Dosimetric validation of the couch and coil model for high-field MR-linac treatment planning.

PURPOSE: The precision of the dose delivery in radiation therapy with high-field MR-linacs is challenging due to the substantial variation in the beam attenuation of the patient positioning system (PPS) (the couch and coils) as a function of the gantry angle. This work aimed to compare the attenuation of two PPSs located at two different MR-linac sites through measurements and calculations in the treatment planning system (TPS). METHODS: Attenuation measurements were performed at every 1° gantry angle at the two sites with a cylindrical water phantom with a Farmer chamber inserted along the rotational axis of the phantom. The phantom was positioned with the chamber reference point (CRP) at the MR-linac isocentre. A compensation strategy was applied to minimise sinusoidal measurement errors due to, e.g. air cavity or setup. A series of tests were performed to assess the sensitivity to measurement uncertainties. The dose to a model of the cylindrical water phantom with the PPS added was calculated in the TPS (Monaco v5.4 as well as in a development version Dev of an upcoming release), for the same gantry angles as for the measurements. The TPS PPS model dependency of the dose calculation voxelisation resolution was also investigated. RESULTS: A comparison of the measured attenuation of the two PPSs yielded differences of less than 0.5% for most gantry angles. The maximum deviation between the attenuation measurements for the two different PPSs exceeded ±1% at two specific gantry angles 115° and 245°, where the beam traverses the most complex PPS structures. The attenuation increases from 0% to 25% in 15° intervals around these angles. The measured and calculated attenuation, as calculated in v5.4, was generally within 1-2% with a systematic overestimation of the attenuation for gantry angles around 180°, as well as a maximum error of 4-5% for a few discrete angles in 10° gantry angle intervals around the complex PPS structures. The PPS modelling was improved compared to v5.4 in Dev, especially around 180°, and the results of those calculations were within ±1%, but with a similar 4% maximum deviation for the most complex PPS structures. CONCLUSIONS: Generally, the two tested PPS structures exhibit very similar attenuation as a function of the gantry angle, including the angles with a steep change in attenuation. Both TPS versions, v5.4 and Dev delivered clinically acceptable accuracy of the calculated dose, as the differences in the measurements were overall better than ±2%. Additionally, Dev improved the accuracy of the dose calculation to ±1% for gantry angles around 180°.

Modelling tissue specific RBE for different radiation qualities based on a multiscale characterization of energy deposition.

PURPOSE: We present the nanoCluE model, which uses nano- and microdosimetric quantities to model RBE for protons and carbon ions. Under the hypothesis that nano- and microdosimetric quantities correlates with the generation of complex DNA double strand breakes, we wish to investigate whether an improved accuracy in predicting LQ parameters may be achieved, compared to some of the published RBE models. METHODS: The model is based on experimental LQ data for protons and carbon ions. We generated a database of track structure data for a number of proton and carbon ion kinetic energies with the Geant4-DNA Monte Carlo code. These data were used to obtain both a nanodosimetric quantity and a set of microdosimetric quantities. The latter were tested with different parameterizations versus experimental LQ-data to select the variable and parametrization that yielded the best fit. RESULTS: For protons, the nanoCluE model yielded, for the ratio of the linear LQ term versus the test data, a root mean square error (RMSE) of 1.57 compared to 1.31 and 1.30 for two earlier other published proton models. For carbon ions the RMSE was 2.26 compared to 3.24 and 5.24 for earlier published carbon ion models. CONCLUSION: These results demonstrate the feasibility of the nanoCluE RBE model for carbon ions and protons. The increased accuracy for carbon ions as compared to two other considered models warrants further investigation.

Patterns of practice for adaptive and real-time radiation therapy (POP-ART RT) part I: Intra-fraction breathing motion management.

