Search

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. 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-1β, IL-10, IL-17A, IFN-γ, and TNFα was measured in plasma using bead-based immunoassays. The cytokines IL-6, IL-1β, 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. 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

At EuXFEL, a stray field of ionizing radiation is present near undulator magnets which eventually can lead to their demagnetization and decreased efficiency of the Self-Amplified Spontaneous Emission (SASE) process. In this work we investigate both the origin and composition of the radiation field at the undulator magnets with gafchromic film measurements and Geant4 Monte Carlo simulations. Both measurements and simulations suggest that the radiation field in the upstream undulator cells comes from high-energy electrons striking the beam pipe. In addition, horizontal dose distributions at the entrance of the undulator segments depend on where the electrons hit the beam pipe. Geant4 simulations show that the radiation fluence near magnets is dominated by photons, while charged secondary electrons and positrons contribute almost entirely to the ionizing dose absorbed by magnets. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 irradiatedin 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 asIL6,IL8andCXCL12. MedianIL6expression 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. [ABSTRACT FROM AUTHOR]

Introduction:The aim of the present study was to examine the RBE for early damage in anin vivomouse 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 MDD50values 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 = 1was 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 =1was 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 effectin vivofor early skin damage in the distal edge was demonstrated. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Purpose: Accurately predicting the range of radiotherapy ions in vivo is important for the precise delivery of dose in particle therapy. Range uncertainty is currently the single largest contribution to the dose margins used in planning and leads to a higher dose to normal tissue. The use of ion CT has been proposed as a method to improve the range uncertainty and thereby reduce dose to normal tissue of the patient. A wide variety of ions have been proposed and studied for this purpose, but no studies evaluate the image quality obtained with different ions in a consistent manner. However, imaging doses ion CT is a concern which may limit the obtainable image quality. In addition, the imaging doses reported have not been directly comparable with x-ray CT doses due to the different biological impacts of ion radiation. The purpose of this work is to develop a robust methodology for comparing the image quality of ion CT with respect to particle therapy, taking into account different reconstruction methods and ion species. Methods: A comparison of different ions and energies was made. Ion CT projections were simulated for five different scenarios: Protons at 230 and 330 MeV, helium ions at 230 MeV/u, and carbon ions at 430 MeV/u. Maps of the water equivalent stopping power were reconstructed using a weighted least squares method. The dose was evaluated via a quality factor weighted CT dose index called the CT dose equivalent index (CTDEI). Spatial resolution was measured by the modulation transfer function. This was done by a noise-robust fit to the edge spread function. Second, the image quality as a function of the number of scanning angles was evaluated for protons at 230 MeV. In the resolution study, the CTDEI was fixed to 10 mSv, similar to a typical x-ray CT scan. Finally, scans at a range of CTDEI's were done, to evaluate dose influence on reconstruction error. Results: All ions yielded accurate stopping power estimates, none of which were statistically different from the ground truth image. Resolution (as defined by the modulation transfer function = 10% point) was the best for the helium ions (18.21 line pairs/cm) and worst for the lower energy protons (9.37 line pairs/cm). The weighted quality factor for the different ions ranged from 1.23 for helium to 2.35 for carbon ions. For the angle study, a sharp increase in absolute error was observed below 45 distinct angles, giving the impression of a threshold, rather than smooth, limit to the number of angles. Conclusions: The method presented for comparing various ion CT modalities is feasible for practical use. While all studied ions would improve upon x-ray CT for particle range estimation, helium appears to give the best results and deserves further study for imaging. [ABSTRACT FROM AUTHOR]

LET-painting was suggested as a method to overcome tumour hypoxia. In vitro experiments have demonstrated a well-established relationship between the oxygen enhancement ratio (OER) and linear energy transfer (LET), where OER approaches unity for high-LET values. However, high-LET radiation also increases the risk for side effects in normal tissue. LET-painting attempts to restrict high-LET radiation to compartments that are found to be hypoxic, while applying lower LET radiation to normoxic tissues. Methods. Carbon-12 and oxygen-16 ion treatment plans with four fields and with homogeneous dose in the target volume, are applied on an oropharyngeal cancer case with an identified hypoxic entity within the tumour. The target dose is optimised to achieve a tumour control probability (TCP) of 95% when assuming a fully normoxic tissue. Using the same primary particle energy fluence needed for this plan, TCP is recalculated for three cases assuming hypoxia: first, redistributing LET to match the hypoxic structure (LET-painting). Second, plans are recalculated for varying hypoxic tumour volume in order to investigate the threshold volume where TCP can be established. Finally, a slight dose boost (5-20%) is additionally allowed in the hypoxic subvolume to assess its impact on TCP. Results. LET-painting with carbon-12 ions can only achieve tumour control for hypoxic subvolumes smaller than 0.5 cm3. Using oxygen-16 ions, tumour control can be achieved for tumours with hypoxic subvolumes of up to 1 or 2 cm3. Tumour control can be achieved for tumours with even larger hypoxic subvolumes, if a slight dose boost is allowed in combination with LET-painting. Conclusion. Our findings clearly indicate that a substantial increase in tumour control can be achieved when applying the LET-painting concept using oxygen-16 ions on hypoxic tumours, ideally with a slight dose boost. [ABSTRACT FROM AUTHOR]

