Tuning spatially fractionated radiotherapy dose profiles using the moiré effect.

Spatially Fractionated Radiotherapy (SFRT) has demonstrated promising potential in cancer treatment, combining the advantages of reduced post-radiation effects and enhanced local control rates. Within this paradigm, proton minibeam radiotherapy (pMBRT) was suggested as a new treatment modality, possibly producing superior normal tissue sparing to conventional proton therapy, leading to improvements in patient outcomes. However, an effective and convenient beam generation method for pMBRT, capable of implementing various optimum dose profiles, is essential for its real-world application. Our study investigates the potential of utilizing the moiré effect in a dual collimator system (DCS) to generate pMBRT dose profiles with the flexibility to modify the center-to-center distance (CTC) of the dose distribution in a technically simple way.We employ the Geant4 Monte Carlo simulations tool to demonstrate that the angle between the two collimators of a DCS can significantly impact the dose profile. Varying the DCS angle from 10 ∘ to 50 ∘ we could cover CTC ranging from 11.8 mm to 2.4 mm, respectively. Further investigations reveal the substantial influence of the multi-slit collimator's (MSC) physical parameters on the spatially fractionated dose profile, such as period (CTC), throughput, and spacing between MSCs. These findings highlight opportunities for precision dose profile adjustments tailored to specific clinical scenarios.The DCS capacity for rapid angle adjustments during the energy transition stages of a spot scanning system can facilitate dynamic alterations in the irradiation profile, enhancing dose contrast in normal tissues. Furthermore, its unique attribute of spatially fractionated doses in both lateral directions could potentially improve normal tissue sparing by minimizing irradiated volume. Beyond the realm of pMBRT, the dual MSC system exhibits remarkable versatility, showing compatibility with different types of beams (X-rays and electrons) and applicability across various SFRT modalities.Our study illuminates the dual MSC system's potential as an efficient and adaptable tool in the refinement of pMBRT techniques. By enabling meticulous control over irradiation profiles, this system may expedite advancements in clinical and experimental applications, thereby contributing to the evolution of SFRT strategies.

Evaluation of in vitro irradiation setup: Designed for the horizontal beamline at the Danish Centre for Particle Therapy.

BACKGROUND: Radiobiological experimental setups are challenged by precise sample positioning along depth dose profile, scattering conditions, and practical difficulties that must be addressed in individual designs. The aim of this study was to produce cell survival curves with several irradiation modalities, by using a setup designed at the Danish Centre for Particle Therapy (DCPT) for in vitro proton irradiations using a horizontal beam line and thereby evaluating the setups use for in vitro irradiations experiments. MATERIALS AND METHODS: The setup is a water phantom suitable for in vitro research with multiple irradiation modalities, in particular the pencil scanning proton beam available from a horizontal experimental beamline. The phantom included a water tank of 39.0 × 17.0 × 20.5 cm. Cell survival-curves were produced using the cell line V79 Chinese hamster lung fibroblast cells (V79s) in biological triplicates of clonogenic assays. Cell survival curves were produced with both a 18 MeV electron beam, 6 MV photon beam, and a Spread-Out Bragg Peak (SOBP) proton beam formed by pristine energies of 85-111 MeV where three positions were examined. RESULTS: Survival curves with uncertainty areas were made for all modalities. Dosimetric uncertainty amounted to, respectively, 4%, 3% and 3% for proton, electron, and high energy photon irradiations. Cell survival fraction uncertainty was depicted as the standard deviation between replications of the experiment. CONCLUSION: Cell survival curves could be produced with acceptable uncertainties using this novel water phantom and cellular laboratory workflow. The setup is useful for future in vitro irradiation experiments.

An experimental setup for proton irradiation of a murine leg model for radiobiological studies.