PURPOSE: The POP-ART RT study aims to determine to what extent and how intra-fractional real-time respiratory motion management (RRMM) and plan adaptation for inter-fractional anatomical changes (ART), are used in clinical practice and to understand barriers to implementation. Here we report on part I: RRMM. MATERIAL AND METHODS: A questionnaire was distributed worldwide to assess current clinical practice, wishes for expansion or new implementation and barriers to implementation. RRMM was defined as inspiration/expiration gating in free-breathing or breath-hold, or tracking where the target and the beam are continuously realigned. RESULTS: The questionnaire was completed by 200 centres from 41 countries. RRMM was used by 68% of respondents ('users') for a median (range) of 2 (1-6) tumour sites. Eighty-one percent of users applied inspiration breath-hold in at least one tumour site (breast: 96%). External marker was used to guide RRMM by 61% of users. KV/MV imaging was frequently used for liver and pancreas (with fiducials) and for lung (with or without fiducials). Tracking was mainly performed on robotic linacs with hybrid internal-external monitoring. For breast and lung, approximately 75% of respondents used or wished to implement RRMM, which was lower for liver (44%) and pancreas (27%). Seventy-one percent of respondents wished to implement RRMM for a new tumour site. Main barriers were human/financial resources and capacity on the machine. CONCLUSION: Sixty-eight percent of respondents used RRMM and 71% wished to implement RRMM for a new tumour site. The main barriers to implementation were human/financial resources and capacity on treatment machines.

Patterns of practice for adaptive and real-time radiation therapy (POP-ART RT) part II: Offline and online plan adaption for interfractional changes.

PURPOSE: The POP-ART RT study aims to determine to what extent and how intrafractional real-time respiratory motion management (RRMM), and plan adaptation for interfractional anatomical changes (ART) are used in clinical practice and to understand barriers to implementation. Here we report on part II: ART using more than one plan per target per treatment course. MATERIALS AND METHODS: A questionnaire on the current practice of ART, wishes for expansion or implementation, and barriers to implementation was distributed worldwide. Four types of ART were discriminated: daily online replanning, online plan library, protocolled offline replanning (all three based on a protocol), and ad-hoc offline replanning. RESULTS: The questionnaire was completed by 177 centres from 40 countries. ART was used by 61% of respondents (31% with protocol) for a median (range) of 3 (1-8) tumour sites. CBCT/MVCT was the main imaging modality except for online daily replanning (11 users) where 10 users used MR. Two thirds of respondents wished to implement ART for a new tumour site; 40% of these had plans to do it in the next 2 years. Human/material resources and technical limitations were the main barriers to further use and implementation. CONCLUSIONS: ART was used for a broad range of tumour sites, mainly with ad-hoc offline replanning and for a median of 3 tumour sites. There was a large interest in implementing ART for more tumour sites, mainly limited by human/material resources and technical limitations. Daily online replanning was primarily performed on MR-linacs.

Target Size Variation in Microdosimetric Distributions and its Impact on the Linear-Quadratic Parameterization of Cell Survival.

The linear-quadratic (LQ) parameterization of survival fraction [SF( D)] inherently assumes that all cells in a population receive the same dose ( D), albeit the distribution of specific energy z over the individual cells f( z, D) can be very wide. From these microdosimetric distributions, which are target size dependent, we estimate the size of the cellular sensitive volume by analyzing its influence on the LQ parameterization of cell survival. A Monte Carlo track structure code was used to simulate detailed tracks from a 60Co source as well as proton and carbon ions of various energies. From these tracks, f( z, D) distributions were calculated for spherical targets with diameters ranging from 10 nm to 12 µm. A cell survival function based on f( z, D) was fitted to experimental LQ α values, revealing an intrinsic limitation that target size imposes on the usage of f( z, D) to describe the linear term of the LQ parameterization. The results indicate that such threshold volume arises naturally from the relationship between the particle's probability of no-hit and the probability of cell survival. Further analysis led to the proposal of a radiobiological property [Formula: see text], defined as the mean lineal energy corresponding to the target size that allows equivalence between the mean inactivation dose (MID) and the mean specific energy [Formula: see text]. The fact that [Formula: see text] is an increasing continuous function of target size within the range of biological targets of interest in radiobiology, ensures the uniqueness of [Formula: see text] for any radiation quality, thus, its potential usefulness in modeling. In conclusion, an accurate estimation of such threshold volumes may be useful for improving modeling of cell survival curves.