Introduction. Modern particle therapy facilities enable sub-millimeter precision in dose deposition. Here, also ionization chambers (ICs) are used, which requires knowledge of the recombination effects. Up to now, recombination is corrected using phenomenological approaches for practical reasons. In this study the effect of the underlying dose distribution on columnar recombination, a quantitative model for initial recombination, is investigated. Material and methods. Jaffé's theory, formulated in 1913 quantifies initial recombination by elemental processes, providing an analytical (closed) solution. Here, we investigate the effect of the underlying charged carrier distribution around a carbon ion track. The fundamental partial differential equation, formulated by Jaffé, is solved numerically taking into account more realistic charge carrier distributions by the use of a computer program (Gascoigne 3D). The investigated charge carrier distributions are based on track structure models, which follow a 1/ r2 behavior at larger radii and show a constant value at small radii. The results of the calculations are compared to the initial formulation and to data obtained in experiments using carbon ion beams. Results. The comparison between the experimental data and the calculations shows that the initial approach made by Jaffé is able to reproduce the effects of initial recombination. The amorphous track structure based charge carrier distribution does not reproduce the experimental data well. A small additional correction in the assessment of the saturation current or charge is suggested by the data. Conclusion. The established model of columnar recombination reproduces the experimental data well, whereas the extensions using track structure models do not show such an agreement. Additionally, the effect of initial recombination on the saturation curve (i.e. Jaffé plot) does not follow a linear behavior as suggested by current dosimetry protocols, therefore higher order corrections (such as the investigated ones) might be necessary. [ABSTRACT FROM AUTHOR]

Introduction: A significant part of the secondary particle spectrum from antiproton annihilation consists of fast neutrons, which may contribute to a significant dose background found outside the primary beam. Materials and Methods: Using a polystyrene phantom as a moderator, we have performed absolute fluence measurements of the thermalized part of the fast neutron spectrum using Lithium-6 and −7 Fluoride TLD pairs. The results were compared with the Monte Carlo particle transport code FLUKA. Results: The experimental results are found to be in good agreement with simulations. The thermal neutron kerma resulting from the measured thermal neutron fluence is insignificant compared to the contribution from fast neutrons. Discussion: The secondary neutron fluences encountered in antiproton therapy are found to be similar to values calculated for pion treatment, however exact modeling under more realistic treatment scenarios is still required to quantitatively compare these treatment modalities. [ABSTRACT FROM AUTHOR]

Tumour hypoxia is one of the limiting factors in obtaining tumour control in radiotherapy. The high-LET region of a beam of heavy charged particles such as carbon ions is located in the distal part of the Bragg peak. A modulated or spread out Bragg peak (SOBP) is a weighted function of several Bragg peaks at various energies, which however results in a dilution of the dose-average LET in the target volume. Here, we investigate the possibility to redistribute the LET by dedicated treatment plan optimisation, in order to maximise LET in the target volume. This may be a strategy to potentially overcome hypoxia along with dose escalation or dose painting. The high-LET region can be shaped in very different ways, while maintaining the distribution of the absorbed dose or biological effective dose. Treatment plans involving only carbon ion beams, show very different LET distributions depending on how the fields are arranged. Alternatively, a LET boost can be applied in multi-modal treatment planning, such as combining carbon ions with protons and/or photons. For such mixed radiation modalities, significant “LET boosts” can be achieved at nearly arbitrary positions within the target volume. Following the general understanding of the relationship between hypoxia, LET and the oxygen enhancement ratio (OER), we conclude, that an additional therapeutic advantage can be achieved by confining the high-LET part of the radiation in hypoxic compartments of the tumour, and applying low-LET radiation to the normoxic tissue. We also anticipate that additional advantages may be achieved by deliberate sparing of normal tissue from high LET regions. Consequently, treatment planning based on simultaneous dose and LET optimisation has a potential to achieve higher tumour control and/or reduced normal tissue control probability (NTCP). [ABSTRACT FROM AUTHOR]

