energy. Measurements at all depths exhibit an energy dependence that is characteristic of silicon diodes and requires correction.Detectors provided by IBA Dosimetry GmbH, Schwarzenbruck, Germany

Pencil beam scanning (PBS) proton therapy requires the delivery of many thousand proton beams, each modulated for position, energy and monitor units, to provide a highly conformal patient treatment. The quality of the treatment is dependent on the delivery accuracy of each beam and at each fraction. In this work we describe the use of treatment log files, which are a record of the machine parameters for a given field delivery on a given fraction, to investigate the integrity of treatment delivery compared to the nominal planned dose. The dosimetry-relevant log file parameters are used to reconstruct the 3D dose distribution on the patient anatomy, using a TPS-independent dose calculation system. The analysis was performed for patients treated at Paul Scherrer Institute on Gantry 2, both for individual fields and per series (or plan), and delivery quality was assessed by determining the percentage of voxels in the log file dose distribution within +/− 1% of the nominal dose. It was seen that, for all series delivered, the mean pass rate is 96.4%. Furthermore, this work establishes a correlation between the delivery quality of a field and the beam position accuracy. This correlation is evident for all delivered fields regardless of individual patient or plan characteristics. We have also detailed further usefulness of log file analysis within our clinical workflow.In summary, we have highlighted that the integrity of PBS treatment delivery is dependent on daily machine performance and is specifically highly correlated with the accuracy of beam position. We believe this information will be useful for driving machine performance improvements in the PBS field.

Purpose: To evaluate potential gain in therapeutic effect from delivery of daily inhomogeneous fractional dose distributions in proton therapy, using pencil beam scanning. Methods: For a sample case of prostate cancer, we consider a standard course of 39 fractions of 2 Gy (78 Gy total), and a hypofractionated course of 20 fractions of 3 Gy (assuming alpha/beta=1.5, the equivalent dose in 2 Gy fractions (ED2Gy) is 77.1 Gy). Two sets of dose distributions were planned: (1) the standard approach, with a uniform dose (100% of prescription) delivered in every fraction to the entire target; (2) delivery of inhomogeneous fractional dose (IFD) distributions, which varied within the target volume between 65% and 135% of the nominal prescription. For IFD, the daily distributions were optimized in such a way that the two hemispheres of the prostate (split sagittally through the urethra) received, in alternating fractions, either 65% or 135% of the nominal fractional dose (e.g., 1.3 and 2.7 Gy), while the urethra received approximately 100% (e.g., 2 Gy) daily. The equivalent uniform dose (EUD), and ED2Gy were compared for different plans. Results: In the IFD course, the whole prostate received a nearly uniform dose over every 2 fractions, however ED2Gy was higher than with standard uniform dose: 81.9 Gy (5% increase) for the conventional, and 82.6 Gy (7% increase) for the hypofractionated course. Rectal and bladder EUD increased by <5%, while urethral EUD was unchanged. Conclusions: In treatment of prostate and other sites, improved therapeutic outcome can be expected with delivery of inhomogeneous daily dose distributions, while administering the prescribed uniform dose to target over the entire course of treatment. The extent of expected gain is dependent on model parameters (alpha/beta, EUD‐a, etc.), and dose distributions may potentially be designed to maximize the gain specifically for a certain assumed range of parameters.No disclosures or conflict of interest. Supported by the Federal Share of program income earned on C06‐CA059267, Proton Therapy Research and Treatment Center.

Beta dose rate heterogeneity is a known source of scatter in OSL measurement and equivalent dose distributions. Without proper methods to describe and account for it, it can contribute significantly to the uncertainties in OSL ages. For this reason, investigating the beta dose rate (β Dr) distribution is necessary to improve the dating of heterogeneous samples. Here we present a method for quantitative and high sensitivity autoradiographic imaging of beta dose rates. It is demonstrated using highly heterogeneous granulite rock samples. The accuracy and sensitivity of this method is improved using pulsed laser stimulation, and by underground exposure of samples in an ultra-low background environment. Results are calibrated using gamma (γ)irradiation and Monte Carlo simulation and have been validated using homogeneous dose rate standards. Combining analysis of autoradiography results and SEM backscattered images of the same samples allows determination of the dose rate distributions in the different mineral phases. A significant difference between the dose rate of K-feldspar grains obtained from the imaging and the dose rates calculated using methods commonly used in OSL dating is noted because of the clustering of grains in the sample. This represents a risk of bias in age determination in coarse grained rock samples which can be analysed using dose rate imaging methods. The beta Dr spatial distributions result in a significant dose scattering received by single grains, even compared to the total dose rate. The effect of such beta dose rate distributions on OSL dating of coarse-grained crystalline materials is discussed.