Energy deposition clustering as a functional radiation quality descriptor for modeling relative biological effectiveness.

PURPOSE: To explore the use of the frequency of the energy deposition (ED) clusters of different sizes (cluster order, CO) as a surrogate (instead of, e.g., LET) classification of the physical characteristics of ionizing radiation at a nanometer scale, to construct a framework for the calculation of relative biological effectiveness (RBE) with cell survival as endpoint. METHODS: The frequency of cluster order fCO is calculated by sorting the ED sites generated with the Monte Carlo track structure code LIonTrack into clusters based on a single parameter called the cluster distance dC being the maximum allowed distance between two neighboring EDs belonging to a cluster. Published cell survival data parameterized with the linear-quadratic (LQ) model for V79 cells exposed to 15 different radiation qualities (including brachytherapy sources, proton, and carbon ions) were used as input to a fitting procedure, designed to determine a weighting function wCO that describes the capacity of a cluster of a certain CO to damage the cell's sensitive volume. The proposed framework uses both fCO and wCO to construct surrogate based functions for the LQ parameters α and ß from which RBE values can be derived. RESULTS: The results demonstrate that radiation quality independent weights wCO exist for both the α and ß parameters. This enables the calculation of α values that correlate to their experimental counterparts within experimental uncertainties (relative residual of 15% for dC = 2.5 nm). The combination of both α and ß surrogate based functions, despite the higher relative residuals for ß values, yielded an RBE function that correlated to experimentally derived RBE values (relative residual of 16.5% for dC = 2.5 nm) for all radiation qualities included in this work. CONCLUSIONS: The fCO cluster characterization of ionizing radiation at a nanometer scale can effectively be used to calculate particle and energy dependent α and ß values to predict RBE values with potential applications to, e.g., treatment planning systems in radiotherapy.

Cluster pattern analysis of energy deposition sites for the brachytherapy sources 103Pd, 125I, 192Ir, 137Cs, and 60Co.

Analysing the pattern of energy depositions may help elucidate differences in the severity of radiation-induced DNA strand breakage for different radiation qualities. It is often claimed that energy deposition (ED) sites from photon radiation form a uniform random pattern, but there is indication of differences in RBE values among different photon sources used in brachytherapy. The aim of this work is to analyse the spatial patterns of EDs from 103Pd, 125I, 192Ir, 137Cs sources commonly used in brachytherapy and a 60Co source as a reference radiation. The results suggest that there is both a non-uniform and a uniform random component to the frequency distribution of distances to the nearest neighbour ED. The closest neighbouring EDs show high spatial correlation for all investigated radiation qualities, whilst the uniform random component dominates for neighbours with longer distances for the three higher mean photon energy sources (192Ir, 137Cs, and 60Co). The two lower energy photon emitters (103Pd and 125I) present a very small uniform random component. The ratio of frequencies of clusters with respect to 60Co differs up to 15% for the lower energy sources and less than 2% for the higher energy sources when the maximum distance between each pair of EDs is 2 nm. At distances relevant to DNA damage, cluster patterns can be differentiated between the lower and higher energy sources. This may be part of the explanation to the reported difference in RBE values with initial DSB yields as an endpoint for these brachytherapy sources.

Monte Carlo calculated microdosimetric spread for cell nucleus-sized targets exposed to brachytherapy 125I and 192Ir sources and 60Co cell irradiation.