Abstract: Background and purpose: Antiprotons have been suggested as a possibly superior modality for radiotherapy, due to the energy released when antiprotons annihilate, which enhances the Bragg peak and introduces a high-LET component to the dose. However, concerns are expressed about the inferior lateral dose distribution caused by the annihilation products. Methods: We use the Monte Carlo code FLUKA to generate depth–dose kernels for protons, antiprotons, and carbon ions. Using these we then build virtual treatment plans optimized according to ICRU recommendations for the different beam modalities, which then are recalculated with FLUKA. Dose–volume histograms generated from these plans can be used to compare the different irradiations. Results: The enhancement in physical and possibly biological dose from annihilating antiprotons can significantly lower the dose in the entrance channel; but only at the expense of a diffuse low dose background from long-range secondary particles. Lateral dose distributions are improved using active beam delivery methods, instead of flat fields. Conclusions: Dose–volume histograms for different treatment scenarios show that antiprotons have the potential to reduce the volume of normal tissue receiving medium to high dose, however, in the low dose region antiprotons are inferior to both protons and carbon ions. This limits the potential usage to situations where dose to normal tissue must be reduced as much as possible. [Copyright &y& Elsevier]

Purpose: Radiotherapy of cancer carries a perceived risk of inducing secondary cancer and other damage due to dose delivered to normal tissue. While expectedly small, this risk must be carefully analysed for all modalities. Especially in the use of exotic particles like pions and antiprotons, which annihilate and produce a mixed radiation field when interacting with normal matter nuclei, the biological effective dose far out of field needs to be considered in evaluating this approach. We describe first biological measurements to address the concern that medium and long range annihilation products may produce a significant background dose and reverse any benefits of higher biological dose in the target area. Materials and methods: Using the Antiproton Decelerator (AD) at CERN (Conseil Européen pour la Recherche Nucléaire) we irradiated V-79 Chinese Hamster cells embedded in gelatine using an antiproton beam with fluence ranging from 4.5 × 108 to 4.5 × 109 particles, and evaluated the biological effect on cells located distal to the Bragg peak using clonogenic survival and the COMET assay. Results: Both methods show a substantial biological effect on the cells in the entrance channel and the Bragg Peak area, but any damage is reduced to levels well below the effect in the entrance channel 15 mm distal to the Bragg peak for even the highest particle fluence used. Conclusions: The annihilation radiation generated by antiprotons stopping in biological targets causes an increase of the penumbra of the beam but the effect rapidly decreases with distance from the target volume. No major increase in the biological effect is found in the far field outside of the primary beam. [ABSTRACT FROM AUTHOR]

Many papers discussed the I value for water given by the ICRU, concluding that a value of about 80±2 eV instead of 67.2 eV would reproduce measured ion depth-dose curves. A change in the I value for water would have an effect on the stopping power and, hence, on the water-to-air stopping power ratio, which is important in clinical dosimetry of proton and ion beams. For energies ranging from 50 to 330 MeV/u and for one spread out Bragg peak, the authors compare the impact of the I value on the water-to-air stopping power ratio. The authors calculate ratios from different ICRU stopping power tables and ICRU reports. The stopping power ratio is calculated via track-length dose calculation with SHIELD-HIT07. In the calculations, the stopping power ratio is reduced to a value of 1.119 in the plateau region as compared to the cited value of 1.13 in IAEA TRS-398. At low energies the stopping power ratio increases by up to 6% in the last few tenths of a mm toward the Bragg peak. For a spread out Bragg peak of 13.5 mm width at 130 mm depth, the stopping power ratio increases by about 1% toward the distal end. [ABSTRACT FROM AUTHOR]

Introduction. Antiprotons have been proposed as a potential modality for radiotherapy because the annihilation at the end of range leads to roughly a doubling of physical dose in the Bragg peak region. So far it has been anticipated that the radiobiology of antiproton beams is similar to that of protons in the entry region of the beam, but very different in the annihilation region, due to the expected high-LET components resulting from the annihilation. On closer inspection we find that calculations of dose averaged LET in the entry region may suggest that the RBE of antiprotons in the plateau region could significantly differ from unity, which seems to warrant closer inspection of the radiobiology in this region. Materials and Methods. Monte Carlo simulations using FLUKA were performed for calculating the entire particle spectrum of a beam of 126 MeV antiprotons hitting a water phantom. Results and Discussion. In the plateau region of the simulated antiproton beam we observe a dose-averaged unrestricted LET of about 4 keV/µm, which is very different from the expected 0.6 keV/µm of an equivalent primary proton beam. Even though the fluence of secondaries is a magnitude less than the fluence of primary particles, the increased stopping power of the secondary particles causes an increase in the dose averaged LET which is expected to result in a RBE different from unity. [ABSTRACT FROM AUTHOR]

