Proton Relative Biological Effectiveness Research Articles

Feasibility Study of a Proton Irradiation Facility for Radiobiological Measurements at an 18 MeV Cyclotron

A feasibility study of an experimental setup for the irradiation of biological samples at the cyclotron facility installed at the National Centre of Accelerators (Seville, Spain) is presented. This cyclotron, which counts on an external beam line for interdisciplinary research purposes, produces an 18 MeV proton beam, which is suitable for the irradiation of mono-layer cultures for the measurement of proton cell damages and Relative Biological Effectiveness (RBE) at energies below the beam nominal value. Measurements of this kind are of interest for proton therapy, since the variation of proton RBE at the distal edge of the Bragg curve may have implications in clinical proton therapy treatments. In the following, the characteristics of the beam line and the solutions implemented for the irradiation of biological samples are described. When dealing with the irradiation of cell cultures, low beam intensities and broad homogeneous irradiation fields are required, in order to assure that all the cells receive the same dose with a suitable dose rate. At the cyclotron, these constraints have been achieved by completely defocusing the beam, intercepting the beam path with tungsten scattering foils and varying the exit-window-to-sample distance. The properties of the proton beam thus obtained have been analysed and compared with Monte Carlo simulations. The results of this comparison, as well as the experimental measurement of the lateral dose profiles expected at the position of samples are presented. Meaningful dose rates of about 2–3 Gy/min have been obtained. Homogeneous lateral dose profiles, with maximum deviations of 5%, have been measured at a distance of approximately 50 cm in air from the exit window, placing a tungsten scattering foil of 200 μm in the beam path.

Radiobiological effects and proton RBE determined by wildtype zebrafish embryos.

The increasing use of proton radiotherapy during the last decade and the rising number of long-term survivors has given rise to a vital discussion on potential effects on normal tissue. So far, deviations from clinically applied generic RBE (relative biological effectiveness) of 1.1 were only obtained by in vitro studies, whereas indications from in vivo trials and clinical studies are rare. In the present work, wildtype zebrafish embryos (Danio rerio) were used to characterize the effects of plateau and mid-SOBP (spread-out Bragg peak) proton radiation relative to that induced by clinical MV photon beam reference. Based on embryonic survival data, RBE values of 1.13 ± 0.08 and of 1.20 ± 0.04 were determined four days after irradiations with 20 Gy plateau and SOBP protons relative to 6 MV photon beams. These RBE values were confirmed by relating the rates of embryos with morphological abnormalities for the respective radiation qualities and doses. Besides survival, the rate of spine bending, as one type of developmental abnormality, and of pericardial edema, as an example for acute radiation effects, were assessed. The results revealed that independent on radiation quality both rates increased with time approaching almost 100% at the 4th day post irradiation with doses higher than 15 Gy. To sum up, the applicability of the zebrafish embryo as a robust and simple alternative model for in vivo characterization of radiobiological effects in normal tissue was validated and the obtained RBE values are comparable to previous finding in animal trials.

LET-weighted doses effectively reduce biological variability in proton radiotherapy planning

Variations in proton relative biological effectiveness (RBE) with linear energy transfer (LET) remain one of the largest sources of uncertainty in proton radiotherapy. This work seeks to identify metrics which can be applied to mitigate these effects in treatment optimisation, and quantify their effectiveness. Three different metrics—dose, dose × LET and an LET-weighted dose defined as where is the dose-averaged LET—were compared with in vitro experimental studies of proton RBE and clinical treatment plans incorporating RBE models. In each system the biological effects of protons were plotted against these metrics to quantify the degree of variation introduced by unaccounted-for RBE uncertainties. As expected, the LET-dependence of RBE introduces significant variability in the biological effects of protons when plotted against dose alone. Plotting biological effects against dose × LET significantly over-estimated the impact of LET on cell survival, and typically produced even larger spreads in biological effect. LET-weighted dose was shown to have superior correlation to biological effect in both experimental data and clinical plans. For prostate and medulloblastoma treatment plans, the average RBE-associated variability in biological effect is ±5% of the prescribed dose, but is reduced to less than 1% using LET-weighting. While not a replacement for full RBE models, simplified metrics such as this LET-weighted dose can be used to account for the majority of variability which arises from the LET-dependence of RBE with reduced need for biological parameterisation. These metrics may be used to identify regions in normal tissues which may see unexpectedly high effects due to end-of-range elevations of RBE, or as part of a more general tool for biological optimisation in proton therapy.