The stochastic nature of ionizing radiation interactions causes a microdosimetric spread in energy depositions for cell or cell nucleus-sized volumes. The magnitude of the spread may be a confounding factor in dose response analysis. The aim of this work is to give values for the microdosimetric spread for a range of doses imparted by (125)I and (192)Ir brachytherapy radionuclides, and for a (60)Co source. An upgraded version of the Monte Carlo code PENELOPE was used to obtain frequency distributions of specific energy for each of these radiation qualities and for four different cell nucleus-sized volumes. The results demonstrate that the magnitude of the microdosimetric spread increases when the target size decreases or when the energy of the radiation quality is reduced. Frequency distributions calculated according to the formalism of Kellerer and Chmelevsky using full convolution of the Monte Carlo calculated single track frequency distributions confirm that at doses exceeding 0.08 Gy for (125)I, 0.1 Gy for (192)Ir, and 0.2 Gy for (60)Co, the resulting distribution can be accurately approximated with a normal distribution. A parameterization of the width of the distribution as a function of dose and target volume of interest is presented as a convenient form for the use in response modelling or similar contexts.

Dose mapping sensitivity to deformable registration uncertainties in fractionated radiotherapy - applied to prostate proton treatments.

BACKGROUND: Calculation of accumulated dose in fractionated radiotherapy based on spatial mapping of the dose points generally requires deformable image registration (DIR). The accuracy of the accumulated dose thus depends heavily on the DIR quality. This motivates investigations of how the registration uncertainty influences dose planning objectives and treatment outcome predictions.A framework was developed where the dose mapping can be associated with a variable known uncertainty to simulate the DIR uncertainties in a clinical workflow. The framework enabled us to study the dependence of dose planning metrics, and the predicted treatment outcome, on the DIR uncertainty. The additional planning margin needed to compensate for the dose mapping uncertainties can also be determined. We applied the simulation framework to a hypofractionated proton treatment of the prostate using two different scanning beam spot sizes to also study the dose mapping sensitivity to penumbra widths. RESULTS: The planning parameter most sensitive to the DIR uncertainty was found to be the target D95. We found that the registration mean absolute error needs to be ≤0.20 cm to obtain an uncertainty better than 3% of the calculated D95 for intermediate sized penumbras. Use of larger margins in constructing PTV from CTV relaxed the registration uncertainty requirements to the cost of increased dose burdens to the surrounding organs at risk. CONCLUSIONS: The DIR uncertainty requirements should be considered in an adaptive radiotherapy workflow since this uncertainty can have significant impact on the accumulated dose. The simulation framework enabled quantification of the accuracy requirement for DIR algorithms to provide satisfactory clinical accuracy in the accumulated dose.

Limitations (and merits) of PENELOPE as a track-structure code.

PURPOSE: To outline the limitations of PENELOPE (acronym of PENetration and Energy LOss of Positrons and Electrons) as a track-structure code, and to comment on modifications that enable its fruitful use in certain microdosimetry and nanodosimetry applications. METHODS: Attention is paid to the way in which inelastic collisions of electrons are modelled and to the ensuing implications for microdosimetry analysis. RESULTS: Inelastic mean free paths and collision stopping powers calculated with PENELOPE and two well-known optical-data models are compared. An ad hoc modification of PENELOPE is summarized where ionization and excitation of liquid water by electron impact is simulated using tables of realistic differential and total cross sections. CONCLUSIONS: PENELOPE can be employed advantageously in some track-structure applications provided that the default model for inelastic interactions of electrons is replaced by suitable tables of differential and total cross sections.

Reference dosimetry in a scanned pulsed proton beam using ionisation chambers and a Faraday cup.

In order to give the correct dose to a patient, the monitor chamber for a proton scanning system has to be calibrated. As recombination of ion pairs occurs in the monitor chamber, the relation between the number of particles traversing it per time unit and the ionization chamber signal is not linear. A method developed for a scanned pulsed proton beam taking the nonlinear monitor signal into account is described. A vital part of the reference dosimetry procedure is to determine the absorbed dose under reference conditions, which is recommended to be done with an ionization chamber. For a scanned pulsed proton beam, the recombination in the ionization chamber is not negligible and the signal from the ionization chamber has to be corrected. In this work, it is shown that although the pulse length is comparable to the ion transit time the beam can be considered as continuously scanned if the applied high voltage is not too small. Also shown is that the two-voltage formula for a continuous beam is under some conditions applicable for a continuous scanned beam as well.

