In Silico Models of DNA Damage and Repair in Proton Treatment Planning: A Proof of Concept.

There is strong in vitro cell survival evidence that the relative biological effectiveness (RBE) of protons is variable, with dependence on factors such as linear energy transfer (LET) and dose. This is coupled with the growing in vivo evidence, from post-treatment image change analysis, of a variable RBE. Despite this, a constant RBE of 1.1 is still applied as a standard in proton therapy. However, there is a building clinical interest in incorporating a variable RBE. Recently, correlations summarising Monte Carlo-based mechanistic models of DNA damage and repair with absorbed dose and LET have been published as the Manchester mechanistic (MM) model. These correlations offer an alternative path to variable RBE compared to the more standard phenomenological models. In this proof of concept work, these correlations have been extended to acquire RBE-weighted dose distributions and calculated, along with other RBE models, on a treatment plan. The phenomenological and mechanistic models for RBE have been shown to produce comparable results with some differences in magnitude and relative distribution. The mechanistic model found a large RBE for misrepair, which phenomenological models are unable to do. The potential of the MM model to predict multiple endpoints presents a clear advantage over phenomenological models.

Comparing stochastic proton interactions simulated using TOPAS-nBio to experimental data from fluorescent nuclear track detectors.

Whilst Monte Carlo (MC) simulations of proton energy deposition have been well-validated at the macroscopic level, their microscopic validation remains lacking. Equally, no gold-standard yet exists for experimental metrology of individual proton tracks. In this work we compare the distributions of stochastic proton interactions simulated using the TOPAS-nBio MC platform against confocal microscope data for Al2O3:C,Mg fluorescent nuclear track detectors (FNTDs). We irradiated [Formula: see text] mm3 FNTD chips inside a water phantom, positioned at seven positions along a pristine proton Bragg peak with a range in water of 12 cm. MC simulations were implemented in two stages: (1) using TOPAS to model the beam properties within a water phantom and (2) using TOPAS-nBio with Geant4-DNA physics to score particle interactions through a water surrogate of Al2O3:C,Mg. The measured median track integrated brightness (IB) was observed to be strongly correlated to both (i) voxelized track-averaged linear energy transfer (LET) and (ii) frequency mean microdosimetric lineal energy, [Formula: see text], both simulated in pure water. Histograms of FNTD track IB were compared against TOPAS-nBio histograms of the number of terminal electrons per proton, scored in water with mass-density scaled to mimic Al2O3:C,Mg. Trends between exposure depths observed in TOPAS-nBio simulations were experimentally replicated in the study of FNTD track IB. Our results represent an important first step towards the experimental validation of MC simulations on the sub-cellular scale and suggest that FNTDs can enable experimental study of the microdosimetric properties of individual proton tracks.

Application of the Exradin W1 scintillator to determine Ediode 60017 and microDiamond 60019 correction factors for relative dosimetry within small MV and FFF fields.

In this work we use EBT3 film measurements at 10 MV to demonstrate the suitability of the Exradin W1 (plastic scintillator) for relative dosimetry within small photon fields. We then use the Exradin W1 to measure the small field correction factors required by two other detectors: the PTW unshielded Ediode 60017 and the PTW microDiamond 60019. We consider on-axis correction-factors for small fields collimated using MLCs for four different TrueBeam energies: 6 FFF, 6 MV, 10 FFF and 10 MV. We also investigate percentage depth dose and lateral profile perturbations. In addition to high-density effects from its silicon sensitive region, the Ediode exhibited a dose-rate dependence and its known over-response to low energy scatter was found to be greater for 6 FFF than 6 MV. For clinical centres without access to a W1 scintillator, we recommend the microDiamond over the Ediode and suggest that 'limits of usability', field sizes below which a detector introduces unacceptable errors, can form a practical alternative to small-field correction factors. For a dosimetric tolerance of 2% on-axis, the microDiamond might be utilised down to 10 mm and 15 mm field sizes for 6 MV and 10 MV, respectively.

Validation of a prototype DiodeAir for small field dosimetry.

