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Background: For proton therapy, a relative biological effectiveness (RBE) of 1.1 is widely applied clinically. However, due to abundant evidence of variable RBE in vitro, and as suggested in studies of patient outcomes, RBE might increase by the end of the proton tracks, as described by several proposed variable RBE models. Typically, the dose averaged linear energy transfer (LETd) has been used as a radiation quality metric (RQM) for these models. However, the optimal choice of RQM has not been fully explored. Purpose: This study aims to propose novel RQMs that effectively weight protons of different energies, and assess their predictive power for variable RBE in proton therapy. The overall objective is to identify an RQM that better describes the contribution of individual particles to the RBE of proton beams. Methods: High-throughput experimental set-ups of in vitro cell survival studies for proton RBE determination are simulated utilizing the SHIELD-HIT12A Monte Carlo particle transport code. For every data point, the proton energy spectra are simulated, allowing the calculation of novel RQMs by applying different power levels to the spectra of LET or effective Q (Qeff) values. A phenomenological linear-quadratic-based RBE model is then applied to the in vitro data, using various RQMs as input variables, and the model performance is evaluated by root-mean-square-error (RMSE) for the logarithm of cell surviving fractions of each data point. Results: Increasing the power level, that is, putting an even higher weight on higher LET particles when constructing the RQM is generally associated with an increased model performance, with dose averaged LET3 (i.e., dose averaged cubed LET, cLETd) resulting in a RMSE value 0.31, compared to 0.45 for a model based on (linearly weighted) LETd, with similar trends also observed for track averaged and Qeff-based RQMs. Conclusions: The results indicate that improved proton variable RBE models can be constructed assuming a non-lin

Linear Energy Transfer (LET) is widely used to express the radiation quality of ion beams, when characterizing the biological effectiveness. However, averaged LET may be defined in multiple ways, and the chosen definition may impact the resulting reported value. We review averaged LET definitions found in the literature, and quantify which impact using these various definitions have for different reference setups. We recorded the averaged LET definitions used in 354 publications quantifying the relative biological effectiveness (RBE) of hadronic beams, and investigated how these various definitions impact the reported averaged LET using a Monte Carlo particle transport code. We find that the kind of averaged LET being applied is, generally, poorly defined. Some definitions of averaged LET may influence the reported averaged LET values up to an order of magnitude. For publications involving protons, most applied dose averaged LET when reporting RBE. The absence of what target medium is used and what secondary particles are included further contributes to an ill-defined averaged LET. We also found evidence of inconsistent usage of averaged LET definitions when deriving LET-based RBE models. To conclude, due to commonly ill-defined averaged LET and to the inherent problems of LET-based RBE models, averaged LET may only be used as a coarse indicator of radiation quality. We propose a more rigorous way of reporting LET values, and suggest that ideally the entire particle fluence spectra should be recorded and provided for future RBE studies, from which any type of averaged LET (or other quantities) may be inferred.

Ion beams passing through lung tissue show more pronounced energy straggling than expected for solid materials of the same thickness. Energy straggling in active scanning particle therapy can enlarge the pencil beam Bragg peaks in-depth as well as displace them, deteriorating the dose coverage of a target within the lung. While this is not yet considered in any known treatment planning system, we implement a mathematical model to be used for treatment planning, using TRiP98, which relies on a deterministic pencil beam algorithm. Through a randomization process based on a continuous Poisson probability distribution, the HU values of lung voxels are replaced with a modified value in successive iterations. The beam-modulation effect of the lung can thus be taken into account in treatment planning by recalculating the dose n times for n randomized CTs using the raster scan file of a plan that was optimized on the nonmodulated CT. The evaluation follows by averaging the resulting n dose distributions and comparing to the corresponding nonmodulated dose distribution, attending at dosimetric indices and dose-volume histograms. In this work, the functionality of these routines was tested for proton and carbon ion plans for two selected lung cancer patient cases with deep-seated tumors, showing that, with existing standard tools, it is possible to calculate the beam-modulation effect of the lung in TRiP98 in a transparent way. Variable model parameters, such as modulation power, voxel size and density voxel selection range, were evaluated. Furthermore, a systematic study for spherical geometries in a lung tissue CT cube is presented to investigate general trends.

Purpose: Conventional X-ray radiotherapy induces a pro-inflammatory response mediated by altered expression of inflammation-regulating cytokines. Proton scanning and X-ray irradiation produce distinct changes to cytokine gene expression in vitro suggesting that proton beam therapy may induce an inflammatory response dissimilar to that of X-ray radiation. The purpose of the present study was to determine whether proton scanning beam radiation and conventional X-ray photon radiation would induce differential regulation of circulating cytokines in vivo. Materials and methods: Female CDF1 mice were irradiated locally at the right hind leg using proton pencil beam scanning or X-ray photons. Blood samples were obtained from two separate mice groups. Samples from one group were drawn by retro-orbital puncture 16 months post irradiation, while samples from the other group were drawn 5 and 30 days post irradiation. Concentration of the cytokines IL-6, IL-1 beta, IL-10, IL-17A, IFN-gamma, and TNF alpha was measured in plasma using bead-based immunoassays. Results: The cytokines IL-6, IL-1 beta, IL-10, IFN-gamma, and TNF alpha were expressed at lower levels in plasma samples from proton-irradiated mice compared with X-ray-irradiated mice 16 months post irradiation. The same cytokines were downregulated in proton-irradiated mice 5 days post irradiation when compared to controls, while at day 30 expression had increased to the same level or higher. X-ray radiation did not markedly change expression levels at days 5 and 30. Conclusions: The inflammatory response to proton and X-ray irradiation seem to be distinct as the principal pro-inflammatory cytokines are differentially regulated short- and long-term following irradiation. Both the development of normal tissue damage and efficacy of immunotherapy could be influenced by an altered inflammatory response to irradiation.