Impact of potentially variable RBE in liver proton therapy

Currently, the relative biological effectiveness (RBE) is assumed to be constant with a value of 1.1 in proton therapy. Although trends of RBE variations are well known, absolute values in patients are associated with considerable uncertainties. This study aims to evaluate the impact of a variable proton RBE in proton therapy liver trials using different fractionation schemes.Sixteen liver cancer cases were evaluated assuming two clinical schedules of 40 Gy/5 fractions and 58.05 Gy/15 fractions. The linear energy transfer (LET) and physical dose distribution in patients were simulated using Monte Carlo. The variable RBE distribution was calculated using a phenomenological model, considering the influence of the LET, fraction size and α/β value. Further, models to predict normal tissue complication probability (NTCP) and tumor control probability (TCP) were used to investigate potential RBE effects on outcome predictions.Applying the variable RBE model to the 5 and 15 fractions schedules results in an increase in mean fraction-size equivalent dose (FED) to the normal liver of 5.0% and 9.6% respectively. For patients with a mean FED to the normal liver larger than 29.8 Gy, this results in a non-negligible increase in the predicted NTCP of the normal liver averaging 11.6%, ranging from 2.7% to 25.6%. On the other hand, decrease in TCP was less than 5% for both fractionation regimens for all patients when assuming a variable RBE instead of constant. Consequently, the difference in TCP between the two fractionation schedules did not change significantly assuming a variable RBE while the impact on the NTCP difference was highly case specific. In addition, both the NTCP and TCP decrease with increasing α/β value for both fractionation schemes, with the decreases being more pronounced when using a variable RBE compared to using RBE = 1.1.Assuming a constant RBE of 1.1 most likely overestimates the therapeutic ratio in proton therapy for liver cancer, predominantly due to underestimation of the RBE-weighted dose to the normal liver. The impact of applying a variable RBE (as compared to RBE = 1.1) on the NTCP difference of the two fractionation regimens is case dependent. A variable RBE results in a slight increase in TCP difference. Variations in patient radiosensitivity increase when using a variable RBE.

Proton relativebiologicaleffectiveness (RBE): a multiscale problem.

Proton radiotherapy is undergoing rapid expansion both within the UK and internationally, but significant challenges still need to be overcome if maximum benefit is to be realised from this technique. One major limitation is the persistent uncertainty in proton relative biological effectiveness (RBE). While RBE values are needed to link proton radiotherapy to our existing experience with photon radiotherapy, RBE remains poorly understood and is typically incorporated as a constant dose scaling factor of 1.1 in clinical plans. This is in contrast to extensive experimental evidence indicating that RBE is a function of dose, tissue type, and proton linear energy transfer, among other parameters. In this article, we discuss the challenges associated with obtaining clinically relevant values for proton RBE through commonly-used assays, and highlight the wide range of other experimental endpoints which can inform our understanding of RBE. We propose that accurate and robust optimization of proton radiotherapy ultimately requires a multiscale understanding of RBE, integrating subcellular, cellular, and patient-level processes.

RBE Model-Based Biological Dose Optimization for Proton Radiobiology Studies.

The purpose of the current study was (1) to develop a straightforward and rapid method to incorporate a dose-averaged linear energy transfer (LET d )-based biological effect model into a dose optimization algorithm for scanned protons; and (2) to apply a novel beam delivery strategy with increased LET d within the target, thereby enhancing the biological effect predicted using the selected relative biological effectiveness (RBE) model. We first generated pristine dose Bragg curves in water and their corresponding LET d distributions for 94 groups of proton beams, using experimentally validated Geant4 Monte Carlo simulations. Next, we developed 1-dimensional dose optimization algorithms by using the Python programming language. To calculate the RBE of protons for biological dose optimization, we invoked the McNamara RBE model and applied the radiobiological parameters of the lung cancer H460 cell line with 137Cs reference photons. High-accuracy optimization results were obtained. The relative difference between the delivered dose and the prescribed dose was approximately within ±1.0% in the target. In addition, we obtained the RBE enhancement within the target by applying the LET-painting technique. For example, considering a simple case in which 2 opposed downslope dose fields were superimposed to form a uniform dose in the 5- to 10-cm target region, the center RBE was 1.23 ± 0.01, which was greater than the center RBE of 1.16 ± 0.01 found when using the traditional method of delivering 2 opposed flat dose fields. We have successfully developed an easy-to-implement method to perform the biological dose optimization procedure by invoking the McNamara RBE model in the iteration process using the Python programming language. According to the RBE model predictions, we conclude that the increased target LET d enhances the RBE. The accuracy of the RBE model predictions needs to be validated in radiobiological experiments.