Standard commercial diode detectors over-respond within small radiation fields, an effect largely attributable to the relatively high mass-density of silicon. However, Monte Carlo studies can be used to optimise dosimeter designs and have demonstrated that 'mass-density compensation'-for example, introducing a low-density air-gap upstream of a diode's high-density silicon volume-can substantially improve instrument response. In this work we used egs_chamber Monte Carlo simulations to predict the ideal air-gap thickness for a PTW 60017 unshielded diode detector. We then developed a prototype instrument incorporating that air-gap and, for a 6 MV linac, tested it experimentally against EBT3 film. We also tested a further three prototypes with different air-gap thicknesses. Our results demonstrate that for a 10 × 10 cm(2) reference field the DiodeAir, a PTW 60017 diode with a built-in air-gap of 1 mm, has on-axis correction factors near unity. Laterally the DiodeAir performs very well off-axis and reports FWHM and penumbra values consistent with those measured using EBT3. For PDD measurement, the performance of the DiodeAir matches that of the original PTW 60017. The experimental focus of this work was 6 MV but we also simulated the on-axis response of the DiodeAir within 15 MV beams and found that our modification proved robust to this substantial increase in beam energy. However, the original diode 60017 does exhibit low energy scatter dependencies and may over-respond to high linac dose-rates such that applying the mass-density compensation method to an alternative instrument (particularly a diamond detector) could ultimately take us even closer to the small-field ideal.

Mass-density compensation can improve the performance of a range of different detectors under non-equilibrium conditions.

Dosimeters often consist of several components whose mass densities differ substantially from water. These components cause small-field correction factors to vary significantly as lateral electronic equilibrium breaks down. Even amongst instruments designed for small-field dosimetry, inter-detector variation in the correction factors associated with very small (∼0.5 cm) fields can amount to tens of per cent. For a given dosimeter, small-field correction factors vary not only with field size but also with detector azimuthal angle and position within the field. Furthermore the accurate determination of these factors typically requires time-intensive Monte Carlo simulations. Thus, if achievable, 'correction factor free' small-field dosimetry would be highly desirable. This study demonstrates that a new generation of mass-density compensated detectors could take us towards this goal. Using a 6 MV beam model, it shows that 'mass-density compensation' can be utilized to improve the performance of a range of different detectors under small-field conditions. Non-sensitive material of appropriate mass-density is incorporated into detector designs in order to make the instruments behave as if consisting only of water. The dosimeter perturbative effects are then reduced to those associated with volume averaging. An even better solution-which modifies detectors to obtain profiles that look like those measured by a point-like water structure-is also considered. Provided that adequate sensitivity can be achieved for a small measurement volume, this study shows that it may be possible to use mass-density compensation (and Monte Carlo-driven design) to produce a solid-state dosimeter/ionization chamber with a near-perfect non-equilibrium response.

Detector density and small field dosimetry: integral versus point dose measurement schemes.

PURPOSE: The Alfonso et al. [Med. Phys. 35, 5179-5186 (2008)] formalism for small field dosimetry proposes a set of correction factors (kQclin,Qmsrfclin,fmsr) which account for differences between the detector response in nonstandard (clinical) and machine-specific-reference fields. In this study, the Monte Carlo method was used to investigate the viability of such small field correction factors for four different detectors irradiated under a variety of conditions. Because kQclin,Qmsrfclin,fmsr values for single detector position measurements are influenced by several factors, a new theoretical formalism for integrated-detector-position [dose area product (DAP)] measurements is also presented and was tested using Monte Carlo simulations. METHODS: A BEAMnrc linac model was built and validated for a Varian Clinac iX accelerator. Using the egs++ geometry package, detailed virtual models were built for four different detectors: a PTW 60012 unshielded diode, a PTW 60003 Diamond detector, a PTW 31006 PinPoint (ionization chamber), and a PTW 31018 MicroLion (liquid-filled ionization chamber). The egs_chamber code was used to investigate the variation of kQclin,Qmsrfclin,fmsr with detector type, detector construction, field size, off-axis position, and the azimuthal angle between the detector and beam axis. Simulations were also used to consider the DAP obtained by each detector: virtual detectors and water voxels were scanned through high resolution grids of positions extending far beyond the boundaries of the fields under consideration. RESULTS: For each detector, the correction factor (kQclin,Qmsrfclin,fmsr) was shown to depend strongly on detector off-axis position and detector azimuthal angle in addition to field size. In line with previous studies, substantial interdetector variation was also observed. However, it was demonstrated that by considering DAPs rather than single-detector-position dose measurements the high level of interdetector variation could be eliminated. Under small field conditions, mass density was found to be the principal determinant of water equivalence. Additionally, the mass densities of components outside the sensitive volumes were found to influence the detector response. CONCLUSIONS: kQclin,Qmsrfclin,fmsr values for existing detector designs depend on a host of variables and their calculation typically relies on the use of time-intensive Monte Carlo methods. Future moves toward density-compensated detector designs or DAP based protocols may simplify the methodology of small field dosimetry.