Purpose: The dose response of Gafchromic EBT3 films exposed to proton beams depends on the dose, and additionally on the beam quality, which is often quantified with the linear energy transfer (LET) and, hence, also referred to as LET quenching. Fundamentally different methods to determine correction factors for this LET quenching effect have been reported in literature and a new method using the local proton fluence distribution differential in LET is presented. This method was exploited to investigate whether a more practical correction based on the dose- or fluence-averaged LET is feasible in a variety of clinically possible beam arrangements. Methods: The relative effectiveness (RE) was characterized within a high LET spread-out Bragg peak (SOBP) in water made up by the six lowest available energies (62.4-67.5 MeV, configuration b(1)) resulting in one of the highest clinically feasible dose-averaged LET distributions. Additionally, two beams were measured where a low LET proton beam (252.7 MeV) was superimposed on b1, which contributed either 50% of the initial particle fluence or 50% of the dose in the SOBP, referred to as configuration b(2) and b(3), respectively. The proton LET spectrum was simulated with GATE/Geant4 at all measurement positions. The net optical density change differential in LET was integrated over the local proton spectrum to calculate the net optical density and therefrom the beam quality correction factor. The LET dependence of the film response was accounted for by an LET dependence of one of the three parameters in the calibration function and was determined from inverse optimization using measurement b(1). This method was then validated on the measurements of b(2) and b(3) and subsequently used to calculate the RE at 900 positions in nine clinically relevant beams. The extrapolated RE set was used to derive a simple linear correction function based on dose-averaged LET (L-d) and verify the validity in all points of the comprehensive RE

The ion recombination is examined in parallel-plate ionization chambers in scanning proton beams at the Danish Centre for Particle Therapy and the Skandion Clinic. The recombination correction factor k(s) is investigated for clinically relevant energies between 70 MeV and 244 MeV for dose rates below 400 Gy min(-1) in air. The Boutillon formalism is used to separate the initial and general recombination. The general recombination is compared to predictions from the numerical recombination code IonTracks and the initial recombination to the Jaffe theory. k(s) is furthermore calculated with the two-voltage method (TVM) and extrapolation approaches, in particular the recently proposed three-voltage (3VL) method. The TVM is in agreement with the Boutillon method and IonTracks for dose rates above 100 Gy min(-1). However, the TVM calculated k(s) is closer related to the Jaffe theory for initial recombination for lower dose rate, indicating a limited application in scanning light ion beams. The 3VL is in turn found to generally be in agreement with Boutillon's method. The recombination is mapped as a function of the dose rate and proton energy at the two centres using the Boutillon formalism: the initial recombination parameter was found to be A = (0.10 +/- 0.01) V at DCPT and A = (0.22 +/- 0.13) V at Skandion, which is in better agreement with the Jaffe theory for initial recombination than previously reported values. The general recombination parameter was estimated to m2=(4.7 +/- 0.1).103V2nA-1cm-1m2=(7.2 +/- 0.1).103V2nA-1cm-1

The ion recombination is examined in parallel-plate ionization chambers in scanning proton beams at the Danish Centre for Particle Therapy and the Skandion Clinic. The recombination correction factorksis investigated for clinically relevant energies between 70 MeV and 224 MeV for dose rates below 400 Gy/min in air. The Boutillon formalism is used to separate the initial and general recombination. The general recombination is compared to predictions from the numerical recombination code IonTracks and the initial recombination to the Jaffé theory.ksis furthermore calculated with the two-voltage method (TVM) and extrapolation approaches, in particular the recently proposed three-voltage (3VL) method.. The TVM is in agreement with the Boutillon method and IonTracks for dose rates above 100 Gy/min. However, the TVM calculatedksis closer related to the Jaffé theory for initial recombination for lower dose rate, indicating a limited application in scanning light ion beams. The 3VL is in turn found to generally be in agreement with Boutillon's method. The recombination is mapped as a function of the dose rate and proton energy at the two centres using the Boutillon formalism: the initial recombination parameter was found to beA=(0.10±0.01) V at DCPT andA=(0.22±0.13) V at Skandion, which is in better agreement with the Jaffé theory for initial recombination than previously reported values. The general recombination parameter was estimated tom2= (4.7±0.1)×103V2nA-1cm-1andm2= (7.2±0.1)×103V2nA-1cm-1. Furthermore, the numerical algorithm IonTracks is demonstrated to correctly predict the initial recombination at low dose rates and general recombination at high dose rates.