BACKGROUND: The purpose of this study was to introduce an experimental radiobiological setup used for in vivo irradiation of a mouse leg target in multiple positions along a proton beam path to investigate normal tissue- and tumor models with varying linear energy transfer (LET). We describe the dosimetric characterizations and an acute- and late-effect assay for normal tissue damage. METHODS: The experimental setup consists of a water phantom that allows the right hind leg of three to five mice to be irradiated at the same time. Absolute dosimetry using a thimble (Semiflex) and a plane parallel (Advanced Markus) ionization chamber and Monte Carlo simulations using Geant4 and SHIELD-HIT12A were applied for dosimetric validation of positioning along the spread-out Bragg peak (SOBP) and at the distal edge and dose fall-off. The mice were irradiated in the center of the SOBP delivered by a pencil beam scanning system. The SOBP was 2.8 cm wide, centered at 6.9 cm depth, with planned physical single doses from 22 to 46 Gy. The biological endpoint was acute skin damage and radiation-induced late damage (RILD) assessed in the mouse leg. RESULTS: The dose-response curves illustrate the percentage of mice exhibiting acute skin damage, and at a later point, RILD as a function of physical doses (Gy). Each dose-response curve represents a specific severity score of each assay, demonstrating a higher ED50 (50% responders) as the score increases. Moreover, the results reveal the reversible nature of acute skin damage as a function of time and the irreversible nature of RILD as time progresses. CONCLUSIONS: We want to encourage researchers to report all experimental details of their radiobiological setups, including experimental protocols and model descriptions, to facilitate transparency and reproducibility. Based on this study, more experiments are being performed to explore all possibilities this radiobiological experimental setup permits.

Optically stimulated luminescence detectors for dosimetry and LET measurements in light ion beams.

Objective.This work investigates the use of Al2O3:C and Al2O3:C,Mg optically stimulated luminescence (OSL) detectors to determine both the dose and the radiation quality in light ion beams. The radiation quality is here expressed through either the linear energy transfer (LET) or the closely related metricQeff, which depends on the particle's speed and effective charge. The derived LET andQeffvalues are applied to improve the dosimetry in light ion beams.Approach.OSL detectors were irradiated in mono-energetic1H-,4He-,12C-, and16O-ion beams. The OSL signal is associated with two emission bands that were separated using a pulsed stimulation technique and subjected to automatic corrections based on reference irradiations. Each emission band was investigated independently for dosimetry, and the ratio of the two emission intensities was parameterized as a function of fluence- and dose-averaged LET, as well asQeff. The determined radiation quality was subsequently applied to correct the dose for ionization quenching.Main results.For both materials, theQeffdeterminations in1H- and4He-ion beams are within 5 % of the Monte Carlo simulated values. Using the determined radiation quality metrics to correct the nonlinear (ionization quenched) detector response leads to doses within 2 % of the reference doses.Significance.Al2O3:C and Al2O3:C,Mg OSL detectors are applicable for dosimetry and radiation quality estimations in1H- and4He-ions. Only Al2O3:C,Mg shows promising results for dosimetry in12C-ions. Across both materials and the investigated ions, the estimatedQeffvalues were less sensitive to the ion types than the estimated LET values were. The reduced uncertainties suggest new possibilities for simultaneously estimating the physical and biological dose in particle therapy with OSL detectors.

Modeling RBE with other quantities than LET significantly improves prediction of in vitro cell survival for proton therapy.