Abstract: In this paper we report on the measurement of the antiproton depth–dose curve, with alanine detectors. The results are compared with simulations using the particle energy spectrum calculated by FLUKA, and using the track structure model of Hansen and Olsen for conversion of calculated dose into response. A good agreement is observed between the measured and calculated relative effectiveness although an underestimation of the measured values beyond the Bragg-peak remains unexplained. The model prediction of response of alanine towards heavy charged particles encourages future use of the alanine detectors for dosimetry of mixed radiation fields. [Copyright &y& Elsevier]

Abstract: Antiprotons are interesting as a possible future modality in radiation therapy for the following reasons: When fast antiprotons penetrate matter, protons and antiprotons have near identical stopping powers and exhibit equal radiobiology well before the Bragg-peak. But when the antiprotons come to rest at the Bragg-peak, they annihilate, releasing almost 2GeV per antiproton–proton annihilation. Most of this energy is carried away by energetic pions, but the Bragg-peak of the antiprotons is still locally augmented with ∼20–30MeV per antiproton. Apart from the gain in physical dose, an increased relative biological effect also has been observed, which can be explained by the fact that some of the secondary particles from the antiproton annihilation exhibit high-LET properties. Finally, the weakly interacting energetic pions, which are leaving the target volume, may provide a real time feedback on the exact location of the annihilation peak. We have performed dosimetry experiments and investigated the radiobiological properties using the antiproton beam available at CERN, Geneva. Dosimetry experiments were carried out with ionization chambers, alanine pellets and radiochromic film. Radiobiological experiments were done with V79 WNRE Chinese hamster cells. The radiobiological experiments were repeated with protons and carbon ions at TRIUMF and GSI, respectively, for comparison. Several Monte Carlo particle transport codes were investigated and compared with our experimental data obtained at CERN. The code that matched our data best was used to generate a set of depth dose data at several energies, including secondary particle-energy spectra. This can be used as base data for a treatment planning software such as TRiP. Our findings from the CERN experiments indicate that the biological effect of antiprotons in the plateau region may be reduced by a factor of 4 for the same biological target dose in a spread-out Bragg-peak, when comparing with protons. The extension of TRiP to handle antiproton beams is currently in progress. This will enable us to perform planning studies, where the potential clinical consequences can be examined, and compared to those of other beam modalities such as protons, carbon ions, or IMRT photons. [Copyright &y& Elsevier]

Abstract: Background and purpose: Antiprotons travel through tissue in a manner similar to that for protons until they reach the end of their range where they annihilate and deposit additional energy. This makes them potentially interesting for radiotherapy. The aim of this study was to conduct the first ever measurements of the biological effectiveness of antiprotons. Materials and methods: V79 cells were suspended in a semi-solid matrix and irradiated with 46.7MeV antiprotons, 48MeV protons, or 60Co γ-rays. Clonogenic survival was determined as a function of depth along the particle beams. Dose and particle fluence response relationships were constructed from data in the plateau and Bragg peak regions of the beams and used to assess the biological effectiveness. Results: Due to uncertainties in antiproton dosimetry we defined a new term, called the biologically effective dose ratio (BEDR), which compares the response in a minimally spread out Bragg peak (SOBP) to that in the plateau as a function of particle fluence. This value was ∼3.75 times larger for antiprotons than for protons. This increase arises due to the increased dose deposited in the Bragg peak by annihilation and because this dose has a higher relative biological effectiveness (RBE). Conclusion: We have produced the first measurements of the biological consequences of antiproton irradiation. These data substantiate theoretical predictions of the biological effects of antiproton annihilation within the Bragg peak, and suggest antiprotons warrant further investigation. [Copyright &y& Elsevier]

Abstract: In the light of recent progress in the study of the biological potential of antiproton tumour treatment it is important to be able to characterize the neutron intensity arising from antiproton annihilation using simple, compact and reliable detectors. The intensity of fast neutrons from antiproton annihilation on polystyrene has been measured with bubble detectors and a multiplicity has been derived as well as an estimated neutron equivalent dose. Additionally the sensitivity of bubble detectors towards protons was measured. [Copyright &y& Elsevier]

Abstract: Modern radiotherapy facilities for cancer treatment such as the Heavy Ion Therapy Centre (HIT) in Heidelberg (Germany) enable sub millimetre precision in dose deposition. For the measurement of such dose distributions and characterization of the particle beams, detectors with high spatial resolution and high sensitivity are necessary. For exact dosimetry which is done using ionization chambers (ICs), the recombination taking place in the IC has to be known. Up to now, recombination is corrected phenomenologically and more practical approaches are currently used. Nevertheless, Jaffés theory of columnar recombination was designed to model the detector efficiency of an ionization chamber. Here, we have shown that despite the approximations and simplification made, the theory is correct for the LETs typically found in clinical radiotherapy employing particles from protons to carbon ions. As no exact closed solution is available, a numerical solver was programmed. [ABSTRACT FROM AUTHOR]