Asymptomatic Late-phase Radiographic Changes Among Chest-Wall Patients Are Associated With a Proton RBE Exceeding 1.1

Clinical practice assumes a fixed proton relative biological effectiveness (RBE) of 1.1, but invitro experiments demonstrate higher RBEs at the distal edge of the proton spread-out Bragg peak, that is, in a region that falls within the lung for chest-wall patients. We performed retrospective qualitative and quantitative analyses of lung-density changes-indicative of asymptomatic fibrosis-for chest-wall patients treated with protons or photons. Our null hypothesis was that, assuming a fixed RBE of 1.1, these changes would be the same for the 2 cohorts, supporting current RBE practice. Our alternative hypothesis was that radiographic abnormalities would be greater for the proton cohort, suggesting an RBE > 1.1. We analyzed follow-up computed tomography (CT) scans for 20 proton and photon patients. All were prescribed 50.4Gy (RBE) in 28 fractions, assuming a fixed RBE of 1.1 for protons and 1 for photons. Deformable registrations enabled us to calculate density changes in the normal lung, specifically (1) median Hounsfield unit (HU) values among posttreatment CT scans and (2) changes in median HU values between pretreatment and posttreatment CT scans, both as a function of grays (RBE). In addition, qualitative abnormality grading was performed by a radiologist. Proton patients exhibited higher values of HU/Gy (RBE) (endpoint 1) and ΔHU/Gy (RBE) (endpoint 2): P=.049 and P=.00019, respectively, were obtained (likelihood ratio tests of full linear mixed-effects models against models without "modality"). Furthermore, qualitative radiologic scoring indicated a significant difference between the cohorts (Wilcoxon P=.018; median score, 3 of 9 for protons and 1.5 of 9 for photons). Our data support the hypothesis that the proton RBE for lung-density changes exceeds 1.1. This RBE elevation could be attributable to (1) the late, normal tissue endpoint that we consider or (2) end-of-range proton linear energy transfer elevation-or a combination of the two. Regardless, our results suggest that variations in proton RBE prove important invivo as well as invitro.

Determination of the proton RBE in the rat spinal cord: Is there an increase towards the end of the spread-out Bragg peak?

Background and purposeTo determine the relative biological effectiveness (RBE) of protons in the rat spinal cord as a function of linear energy transfer (LET) and dose. Materials and methodsThe rat cervical spinal cord was irradiated with single or two equal fractions (split doses) of protons at four positions (LET 1.4–5.5 keV/µm) along a 6 cm spread-out Bragg peak (SOBP). From dose-response analysis, TD50- (dose at 50% effect probability) and RBE-values were derived using the endpoint of radiation-induced myelopathy. ResultsAlong the SOBP, the TD50-values decreased from 21.7 ± 0.3 Gy to 19.5 ± 0.5 Gy for single and from 32.3 ± 0.3 Gy to 27.9 ± 0.5 Gy for split doses. The corresponding RBE-values increased from 1.13 ± 0.04 to 1.26 ± 0.05 (single doses) and from 1.06 ± 0.02 to 1.23 ± 0.03 (split doses). ConclusionsFor the relative high fractional doses, the experimental RBE at the distal edge of the proton SOBP is moderately increased. The conventionally applied RBE of 1.1 appears to be valid for the mid-SOBP region, but the higher values occurring more distally could be of clinical significance, especially if critical structures are located in this area. Further in vivo studies at lower fractional doses are urgently required.

RBE of "Prometeus" Facility Protons for Irradiation of Tumor Cells in vitro with One and Three Fields

The study was aimed to the biological effectiveness of the proton scanning beam of the first Russian medical facility. The clonogenic assay of B-16 tumor cells was used as a test system. Cell irradiation was carried out in a suspension condition in a water phantom. Single and three-field exposures were studied. The dose interval was 2-8 Gy. The energy range from 47.5 to 92.0 MeV was used for the Bragg peak formation. The relative biological effectiveness of protons comparing to gamma-rays was 1.2 for single-field and 1.5 for three-field irradiation. The results obtained agree with literature data related to the used cell culture (B-16) and linear energy transfer range (3÷8 keV/µm).