Parametrization and application of scatter kernels for modelling scanned proton beam collimator scatter dose.

Collimators are routinely used in proton radiotherapy to laterally confine the field and improve the penumbra. Collimator scatter contributes up to 15% of the local dose and is therefore important to include in treatment planning dose calculation. We present a method for reconstruction of the collimator scatter phase space based on the parametrization of pre-calculated scatter kernels. Collimator scatter distributions, generated by the Monte Carlo (MC) package GEANT4.8.2, were scored differential in direction and energy. The distributions were then parametrized so as to enable a fast reconstruction by sampling. MC calculated dose distributions in water based on the parametrized phase space were compared to full MC simulations that included the collimator in the simulation geometry, as well as to experimental data. The experiments were performed at the scanned proton beam line at the The Svedberg Laboratory (TSL) in Uppsala, Sweden. Dose calculations using the parametrization of this work and the full MC for isolated typical cases of collimator scatter were compared by means of the gamma index. The result showed that in total 96.7% (99.3%) of the voxels fulfilled the gamma 2.0%/2.0 mm (3.0%/3.0 mm) criterion. The dose distribution for a collimated field was calculated based on the phase space created by the collimator scatter model incorporated into the generation of the phase space of a scanned proton beam. Comparing these dose distributions to full MC simulations, including particle transport in the MLC, yielded that in total for 18 different collimated fields, 99.1% of the voxels satisfied the gamma 1.0%/1.0 mm criterion and no voxel exceeded the gamma 2.6%/2.6 mm criterion. The dose contribution of collimator scatter along the central axis as predicted by the model showed good agreement with experimental data.

Monte Carlo simulation and analysis of proton energy-deposition patterns in the Bragg peak.

The spatial pattern of energy depositions is crucial for understanding the mechanisms that modify the relative biological effectiveness of different radiation qualities. In this paper, we present data on energy-deposition properties of mono-energetic protons (1-20 MeV) and their secondary electrons in liquid water. Proton-impact ionization was described by means of the Hansen-Kocbach-Stolterfoht doubly differential cross section (DDCS), thus modelling both the initial energy and angle of the emitted electron. Excitation by proton impact was included to account for the contribution of this interaction channel to the electronic stopping power of the projectile. Proton transport was implemented assuming track-segment conditions, whereas electrons were followed down to 50 eV by the Monte Carlo code PENELOPE. Electron intra-track energy-deposition properties, such as slowing-down and energy-imparted spectra of electrons, were calculated. Furthermore, the use of DDCSs enabled the scoring of electron inter-track properties. We present novel results for 1, 5 and 20 MeV single-proton-track frequencies of distances between the nearest inter- (e(-)-e(-), e(-)-H+) and intra-track (e(-)-e(-), e(-)-H+, H+-H+) energy-deposition events. By setting a threshold energy of 17.5 eV, commonly employed as a surrogate to discriminate for elementary damage in the DNA, the variation in these frequencies was studied as well. The energy deposited directly by the proton represents a large amount of the total energy deposited along the track, but when an energy threshold is adopted the relative contribution of the secondary electrons becomes larger for increasing energy of the projectile. We found that the frequencies of closest energy-deposition events per nanometre decrease with proton energy, i.e. for lower proton energies a denser ionization occurs, following the trend of the characteristic LET curves. In conclusion, considering the energy depositions due to the delta electrons and at the core of the track, 1 MeV protons have an intrinsic capability of generating about five times more dual depositions within the characteristic 2 nm of the DNA-chain structure than 20 MeV protons.

Experimental test of Monte Carlo proton transport at grazing incidence in GEANT4, FLUKA and MCNPX.