BACKGROUND: For proton therapy, a relative biological effectiveness (RBE) of 1.1 has broadly been applied clinically. However, as unexpected toxicities have been observed by the end of the proton tracks, variable RBE models have been proposed. Typically, the dose-averaged linear energy transfer (LETd ) has been used as an input variable for these models but the way the LETd was defined, calculated, or determined was not always consistent, potentially impacting the corresponding RBE value. PURPOSE: This study compares consistently calculated LETd with other quantities as input variables for a phenomenological RBE model and attempts to determine which quantity that can best predicts proton RBE. The comparison was performed within the frame of introducing a new model for the proton RBE. METHODS: High-throughput experimental setups of in vitro cell survival studies for proton RBE determination are simulated using the SHIELD-HIT12A Monte Carlo particle transport code. Together with LET, z ∗ 2 / ß 2 $z^{*2}/\beta ^2$ , here called effective Q (Qeff ), and Q are scored. Each quantity is calculated using the dose and track averaging methods, because the scoring includes all hadronic particles, all protons or only primaries. A phenomenological linear-quadratic-based RBE model is subsequently applied to the in vitro data with the various beam quality descriptors used as input variables and the goodness of fit is determined and compared using a bootstrapping approach. Both linear and nonlinear fit functions were tested. RESULTS: Versions of Qeff and Q outperform LET with a statistically significant margin, with the best nonlinear and linear fit having a relative root mean square error (RMSE) for RBE2Gy ± one standard error of 1.55 ± 0.04 (Qeff, t, primary ) and 2.84 ± 0.07 (Qeff, d, primary ), respectively. For comparison, the corresponding best nonlinear and linear fits for LETd, all protons had a relative RMSE of 2.07 ± 0.06 and 3.39 ± 0.08, respectively. Applying Welch's t-test for comparing the calculated RMSE of RBE2Gy resulted in two-tailed p-values of <0.002 for all Q and Qeff quantities compared to LETd, all protons . CONCLUSIONS: The study shows that Q or Qeff could be better RBE descriptors that dose averaged LET.

A systematic review on the usage of averaged LET in radiation biology for particle therapy.

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.

Proton scanning and X-ray beam irradiation induce distinct regulation of inflammatory cytokines in a preclinical mouse model.

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-1ß, IL-10, IL-17A, IFN-γ, and TNFα was measured in plasma using bead-based immunoassays. RESULTS: The cytokines IL-6, IL-1ß, IL-10, IFN-γ, and TNFα 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.

Dose- rather than fluence-averaged LET should be used as a single-parameter descriptor of proton beam quality for radiochromic film dosimetry.

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 " b 1 ", 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 set. RESULTS: The uncorrected film dose deviated up to 26% from the reference dose, whereas the corrected film dose agreed within 3% in all three beams in water (" b 1 ", " b 2 " and " b 3 "). The LET dependence of the calibration function started to strongly increase around 5 keV/µm and flatten out around 30 keV/µm. All REs calculated from the proton fluence in the nine simulated beams could be approximated with a linear function of dose-averaged LET (RE = 1.0258-0.0211 µm/keV L d ). However, no functional relationship of RE- and fluence-averaged LET could be found encompassing all beam energies and modulations. CONCLUSIONS: The film quenching was found to be nonlinear as a function of proton LET as well as of the dose-averaged LET. However, the linear relation of RE on dose-averaged LET was a good approximation in all cases. In contrast to dose-averaged LET, fluence-averaged LET could not describe the RE when multiple beams were applied.

Ionization quenching in scintillators used for dosimetry of mixed particle fields.

Ionization quenching in ion beam dosimetry is often related to the fluence- or dose-averaged linear energy transfer (LET). Both quantities are however averaged over a wide LET range and a mixed field of primary and secondary ions. We propose a novel method to correct the quenched luminescence in scintillators exposed to ion beams. The method uses the energy spectrum of the primaries and accounts for the varying quenched luminescence in heavy, secondary ion tracks through amorphous track structure theory. The new method is assessed against more traditional approaches by correcting the quenched luminescence response from the BCF-12, BCF-60, and 81-0084 plastic scintillators exposed to a 100 MeV pristine proton beam in order to compare the effects of the averaged LET quantities and the secondary ions. Calculations and measurements show that primary protons constitute more than 92% of the energy deposition but account for more than 95% of the luminescence signal in the scintillators. The quenching corrected luminescence signal is in better agreement with the dose measurement when the secondary particles are taken into account. The Birks model provided the overall best quenching corrections, when the quenching corrected signal is adjusted for the number of free model parameters. The quenching parameter kB for the BCF-12 and BCF-60 scintillators is in agreement with literature values and was found to be [Formula: see text] [Formula: see text]m keV-1 for the 81-0084 scintillator. Finally, a fluence threshold for the 100 MeV proton beam was calculated to be of the order of 1010 cm-2, corresponding to 110 Gy, above which the quenching increases non-linearly and the Birks model no longer is applicable.