The Radiobiology of Proton Therapy: Challenges and Opportunities Around Relative Biological Effectiveness

With the current UK expansion of proton therapy there is a great opportunity for clinical oncologists to develop a translational interest in the associated scientific base and clinical results. In particular, the underpinning controversy regarding the conversion of photon dose to proton dose by the relative biological effectiveness (RBE) must be understood, including its important implications. At the present time, the proton prescribed dose includes an RBE of 1.1 regardless of tissue, tumour and dose fractionation. A body of data has emerged against this pragmatic approach, including a critique of the existing evidence base, due to choice of dose, use of only acute-reacting in vivo assays, analysis methods and the reference radiations used to determine the RBE. Modelling systems, based on the best available scientific evidence, and which include the clinically useful biological effective dose (BED) concept, have also been developed to estimate proton RBEs for different dose and linear energy transfer (LET) values. The latter reflect ionisation density, which progressively increases along each proton track. Late-reacting tissues, such as the brain, where α/β = 2 Gy, show a higher RBE than 1.1 at a low dose per fraction (1.2–1.8 Gy) at LET values used to cover conventional target volumes and can be much higher. RBE changes with tissue depth seem to vary depending on the method of beam delivery used. To reduce unexpected toxicity, which does occasionally follow proton therapy, a more rational approach to RBE allocation, using a variable RBE that depends on dose per fraction and the tissue and tumour radiobiological characteristics such as α/β, is proposed.

The relative biological effectiveness of proton and carbon ion beams in photon-sensitive and resistant nasopharyngeal cancer cells

The relative biological effectiveness of proton and carbon ion beams in photon-sensitive and resistant nasopharyngeal cancer cells

First experimental proof of Proton Boron Capture Therapy (PBCT) to enhance protontherapy effectiveness

Protontherapy is hadrontherapy’s fastest-growing modality and a pillar in the battle against cancer. Hadrontherapy’s superiority lies in its inverted depth-dose profile, hence tumour-confined irradiation. Protons, however, lack distinct radiobiological advantages over photons or electrons. Higher LET (Linear Energy Transfer) 12C-ions can overcome cancer radioresistance: DNA lesion complexity increases with LET, resulting in efficient cell killing, i.e. higher Relative Biological Effectiveness (RBE). However, economic and radiobiological issues hamper 12C-ion clinical amenability. Thus, enhancing proton RBE is desirable. To this end, we exploited the p + 11B → 3α reaction to generate high-LET alpha particles with a clinical proton beam. To maximize the reaction rate, we used sodium borocaptate (BSH) with natural boron content. Boron-Neutron Capture Therapy (BNCT) uses 10B-enriched BSH for neutron irradiation-triggered alpha particles. We recorded significantly increased cellular lethality and chromosome aberration complexity. A strategy combining protontherapy’s ballistic precision with the higher RBE promised by BNCT and 12C-ion therapy is thus demonstrated.

Biological and dosimetric characterisation of spatially fractionated proton minibeams

The biological effectiveness of proton beams varies with depth, spot size and lateral distance from the beam central axis. The aim of this work is to incorporate proton relative biological effectiveness (RBE) and equivalent uniform dose (EUD) considerations into comparisons of broad beam and highly modulated proton minibeams. A Monte Carlo model of a small animal proton beamline is presented. Dose and variable RBE is calculated on a per-voxel basis for a range of energies (30–109 MeV). For an open beam, the RBE values at the beam entrance ranged from 1.02–1.04, at the Bragg peak (BP) from 1.3 to 1.6, and at the distal end of the BP from 1.4 to 2.0. For a 50 MeV proton beam, a minibeam collimator designed to produce uniform dose at the depth of the BP peak, had minimal impact on the open beam RBE values at depth. RBE changes were observed near the surface when the collimator was placed flush with the irradiated object, due to a higher neutron contribution derived from proton interactions with the collimator. For proton minibeams, the relative mean RBE weighted entrance dose (RWD) was ~25% lower than the physical mean dose. A strong dependency of the EUD with fraction size was observed. For 20 Gy fractions, the EUD varied widely depending on the radiosensitivity of the cells. For radiosensitive cells, the difference was up to ~50% in mean dose and ~40% in mean RWD and the EUD trended towards the valley dose rather than the mean dose. For comparative studies of uniform dose with spatially fractionated proton minibeams, EUD derived from a per-voxel RWD distribution is recommended for biological assessments of reproductive cell survival and related endpoints.