The ability of the Monte Carlo (MC) particle transport codes GEANT4.8.1 and GEANT4.8.2, FLUKA2006 and MCNPX2.4.0 to model proton transport at grazing incidence onto tungsten blocks has been tested and compared to experimental measurements. The test geometry consisted of a narrow proton beam of two energies, 98 MeV and 180 MeV, impinging on a thick tungsten alloy block at grazing incidence. The distribution of forward out-scatter from the tungsten alloy block was measured with a fluorescent screen viewed with a CCD camera via a mirror. In the MC simulations, the experimental setup was modelled and the dose deposited to the fluorescent screen material was scored. Simulations and measurements were made for four different incidence angles (3.5, 5.0, 7.5 and 10 degrees ). Several different sets of calculations were performed, studying the impact of different user-defined settings in the different MC packages. The study of different parameters settings in the GEANT4.8.1 simulation showed a strong dependence of the calculated out-scatter probability on the maximum allowed step length. For the largest incidence angle an increase of 60% in the out-scatter probability was found when restricting the maximum allowed step length to 0.05 cm. We also observed that the stepping algorithm of GEANT4.8.1 and 4.8.2 introduces a small non-physical directional and positional asymmetry at the exit boundary of the tungsten alloy block. The shape of the energy spectrum of protons being out-scattered agreed between the codes. The dose-weighted forward out-scatter probability, i.e. the ratio between the total signal from the unscattered beam and the out-scattered beam, showed a qualitative agreement of simulations compared to measurements. Quantitatively, the deviation of the simulations reached as high as 37%, while the experimental uncertainty was 14%. The mean emission angle of the simulations was within 16% of the measurement for all incidence angles with a measurement uncertainty of 8%.

A beam source model for scanned proton beams.

A beam source model, i.e. a model for the initial phase space of the beam, for scanned proton beams has been developed. The beam source model is based on parameterized particle sources with characteristics found by fitting towards measured data per individual beam line. A specific aim for this beam source model is to make it applicable to the majority of the various proton beam systems currently available or under development, with the overall purpose to drive dose calculations in proton beam treatment planning. The proton beam phase space is characterized by an energy spectrum, radial and angular distributions and deflections for the non-modulated elementary pencil beam. The beam propagation through the scanning magnets is modelled by applying experimentally determined focal points for each scanning dimension. The radial and angular distribution parameters are deduced from measured two-dimensional fluence distributions of the elementary beam in air. The energy spectrum is extracted from a depth dose distribution for a fixed broad beam scan pattern measured in water. The impact of a multi-slab range shifter for energy modulation is calculated with an own Monte Carlo code taking multiple scattering, energy loss and straggling, non-elastic and elastic nuclear interactions in the slab assembly into account. Measurements for characterization and verification have been performed with the scanning proton beam system at The Svedberg Laboratory in Uppsala. Both in-air fluence patterns and dose points located in a water phantom were used. For verification, dose-in-water was calculated with the Monte Carlo code GEANT 3.21 instead of using a clinical dose engine with approximations of its own. For a set of four individual pencil beams, both with the full energy and range shifted, 96.5% (99.8%) of the tested dose points satisfied the 1%/1 mm (2%/2 mm) gamma criterion.

Development and verification of the pulsed scanned proton beam at The Svedberg Laboratory in Uppsala.

In this paper we present the recent developments made for the scanning system for proton beams at TSL in Uppsala, showing that this system is now fully functional being able to produce conformal intensity modulated scan patterns with sufficient accuracy. A new control and supervising system handling the beam delivery including the control of the synchrocyclotron and the scanning system is developed and described in detail. A complete dosimetry system with transmission ionization chambers and a multi-wire ionization chamber for monitoring of the beam during scanning has been constructed. The details of the dose monitors and the position sensitive multi-wire ionization chamber are presented in this work. Furthermore, we have established procedures for verification measurements to ensure the quality of the beam and also methods for calibration of the beam monitors and relative and absolute dosimetry for complex scanned beams.