Comparison of Coding Transcriptomes in Fibroblasts Irradiated With Low and High LET Proton Beams and Cobalt-60 Photons.

PURPOSE: To identify differential cellular responses after proton and photon irradiation by comparing transcriptomes of primary fibroblasts irradiated with either radiation type. METHODS AND MATERIALS: A panel of primary dermal fibroblast cultures was irradiated with low and higher linear energy transfer (LET) proton beams. Cobalt-60 photon irradiation was used as reference. Dose was delivered in 3 fractions of 3.5 Gy (relative biological effectiveness) using a relative biological effectiveness of 1.1 for proton doses. Cells were harvested 2 hours after the final fraction was delivered, and RNA was purified. RNA sequencing was performed using Illumina NextSeq 500 with high-output kit. The edgeR package in R was used for differential gene expression analysis. RESULTS: Pairwise comparisons of the transcriptomes in the 3 treatment groups showed that there were 84 and 56 differentially expressed genes in the low LET group compared with the Cobalt-60 group and the higher LET group, respectively. The higher LET proton group and the Cobalt-60 group had the most distinct transcriptome profiles, with 725 differentially regulated genes. Differentially regulated canonical pathways and various regulatory factors involved in regulation of biological mechanisms such as inflammation, carcinogenesis, and cell cycle control were identified. CONCLUSIONS: Inflammatory regulators associated with the development of normal tissue complications and malignant transformation factors seem to be differentially regulated by higher LET proton and Cobalt-60 photon irradiation. The reported transcriptome differences could therefore influence the progression of adverse effects and the risk of developing secondary cancers.

THE ROLE OF PARTICLE SPECTRA IN MODELING THE RELATIVE BIOLOGICAL EFFECTIVENESS OF PROTON RADIOTHERAPY BEAMS.

Radiotherapy beams of protons or heavier ions generate secondary particles through nuclear interactions over different patient tissues. The resulting particle spectra depend on the tissue composition and on charge and energy of the primary beam ions. In proton radiotherapy, predictive radiobiological models usually apply dose-averaged linear energy transfer (LET). Microdosimetry-based models for proton or heavier ion primary beams also rely on dose-averaged quantities, the values of which depend on whether the produced secondaries are included or excluded in the calculation. In turn, this will affect the results of calculations of the relative biological effectiveness (RBE) of these beams. In this brief note, we study quantitatively the influence of the secondary radiation spectra on the averaged expectation values of LET and their impact on predictions of RBE. It is noted that for microdosimetry-based quantities and for corresponding LET-based parameters the trends are similar and that fluence-averaged quantities should be studied more closely.

Validation of new 2D ripple filters in proton treatments of spherical geometries and non-small cell lung carcinoma cases.