Proton radiotherapy enables highly conformal dose delivery to the tumor while minimizing exposure to healthy tissues surrounding the target. However, to achieve the most optimal treatment plan, it is necessary to consider various parameters, including variable relative biological effectiveness (RBE) and linear energy transfer (LET) within the target and in the normal tissues. The proton treatment planning systems (TPS) currently under development incorporate both of these parameters. However, before introducing biologically guided treatment planning into the clinic, commissioning and end-to-end tests must be conducted. These procedures require specific tools to verify the planned LET distribution. The same tools will also be necessary for subsequent patient-specific quality assurance (QA). The objective of this work was to evaluate the alanine/EPR dosimetry system developed at the Cyclotron Center Bronowice at the Institute of Nuclear Physics (CCB IFJ PAN) for verifying LET values in therapeutic proton fields. The change in the shape of the EPR spectra of alanine irradiated in proton fields of different LET s, described by the ratio of the intensities of the satellite and central lines (x/y ratio), was used to discriminate LET values. The method does not provide absolute LET values. However, as demonstrated, it can verify the LET values calculated in the TPS after calibration using Monte Carlo (MC) simulation. • A simple and relatively fast method for determining LET in proton fields. • Based on EPR/alanine dosimetry and non-advanced readout techniques, applicable to any type of EPR X-band spectrometer. • Suitable for use in clinical measurements. [ABSTRACT FROM AUTHOR]

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$\text{LET}_d$) 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$Q$ (Qeff$Q_\mathrm{eff}$) 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$\text{LET}^3$ (i.e., dose averaged cubed LET, cLETd$\mathrm{cLET}_d$) resulting in a RMSE value 0.31, compared to 0.45 for a model based on (linearly weighted) LETd$\text{LET}_d$, with similar trends also observed for track averaged and Qeff$Q_\mathrm{eff}$‐based RQMs. Conclusions: The results indicate that improved proton variable RBE models can be constructed assuming a non‐linear RBE(LET) relationship for individual protons. If similar trends hold also for an in vitro‐environment, variable RBE effects are likely better described by cLETd$\mathrm{cLET}_d$ or tracked averaged cubed LET (cLETt$\mathrm{cLET}_t$), or corresponding Qeff$Q_\mathrm{eff}$‐based RQM, rather than linearly weighted LETd$\text{LET}_d$ or LETt$\text{LET}_t$ which is conventionally applied today. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. 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. 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. 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. [ABSTRACT FROM AUTHOR]

Background and purpose Aside from the enhancement of physical dose deposited by antiprotons annihilating in tissue-like material compared to protons of the same range a further increase of biological effective dose has been demonstrated. This enhancement can be expressed in an increase of the relative biological effectiveness (RBE) of antiprotons near the end of range. We have performed the first-ever direct measurement of the RBE of antiprotons both at rest and in flight. Materials and methods Experimental data were generated on the RBE of an antiproton beam entering a tissue-like target consisting of V79 cells embedded in gelatin with an energy providing a range of approximately 10 cm. Results The RBE in the entrance channel (the “plateau”) is only slightly above the value for a comparable proton beam, and remains low until the proximal edge of the spread-out Bragg peak (SOBP). A steep increase of RBE is seen starting from the onset of the SOBP. Conclusions This paper reports the final results of the experiment AD-4/ACE at CERN on the first-ever direct measurement of RBE of antiprotons and constitutes the first step toward developing treatment plans. [ABSTRACT FROM AUTHOR]