Optimization of Monte Carlo particle transport parameters and validation of a novel high throughput experimental setup to measure the biological effects of particle beams.

Accurate modeling of the relative biological effectiveness (RBE) of particle beams requires increased systematic invitro studies with human cell lines with care towards minimizing uncertainties in biologic assays as well as physical parameters. In this study, we describe a novel high-throughput experimental setup and an optimized parameterization of the Monte Carlo (MC) simulation technique that is universally applicable for accurate determination of RBE of clinical ion beams. Clonogenic cell-survival measurements on a human lung cancer cell line (H460) are presented using proton irradiation. Experiments were performed at the Heidelberg Ion Therapy Center (HIT) with support from the Deutsches Krebsforschungszentrum (DKFZ) in Heidelberg, Germany using a mono-energetic horizontal proton beam. A custom-made variable range selector was designed for the horizontal beam line using the Geant4 MC toolkit. This unique setup enabled a high-throughput clonogenic assay investigation of multiple, well defined dose and linear energy transfer (LETs) per irradiation for human lung cancer cells (H460) cultured in a 96-well plate. Sensitivity studies based on application of different physics lists in conjunction with different electromagnetic constructors and production threshold values to the MC simulations were undertaken for accurate assessment of the calculated dose and the dose-averaged LET (LETd ). These studies were extended to helium and carbon ion beams. Sensitivity analysis of the MC parameterization revealed substantial dependence of the dose and LETd values on both the choice of physics list and the production threshold values. While the dose and LETd calculations using FTFP_BERT_LIV, FTFP_BERT_EMZ, FTFP_BERT_PEN and QGSP_BIC_EMY physics lists agree well with each other for all three ions, they show large differences when compared to the FTFP_BERT physics list with the default electromagnetic constructor. For carbon ions, the dose corresponding to the largest LETd value is observed to differ by as much as 78% between FTFP_BERT and FTFP_BERT_LIV. Furthermore, between the production threshold of 700μm and 5μm, proton dose varies by as much as 19% corresponding to the largest LETd value sampled in the current investigation. Based on the sensitivity studies, the FTFP_BERT physics list with the low energy Livermore electromagnetic constructor and a production threshold of 5μm was employed for determining accurate dose and LETd . The optimized MC parameterization results in a different LETd dependence of the RBE curve for 10% SF of the H460 cell line irradiated with proton beam when compared with the results from a previous study using the same cell line. When the MC parameters are kept consistent between the studies, the proton RBE results agree well with each other within the experimental uncertainties. A custom high-throughput, high-accuracy experimental design for accurate invitro cell survival measurements was employed at a horizontal beam line. High sensitivity of the physics-based optimization establishes the importance of accurate MC parameterization and hence the conditioning of the MC system on a case-by-case basis. The proton RBE results from current investigations are observed to agree with a previous measurement made under different experimental conditions. This establishes the consistency of our experimental findings across different experiments and institutions.

Investigating Dependencies of Relative Biological Effectiveness for Proton Therapy in Cancer Cells.

Relative biological effectiveness (RBE) accounts for the differences in biological effect from different radiation types. The RBE for proton therapy remains uncertain, as it has been shown to vary from the clinically used value of 1.1. In this work we investigated the RBE of protons and correlated the biological differences with the underlying physical quantities. Three cell lines were irradiated (CHO, Chinese hamster ovary; A549, human lung adenocarcinoma; and T98, human glioma) and assessed for cell survival by using clonogenic assay. Cells were irradiated with 71- and 160-MeV protons at depths along the Bragg curve and 6-MV photons to various doses. The dose-averaged lineal energy ( ) was measured under similar conditions as the cells by using a microdosimeter. Dose-averaged linear energy transfer (LETd) was also calculated by using Monte Carlo (MC) simulations. Survival data were fit by using the linear quadratic model. The RBE values were calculated by comparing the physical dose (D6MV/Dp) that results in 50% (RBE0.5) and 10% (RBE0.1) cell survival, and survival after 2 Gy (RBE2Gy). Proton RBE values ranged from 0.89 to 2.40. The RBE for all 3 cell lines increased with decreasing proton energy and was higher at 50% survival than at 10% survival. Additionally, both A549 and T98 cells generally had higher RBE values relative to the CHO cells, indicating a greater biological response to protons. An increase in RBE corresponded with an increase in and LETd. Proton RBE was found to depend on mean proton energy, survival end point, and cell type. Changes in both and LETd were also found to impact proton RBE values, but consideration of the energy spectrum may provide additional information. The RBE values in this study vary greatly, indicating the clinical value of 1.1 may not be suitable in all cases.