A ripple filter (RiFi) is a passive energy modulator used in scanned particle therapy to broaden the Bragg peak, thus lowering the number of accelerator energies required for homogeneous target coverage, which significantly reduces the irradiation time. As we have previously shown, a new 6 mm thick RiFi with 2D groove shapes produced with 3D printing can be used in carbon ion treatments with a similar target coverage and only a marginally worse planning conformity compared to treatments with in-use 3 mm thick RiFis of an older 1D design. Where RiFis are normally not used with protons due to larger scattering and straggling effects, this new design would be beneficial in proton therapy too. Measurements of proton Bragg curves and lateral beam profiles were carried out for different RiFi designs and thicknesses as well as for no RiFi at the Heidelberg Ionenstrahl-Therapiezentrum. Base data for proton treatment planning were generated with the Monte Carlo code SHIELD-HIT12A with and without the 2D 6 mm RiFi. Plans on spherical targets in water were calculated with TRiP98 for a systematic RiFi performance analysis and for comparisons with carbon ion plans for the same respective energy depth step sizes. Plans for 9 stage I static non small cell lung cancer patients were calculated with Eclipse 13.7.15. Dose-volume-histograms, spatial dose distributions and dosimetric indexes were used for plan evaluation. Measurements confirm the functionality of the new 2D RiFi design, which reduces the beam spot size compared to 1D RiFis of the same thickness. Planning studies show that a 6 mm thick 2D RiFi could be used in proton therapy to lower the irradiation time. Although slightly worse planning conformity and dose homogeneity were found for plans with the RiFi compared to plans without, satisfactory results within the planning objective were obtained for all cases.

Computational models and tools.

In this chapter, we describe two different methods, analytical (pencil beam) algorithms and Monte Carlo simulations, used to obtain the intended dose distributions in patients and evaluate their strengths and shortcomings. We discuss the difference between the prescribed physical dose and the biologically effective dose, the relative biological effectiveness (RBE) between ions and photons and the dependence of RBE on the linear energy transfer (LET). Lastly, we show how LET- or RBE-based optimization can be used to improve treatment plans and explore how the availability of multimodality ion beam facilities can be used to design a tumor-specific optimal treatment.

Optimal reference genes for normalization of qPCR gene expression data from proton and photon irradiated dermal fibroblasts.

The transcriptional response of cells exposed to proton radiation is not equivalent to the response induced by traditional photon beams. Changes in cellular signalling is most commonly studied using the method Quantitative polymerase chain reaction (qPCR). Stable reference genes must be used to accurately quantify target transcript expression. The study aim was to identify suitable reference genes for normalisation of gene expression levels in normal dermal fibroblasts irradiated with either proton or photon beams. The online tool RefFinder was used to analyse and identify the most stably expressed genes from a panel of 22 gene candidates. To assess the reliability of the identified reference genes, a selection of the most and least stable reference genes was used to normalise target transcripts of interest. Fold change levels varied considerably depending on the used reference gene. The top ranked genes IPO8, PUM1, MRPL19 and PSMC4 produced highly similar target gene expression, while expression using the worst ranked genes, TFRC and HPRT1, was clearly modified due to reference gene instability.

Quantitative evaluation of potential irradiation geometries for carbon-ion beam grid therapy.

PURPOSE: Radiotherapy using grids containing cm-wide beam elements has been carried out sporadically for more than a century. During the past two decades, preclinical research on radiotherapy with grids containing small beam elements, 25 µm-0.7 mm wide, has been performed. Grid therapy with larger beam elements is technically easier to implement, but the normal tissue tolerance to the treatment is decreasing. In this work, a new approach in grid therapy, based on irradiations with grids containing narrow carbon-ion beam elements was evaluated dosimetrically. The aim formulated for the suggested treatment was to obtain a uniform target dose combined with well-defined grids in the irradiated normal tissue. The gain, obtained by crossfiring the carbon-ion beam grids over a simulated target volume, was quantitatively evaluated. METHODS: The dose distributions produced by narrow rectangular carbon-ion beams in a water phantom were simulated with the PHITS Monte Carlo code. The beam-element height was set to 2.0 cm in the simulations, while the widths varied from 0.5 to 10.0 mm. A spread-out Bragg peak (SOBP) was then created for each beam element in the grid, to cover the target volume with dose in the depth direction. The dose distributions produced by the beam-grid irradiations were thereafter constructed by adding the dose profiles simulated for single beam elements. The variation of the valley-to-peak dose ratio (VPDR) with depth in water was thereafter evaluated. The separation of the beam elements inside the grids were determined for different irradiation geometries with a selection criterion. RESULTS: The simulated carbon-ion beams remained narrow down to the depths of the Bragg peaks. With the formulated selection criterion, a beam-element separation which was close to the beam-element width was found optimal for grids containing 3.0-mm-wide beam elements, while a separation which was considerably larger than the beam-element width was found advantageous for grids containing 0.5-mm-wide beam elements. With the single-grid irradiation setup, the VPDRs were close to 1.0 already at a distance of several cm from the target. The valley doses given to the normal tissue at 0.5 cm distance from the target volume could be limited to less than 10% of the mean target dose if a crossfiring setup with four interlaced grids was used. CONCLUSIONS: The dose distributions produced by grids containing 0.5- and 3.0-mm wide beam elements had characteristics which could be useful for grid therapy. Grids containing mm-wide carbon-ion beam elements could be advantageous due to the technical ease with which these beams can be produced and delivered, despite the reduced threshold doses observed for early and late responding normal tissue for beams of millimeter width, compared to submillimetric beams. The treatment simulations showed that nearly homogeneous dose distributions could be created inside the target volumes, combined with low valley doses in the normal tissue located close to the target volume, if the carbon-ion beam grids were crossfired in an interlaced manner with optimally selected beam-element separations. The formulated selection criterion was found useful for the quantitative evaluation of the dose distributions produced by the different irradiation setups.