Purpose: Dosimetry with ionization chambers in clinical ion beams for radiation therapy requires correction for recombination effects. However, common radiation protocols discriminate between initial and general recombination and provide no universal correction method for the presence of both recombination types in ion beams of charged particles heavier than protons. The advent of multiple field optimization in ion beams, allowing for complex patterns of dose delivery in both temporal and spatial domains, results in new challenges for recombination correction where the resulting recombination depends on the plan delivered. Here, the authors present the open source code IonTracks version 1.0, where the combined initial and general recombination effects in principle can be predicted for any ion beam with arbitrary particle-energy spectrum and temporal structure. Methods: IonTracks uses track structure theory to distribute the charge carriers in ion tracks. The charge carrier movements are governed by a pair of coupled differential equations, based on fundamental physical properties as charge carrier drift, diffusion, and recombination, which are solved numerically while the initial and general charge carrier recombination is computed. A space charge screening of the electric field is taken into account and the algorithm furthermore allows an inclusion of a free-electron component. Results: The algorithm is numerically stable and in accordance with experimentally validated theories for initial recombination in heavy ion tracks and general recombination in a proton beam. Conclusions: Given IonTracks' ability to handle arbitrary inputs, IonTracks can in principle be applied to any complex particle field in the spatial and temporal domain. IonTracks is validated against the Jaffé's and Boag's theory of recombination in pulsed beams of multiple ion species. IonTracks is able to calculate the correction factor for initial and general recombination losses in parallel-plate ionization chambers. Even if only few experimental data on recombination effects in ionization chambers are available today, the universal concept of IonTracks is not limited to the ions investigated here. Future experimental investigations of recombination in pulsed and possibly also continuous ion beams may be conducted with IonTracks, which ultimately may lead to a more precise prediction of recombination factors in complex radiation fields. [ABSTRACT FROM AUTHOR]

In proton therapy, a relative biological effectiveness (RBE) of 1.1 is used to reach an isoeffective biological response between photon and proton doses. However, the RBE varies with biological endpoints and linear energy transfer (LET), two key parameters in radiotherapy. Few in vivo studies have investigated the increasing RBE with increasing LET. This study aims to test the hypothesis that the RBE varies between endpoints and has a distal edge effect in vivo. Unanesthetized mice were restrained in jigs where their right hind legs were irradiated with a single dose of protons at the center (LET, all = 5.3 keV/μm) and distal edge (LET, all = 7.6 keV/μm) of a spread-out Bragg peak (SOBP). 6 MV photons were used as reference. The acute damage and skin toxicity were scored daily until day 30, and the late damage was evaluated using a joint contracture assay for one year after treatment. An acute damage RBE of 1.06 ± 0.02(1.02–1.10) and late damage RBE of 1.16 ± 0.08(1.00–1.32) were found, displaying an enhanced RBE for late damage in the center SOBP. The distal edge RBE for acute and late damage was 1.15 ± 0.02(1.10–1.19) and 1.26 ± 0.09(1.07–1.43), showing a similar center-to-distal edge RBE enhancement of 8 % and 9 % for acute and late damage. The findings demonstrate an increased RBE for late damage than acute damage and the distal edge effect is evident with increased RBE at the distal end of the proton SOBP in vivo. [ABSTRACT FROM AUTHOR]

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/β2$z^{*2}/\beta ^2$, here called effectiveQ (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. [ABSTRACT FROM AUTHOR]

Purpose: Proton computed tomography (CT) is a promising image modality for improving the stopping power estimates and dose calculations for particle therapy. However, the finite range of about 33 cm of water of most commercial proton therapy systems limits the sites that can be scanned from a full 360? rotation. In this paper the authors propose a method to overcome the problem using a dual modality reconstruction (DMR) combining the proton data with a cone-beam x-ray prior. Methods: A Catphan 600 phantom was scanned using a cone beam x-ray CT scanner. A digital replica of the phantom was created in the Monte Carlo code Geant4 and a 360? proton CT scan was simulated, storing the entrance and exit position and momentum vector of every proton. Proton CT images were reconstructed using a varying number of angles from the scan. The proton CT images were reconstructed using a constrained nonlinear conjugate gradient algorithm, minimizing total variation and the x-ray CT prior while remaining consistent with the proton projection data. The proton histories were reconstructed along curved cubic-spline paths. Results: The spatial resolution of the cone beam CT prior was retained for the fully sampled case and the 90? interval case, with the MTF = 0.5 (modulation transfer function) ranging from 5.22 to 5.65 linepairs/cm. In the 45? interval case, theMTF = 0.5 dropped to 3.91 linepairs/cm For the fully sampled DMR, the maximal root mean square (RMS) error was 0.006 in units of relative stopping power. For the limited angle cases the maximal RMS error was 0.18, an almost five-fold improvement over the cone beam CT estimate. Conclusions: Dual modality reconstruction yields the high spatial resolution of cone beam x-ray CT while maintaining the improved stopping power estimation of proton CT. In the case of limited angles, the use of prior image proton CT greatly improves the resolution and stopping power estimate, but does not fully achieve the quality of a 360? proton CT scan. [ABSTRACT FROM AUTHOR]