Pulsed brachytherapy: a modelled consideration of repair parameter uncertainties and their influence on treatment duration extension and daytime-only "block-schemes".

OBJECTIVES: The radiobiological modelling of all types of protracted brachytherapy is susceptible to uncertainties in the values of tissue repair parameters. Although this effect has been explored for many aspects of pulsed brachytherapy (PB), it is usually considered within the constraint of a fixed brachytherapy treatment time. Here the impact of repair parameter uncertainty is assessed for PB treatments of variable duration. The potential use of "block-schemes" (blocks of PB pulses separated by night-time gaps) is also investigated. METHODS: PB schedule constraints are based on the cervical cancer protocols of the Royal Marsden Hospital (RMH), but the methodology is applicable to any combination of starting schedule and treatment constraint. Calculations are performed using the biologically effective dose (BED) as a tissue-specific comparison metric. The ratio of normal tissue BED to tumour BED is considered for PB regimens with varying total pulse numbers and/or "block-schemes". RESULTS: For matched brachytherapy duration, PB has a good "window of opportunity" relative to the existing RMH continuous low dose rate (CLDR) practice for all modelled repair half-times. The most clear-cut route to radiobiological optimisation of PB is via modest temporal extension of the PB regimen relative to the CLDR reference. This option may be practicable for those centres with scope to extend their relatively short CLDR treatment durations. CONCLUSION: Although daytime-only "block-scheme" PB for cervical cancer has not yet been employed clinically, the possibilities appear to be theoretically promising, providing the overall (external beam plus brachytherapy) treatment duration is not extended relative to current practice, such that additional tumour repopulation becomes a concern.

Fast neutron relative biological effects and implications for charged particle therapy.

In two fast neutron data sets, comprising in vitro and in vivo experiments, an inverse relationship is found between the low-linear energy transfer (LET) α/ß ratio and the maximum value of relative biological effect (RBE(max)), while the minimum relative biological effect (RBE(min)) is linearly related to the square root of the low-LET α/ß ratio. RBE(max) is the RBE at near zero dose and can be represented by the ratio of the α parameters at high- and low-LET radiation exposures. RBE(min) is the RBE at very high dose and can be represented by the ratio of the square roots of the ß parameters at high- and low-LET radiation exposures. In principle, it may be possible to use the low-LET α/ß ratio to predict RBE(max) and RBE(min, )providing that other LET-related parameters, which reflect intercept and slopes of these relationships, are used. These two limits of RBE determine the intermediate values of RBE at any dose per fraction; therefore, it is possible to find the RBE at any dose per fraction. Although these results are obtained from fast neutron experiments, there are implications for charged particle therapy using protons (when RBE is scaled downwards) and for heavier ion beams (where the magnitude of RBE is similar to that for fast neutrons). In the case of fast neutrons, late reacting normal tissue systems and very slow growing tumours, which have the smallest values of the low-LET α/ß ratio, are predicted to have the highest RBE values at low fractional doses, but the lowest values of RBE at higher doses when they are compared with early reacting tissues and fast growing tumour systems that have the largest low-LET α/ß ratios.

The potential impact of relative biological effectiveness uncertainty on charged particle treatment prescriptions.

There continues to be uncertainty regarding the relative biological effectiveness (RBE) values that should be used in charged particle radiotherapy (CPT) prescriptions using protons and heavier ions. This uncertainty could potentially offset the physical dose advantage gained by exploiting the Bragg peak effect and it needs to be clearly understood by clinicians and physicists. This paper introduces a combined radiobiological and physical sparing factor (S). This factor includes the ratio of the most relevant physical doses in tumour and normal tissues in combination with their respective RBE values and can be extended to contain the uncertainties in RBE. S factors can be used to study, in a simplified way for tentative modelling, those clinical situations in which high-linear energy transfer (LET) irradiations are likely to prove preferable over their low-LET counterparts for a matched tumour iso-effect. In cases where CPT achieves an excellent degree of normal tissue sparing, the radiobiological factors become less important and any uncertainties in the tumour and healthy tissue RBE values are correspondingly less problematic. When less normal tissue sparing can be achieved, however, the RBE uncertainties assume greater relevance and will affect the reliability of the dose-prescription methodology. More research is required to provide accurate RBE estimation, focusing attention on the associated statistical uncertainties and potential differences in RBE between different tissue types.