MONTE CARLO SIMULATIONS OF SPATIAL LET DISTRIBUTIONS IN CLINICAL PROTON BEAMS.

The linear energy transfer (LET) is commonly used as a parameter which describes the quality of the radiation applied in radiation therapy with fast ions. In particular in proton therapy, most models which predict the radiobiological properties of the applied beam, are fitted to the dose-averaged LET, LETd. The related parameter called the fluence- or track-averaged LET, LETt, is less frequently used. Both LETt and in particular LETd depends profoundly on the encountered secondary particle spectrum. For proton beams including all secondary particles, LETd may reach more than 3 keV/um in the entry channel of the proton field. However, typically the charged particle spectrum is only averaged over the primary and secondary protons, which is in the order of 0.5 keV/um for the same region. This is equal to assuming that the secondary particle spectrum from heavier ions is irrelevant for the resulting radiobiology, which is an assertion in the need of closer investigation. Models which rely on LETd should also be clear on what type of LETd is used, which is not always the case. Within this work, we have extended the Monte Carlo particle transport code SHIELD-HIT12A to provide dose- and track-average LET-maps for ion radiation therapy treatment plans.

Differential gene expression in primary fibroblasts induced by proton and cobalt-60 beam irradiation.

INTRODUCTION: Proton beam therapy delivers a more conformal dose distribution than conventional radiotherapy, thus improving normal tissue sparring. Increasing linear energy transfer (LET) along the proton track increases the relative biological effectiveness (RBE) near the distal edge of the Spread-out Bragg peak (SOBP). The severity of normal tissue side effects following photon beam radiotherapy vary considerably between patients. AIM: The dual study aim was to identify gene expression patterns specific to radiation type and proton beam position, and to assess whether individual radiation sensitivity influences gene expression levels in fibroblast cultures irradiated in vitro. METHODS: The study includes 30 primary fibroblast cell cultures from patients previously classified as either radiosensitive or radioresistant. Cells were irradiated at three different positions in the proton beam profile: entrance, mid-SOBP and at the SOBP distal edge. Dose was delivered in three fractions × 3.5 Gy(RBE) (RBE 1.1). Cobalt-60 (Co-60) irradiation was used as reference. Real-time qPCR was performed to determine gene expression levels for 17 genes associated with inflammation response, fibrosis and angiogenesis. RESULTS: Differences in median gene expression levels were observed for multiple genes such as IL6, IL8 and CXCL12. Median IL6 expression was 30%, 24% and 47% lower in entrance, mid-SOBP and SOBP distal edge groups than in Co-60 irradiated cells. No genes were found to be oppositely regulated by different radiation qualities. Radiosensitive patient samples had the strongest regulation of gene expression; irrespective of radiation type. CONCLUSIONS: Our findings indicate that the increased LET at the SOBP distal edge position did not generally lead to increased transcriptive response in primary fibroblast cultures. Inflammatory factors were generally less extensively upregulated by proton irradiation compared with Co-60 photon irradiation. These effects may possibly influence the development of normal tissue damage in patients treated with proton beam therapy.