Background. In vitro RBE values for various high LET radiation types have been determined for many different cell types. Occasionally it is criticized that RBE for a given endpoint cannot be single-value dependent on LET alone, but also on particle species, due to the different dose deposition profiles on microscopic scale. Hence LET is not sufficient as a predictor of RBE, and this is one of the motivations for development of radiobiological models which explicitly depend on the detailed particle energy spectrum of the applied radiation field. The aim of the present study is to summarize the available data in the literature regarding the dependency of RBE on LET for different particles. Method. As RBE is highly dependent on cell type and endpoint, we discriminated the RBE-LET relationship for the three investigated cell lines and at the same endpoint (10% survival in colony formation). Data points were collected from 20, four and four publications for V79, CHO and T1, respectively, in total covering 228 RBE values from a broad range of particle species. Results and discussion. All RBE-LET data points demonstrate surprising agreement within the general error band formed by the numerous data points, and display the expected RBE peak at around 100--200 keV/μμm. For all three cell lines, the influence of varying the particle type on the RBE was far from obvious, compared to the general experimental noise. Therefore, a dependence of particle type cannot be concluded, and LET alone in fact does seem to be an adequate parameter for describing RBE at 10% survival. [ABSTRACT FROM AUTHOR]

Abstract: Radiotherapy is one of the most important means we have for the treatment of localised tumours. It is therefore essential to optimize the technique, and a lot of effort goes into this endeavour. Since the proposal by Wilson in 1946 [R.R. Wilson, Radiology use of fast protons, Radiology 47 (1946) 487.] that proton beams might be better than photon beams at inactivating cancer cells, hadron therapy has been developed in parallel with photon therapy and a substantial knowledge has been gained on the effects of pions, protons and heavy ions (mostly carbon ions). Here we discuss the recent measurements by the CERN ACE collaboration of the biological effects of antiprotons, and argue that these particles very likely are the optimal agents for radiotherapy. [Copyright &y& Elsevier]

We describe an experiment designed to determine whether or not the densely ionizing particles emanating from the annihilation of antiprotons produce an increase in “biological dose” in the vicinity of the narrow Bragg peak for antiprotons compared to protons. This experiment is the first direct measurement of the biological effects of antiproton annihilation. The experiment has been approved by the CERN Research Board for running at the CERN Antiproton Decelerator (AD) as AD-4/ACE (Antiproton Cell Experiment) and has begun data taking in June of 2003. The background, description and the current status of the experiment are given. [Copyright &y& Elsevier]

A new experiment, AD-4/ACE (antiproton cell experiment), has been approved by the CERN Research Board. The experiment is scheduled to begin taking data in June and continue through the 2003 run cycle. The experiment is designed to determine whether or not the densely ionizing particles emanating from the annihilation of antiprotons produce an increase in “biological dose” in the vicinity of the narrow Bragg peak for antiprotons compared to protons. This experiment is the first direct measurement of the biological effects of antiproton annihilation. The background, description, and status of the experiment are given. [Copyright &y& Elsevier]

This review explores current experimental methods for determining the radiation quality in ion beams. In this context, radiation quality is commonly evaluated using the averaged linear energy transfer (LET), a metric employed to assess the response of both biological and physical systems. Dose and averaged LET can be experimentally determined with passive detectors through various techniques that have seen recent improvements. Another metric related to the LET is the mean lineal energy, which is measurable using microdosimetric detectors. This review focuses on the available possibilities for evaluating the radiation quality using three microdosimeters (mini-TEPC, Silicon Telescope, and SOI Microplus), three passive luminescence detectors (based on optical, thermo-, and radiophoto-luminescence), three track-based detectors (track-etched detector, Timepix, fluorescent nuclear track detector), and a chemical detector based on alanine. A comparison of detector properties is provided along with an overview of the underlying mechanisms enabling LET assessment or measurements of the mean lineal energy with each detector type. Finally, this review summarizes the current possibilities of LET determination with respect to the needs for quality assurance in particle therapy. Areas for future research and development are suggested. • Review of experimental radiation quality assessment via LET or yD. • Understand operating principles of passive and active LET detectors. • Tables summarize detector properties for LET or yD assessment. • Gain recommendations for LET-QA in particle therapy. [ABSTRACT FROM AUTHOR]

• Averaged LET values reported for RBE studies may strongly depend on the details of how the averaging was done. Typically, these are not specified. • Some LET-RBE models are derived from data using inconsistent types of averaged LET, introducing a source of error to the RBE(LET) relationship. • We recommend that the averaged LET is recorded more carefully and provide details on how to do so. 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. [ABSTRACT FROM AUTHOR]

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 "b1") 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 "b2" and "b3," 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 "b1." This method was then validated on the measurements of "b2" and "b3" 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 (Ld) 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 ("b1", "b2" and "b3"). 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 Ld). 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. [ABSTRACT FROM AUTHOR]