Relating the proton relative biological effectiveness to tumor control and normal tissue complication probabilities assuming interpatient variability in α/β

Background: Proton therapy uses a constant relative biological effectiveness (RBE) of 1.1. The use of variable RBE values has been suggested but is currently not feasible due to uncertainties. The impact of variable RBE has solely been studied using dosimetric indices. This work elucidates the impact of RBE variations on tumor control and normal tissue complication probabilities (TCP/NTCP).Methods: Models to estimate TCP and NTCP were used in combination with an empirical proton RBE model. Variations in outcome as a function of linear-quadratic model parameters for cellular radiosensitivity were determined for TCP in prostate and ependymoma. In addition, NTCP analysis was done for brainstem necrosis.Results: Considering a variable proton RBE as a dose-modifying factor for prescription doses and dose constraints is misleading, as TCP/NTCP do not simply scale with RBE. The dependency of RBE on α/β cannot be interpreted independent of TCP/NTCP because variations in radiosensitivity affect both photon and proton treatments. Assuming interpatient variability in radiosensitivity results in lower TCP for patients with low α/β. In proton therapy, the magnitude of TCP variations is reduced due to an RBE increase as α/β decreases. The TCP in proton therapy is less affected by interpatient variability in α/β. On the other hand, patients with a lower α/β would have a lower complication probability, which is counteracted by an increase in RBE as α/β decreases. Toxicities in proton therapy would be more affected by α/β variations compared to photon therapy.Conclusions: Assessment of variable RBE in proton therapy should be based on TCP and NTCP. Potential interpatient variability in radiosensitivity causes a smaller variance in TCP but a larger variance in NTCP for proton patients. The relative TCP as a function of α/β was found to be higher than the RBE, whereas the relative NTCP was lower than a calculated RBE.

Combining proton or photon irradiation with epothilone B. An in vitro study of cytotoxicity in human cancer cells

Recently, the use of proton beams in cancer therapy is becoming widespread, and tumour treatment modalities combining radiosensitizing chemical agents with irradiation are under investigation in order to achieve greater tumour local control and reduce the probability of distant failures. The combined treatment modality of radiation and the clinically relevant microtubule-stabilizing compound epothilone B is a promising approach for anticancer therapy. In the present study, we investigated the cytotoxicity of a spread out Bragg peak (SOBP) proton beam, as well as of 6 MV photons, in human glioblastoma (U251 MG) and lung adenocarcinoma (A549) cells pretreated for 24 h, or not, with epothilone B at concentrations of 0.125 and 0.075 nM respectively. Proton irradiation was performed at the middle position of an actively modulated SOBP (12–18 cm depth in water) and cell survival was evaluated by a colony forming assay. For both cell lines, survival curves after proton or photon irradiation alone showed linear quadratic behaviour with proton RBE (relative biological effectiveness), compared with photons at 10% survival, of 1.5 ± 0.2. Treatment of cells with epothilone B at subnanomolar concentration has an anticlonogenic effect. Furthermore, differently from the results found with radiation alone, the survival curves for the combined treatment epothilone B–radiation showed a linear trend and analysis of the interaction of the two cytotoxic agents indicated a slight synergism. These data provide a radiobiological basis for further experiments, as well as clinical studies.

Exploring innovative radiation shielding approaches in space: A material and design study for a wearable radiation protection spacesuit