Development of an interlaced-crossfiring geometry for proton grid therapy.

BACKGROUND: Grid therapy has in the past normally been performed with single field photon-beam grids. In this work, we evaluated a method to deliver grid therapy based on interlacing and crossfiring grids of mm-wide proton beamlets over a target volume, by Monte Carlo simulations. MATERIAL AND METHODS: Dose profiles for single mm-wide proton beamlets (1, 2 and 3 mm FWHM) in water were simulated with the Monte Carlo code TOPAS. Thereafter, grids of proton beamlets were directed toward a cubic target volume, located at the center of a water tank. The aim was to deliver a nearly homogeneous dose to the target, while creating high dose heterogeneity in the normal tissue, i.e., high gradients between valley and peak doses in the grids, down to the close vicinity of the target. RESULTS: The relative increase of the beam width with depth was largest for the smallest beams (+6.9 mm for 1 mm wide and 150 MeV proton beamlets). Satisfying dose coverage of the cubic target volume (σ < ±5%) was obtained with the interlaced-crossfiring setup, while keeping the grid pattern of the dose distribution down to the target (valley-to-peak dose ratio <0.5 less than 1 cm before the target). Center-to-center distances around 7-8 mm between the beams were found to give the best compromise between target dose homogeneity and low peak doses outside of the target. CONCLUSIONS: A nearly homogeneous dose distribution can be obtained in a target volume by crossfiring grids of mm-wide proton-beamlets, while maintaining the grid pattern of the dose distribution at large depths in the normal tissue, close to the target volume. We expect that the use of this method will increase the tumor control probability and improve the normal tissue sparing in grid therapy.

Relative biological effectiveness (RBE) and distal edge effects of proton radiation on early damage in vivo.

INTRODUCTION: The aim of the present study was to examine the RBE for early damage in an in vivo mouse model, and the effect of the increased linear energy transfer (LET) towards the distal edge of the spread-out Bragg peak (SOBP). METHOD: The lower part of the right hind limb of CDF1 mice was irradiated with single fractions of either 6 MV photons, 240 kV photons or scanning beam protons and graded doses were applied. For the proton irradiation, the leg was either placed in the middle of a 30-mm SOBP, or to assess the effect in different positions, irradiated in 4 mm intervals from the middle of the SOBP to behind the distal dose fall-off. Irradiations were performed with the same dose plan at all positions, corresponding to a dose of 31.25 Gy in the middle of the SOBP. Endpoint of the study was early skin damage of the foot, assessed by a mouse foot skin scoring system. RESULTS: The MDD50 values with 95% confidence intervals were 36.1 (34.2-38.1) Gy for protons in the middle of the SOBP for score 3.5. For 6 MV photons, it was 35.9 (34.5-37.5) Gy and 32.6 (30.7-34.7) Gy for 240 kV photons for score 3.5. The corresponding RBE was 1.00 (0.94-1.05), relative to 6 MV photons and 0.9 (0.85-0.97) relative to 240 kV photons. In the mice group positioned at the SOBP distal dose fall-off, 25% of the mice developed early skin damage compared with 0-8% in other groups. LETd,z = 1 was 8.4 keV/µm at the distal dose fall-off and the physical dose delivered was 7% lower than in the central SOBP position, where LETd,z =1 was 3.3 keV/µm. CONCLUSIONS: Although there is a need to expand the current study to be able to calculate an exact enhancement ratio, an enhanced biological effect in vivo for early skin damage in the distal edge was demonstrated.