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 "b1") 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 "b2" and "b3," 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 "b1." This method was then validated on the measurements of "b2" and "b3" 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 (Ld) 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 ("b1", "b2" and "b3"). 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 Ld). 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to investigate whether the stopping power ratio (SPR) of a deformable, silicone-based 3D dosimeter could be determined more accurately using dual energy (DE) CT compared to using conventional methods based on single energy (SE) CT. The use of SECT combined with the stoichiometric calibration method was therefore compared to DECT-based determination. Methods: The SPR of the dosimeter was estimated based on its Hounsfield units (HUs) in both a SECT image and a DECT image set. The stoichiometric calibration method was used for converting the HU in the SECT image to a SPR value for the dosimeter while two published SPR calibration methods for dual energy were applied on the DECT images. Finally, the SPR of the dosimeter was measured in a 60 MeV proton by quantifying the range difference with and without the dosimeter in the beam path. Results: The SPR determined from SECT and the stoichiometric method was 1.10, compared to 1.01 with both DECT calibration methods. The measured SPR for the dosimeter material was 0.97. Conclusions: The SPR of the dosimeter was overestimated by 13% using the stoichiometric method and by 3% when using DECT. If the stoichiometric method should be applied for the dosimeter, the HU of the dosimeter must be manually changed in the treatment planning system in order to give a correct SPR estimate. Using a wrong SPR value will cause differences between the calculated and the delivered treatment plans. [ABSTRACT FROM AUTHOR]

Background.The aim of the present study was to compare the biological effectiveness of carbon ions relative to x-rays between tumor control, acute skin reaction and late RIF of CDF1 mice. Material and methods.CDF1 mice with a C3H mouse mammary carcinoma implanted subcutaneously on the foot of the right hind limb were irradiated with single fractions of either photons, or12C ions using a 30-mm spread-out Bragg peak. The endpoint of the study was local control (no tumor recurrence within 90 days). For the acute skin reaction, non-tumor bearing CDF1 mice were irradiated with a comparable radiation scheme, and monitored for acute skin damage between Day 7 and 40. Late RIF was assessed in the irradiated mice. Results.The TCD50(dose producing tumor control in 50% of mice) values with 95% confidence interval were 29.7 (25.4–34.8) Gy for C ions and 43.9 (39.2–49.2) Gy for photons, with a corresponding Relative biological effectiveness (RBE) value of 1.48 (1.28–1.72). For acute skin damage the MDD50(dose to produce moist desquamation in 50% of mice) values with 95% confidence interval were 26.3 (23.0–30.1) Gy for C ions and 35.8 (32.9–39.0) Gy for photons, resulting in a RBE of 1.36 (1.20–1.54). For late radiation-induced fibrosis the FD50(dose to produce severe fibrosis in 50% of mice) values with 95% confidence interval were 26.5 (23.1–30.3) Gy for carbon ions and 39.8 (37.8–41.8) Gy for photons, with a RBE of 1.50 (1.33–1.69). Conclusion.The observed RBE values were very similar for tumor response, acute skin damage and late RIF when irradiated with large doses of high- linear energy transfer (LET) carbon ions. This study adds information to the variation in biological effectiveness in different tumor and normal tissue models. [ABSTRACT FROM PUBLISHER]

The Monte Carlo particle transport code SHIELD-HIT12A is designed to simulate therapeutic beams for cancer radiotherapy with fast ions. SHIELD-HIT12A allows creation of antiproton beam kernels for the treatment planning system TRiP98, but first it must be benchmarked against experimental data. An experimental depth dose curve obtained by the AD-4/ACE collaboration was compared with an earlier version of SHIELD-HIT, but since then inelastic annihilation cross sections for antiprotons have been updated and a more detailed geometric model of the AD-4/ACE experiment was applied. Furthermore, the Fermi–Teller Z -law, which is implemented by default in SHIELD-HIT12A has been shown not to be a good approximation for the capture probability of negative projectiles by nuclei. We investigate other theories which have been developed, and give a better agreement with experimental findings. The consequence of these updates is tested by comparing simulated data with the antiproton depth dose curve in water. It is found that the implementation of these new capture probabilities results in an overestimation of the depth dose curve in the Bragg peak. This can be mitigated by scaling the antiproton collision cross sections, which restores the agreement, but some small deviations still remain. Best agreement is achieved by using the most recent antiproton collision cross sections and the Fermi–Teller Z -law, even if experimental data conclude that the Z -law is inadequately describing annihilation on compounds. We conclude that more experimental cross section data are needed in the lower energy range in order to resolve this contradiction, ideally combined with more rigorous models for annihilation on compounds. [ABSTRACT FROM AUTHOR]