We present a design study for a wearable radiation-shielding spacesuit, designed to protect astronauts’ most radiosensitive organs. The suit could be used in an emergency, to perform necessary interventions outside a radiation shelter in the space habitat in case of a Solar Proton Event (SPE). A wearable shielding system of the kind we propose has the potential to prevent the onset of acute radiation effects in this scenario. In this work, selection of materials for the spacesuit elements is performed based on the results of dedicated GRAS/Geant4 1-dimensional Monte Carlo simulations, and after a trade-off analysis between shielding performance and availability of resources in the space habitat. Water is the first choice material, but also organic compounds compatible with a human space habitat are considered (such as fatty acids, gels and liquid organic wastes). Different designs and material combinations are proposed for the spacesuits. To quantify shielding performance we use GRAS/Geant4 simulations of an anthropomorphic phantom in an average SPE environment, with and without the spacesuit, and we compare results for the dose to Blood Forming Organs (BFO) in Gy-Eq, i.e. physical absorbed dose multiplied by the proton Relative Biological Effectiveness (RBE) for non-cancer effects. In case of SPE occurrence for Intra-Vehicular Activities (IVA) outside a radiation shelter, dose reductions to BFO in the range of 44–57% are demonstrated to be achievable with the spacesuit designs made only of water elements, or of multi-layer protection elements (with a thin layer of a high density material covering the water filled volume). Suit elements have a thickness in the range 2–6 cm and the total mass for the garment sums up to 35–43 kg depending on model and material combination. Dose reduction is converted into time gain, i.e. the increase of time interval between the occurrence of a SPE and the moment the dose limit to the BFO for acute effects is reached. Wearing a radiation shielding spacesuit of the kind we propose, the astronaut could have up to more than the double the time (e.g. almost 6 instead of 2.5 h) to perform necessary interventions outside a radiation shelter during a SPE, his/her exposure remaining within dose limits. An indicative mass saving thanks to the shielding provided by the suits is also derived, calculating the amount of mass needed in addition to the 1.5 cm thick Al module considered for the IVA scenario to provide the same additional shielding given by the spacesuit. For an average 50% dose reduction to BFO this is equal to about 2.5 tons of Al. Overall, our results offer a proof-of-principle validation of a complementary personal shielding strategy in emergency situations in case of a SPE event. Such results pave the way for the design and realization of a prototype of a water-filled garment to be tested on board the International Space Station for wearability. A successful outcome will possibly lead to the further refining of the design of radiation protection spacesuits and their possible adoption in future long-duration manned missions in deep space.

Scientific Abstracts and Sessions

Purpose: Proton therapy treatments are based on a constant RBE (relative biological effectiveness) of 1.1. However, it has been shown that proton RBE varies with linear energy transfer (LET), physiological and biological factors, and clinical endpoint. After many years of improvement, the micro-kinetic model (MKM) allows now to obtain a fine description of the impact of radiation on tissues by using LET distributions and experimental cell survival curves. But, these measurements are generally performed using a 2D cell configuration, which is far to be realistic, compared to the natural arrangement of cells in tissues.To address this issue, we propose the prediction of RBE using the GATE Monte Carlo platform (www.opengatecollaboration.org) for 2D and 3D melanoma cell models irradiated with a therapeutic proton beam. Methods: Cell lines in 2D and 3D configurations are irradiated using a reference X-ray beam of 250 kVp and a therapeutic proton beam of 65 MeV. For the proton beam, cell survival curves are measured at several positions of a SOBP (spread-out Bragg peak) profile. The measured survival curves are then used to set the biological MKM parameters for both configurations.The MKM method combined with the LET simulation is implemented in the GATE platform. The LET distribution is obtained using a tissue-equivalent proportional counter geometry emulating a sphere of tissue equivalent to a cell nucleus (1 µm in diameter).Finally, Results: RBE calculated along proton SOBP depth profiles using 2D and the 3D cell configurations were compared. Survival curves obtained with the reference X-ray beam for 2D and 3D configurations revealed a higher sensitivity to radiation for 3D cell configuration. Conclusion: The setting of the MKM parameters (α₀, β, rd) in GATE for melanoma cells has been performed; the same methodology will be applied for other cell lines during 2017. Funding Support, Disclosures, and Conflict of Interest: This work was supported by grants from LabEx PRIMES (Physique, Radiobiologie, Imagerie Medicale et Simulation)

Inclusion of a variable RBE into proton and photon plan comparison for various fractionation schedules in prostate radiation therapy.

A constant relative biological effectiveness (RBE) of 1.1 is currently used in proton radiation therapy to account for the increased biological effectiveness compared to photon therapy. However, there is increasing evidence that proton RBE vary with the linear energy transfer (LET), the dose per fraction, and the type of the tissue. Therefore, this study aims to evaluate the impact of disregarding variations in RBE when comparing proton and photon dose plans for prostate treatments for various fractionation schedules using published RBE models and several α/β assumptions. Photon and proton dose plans were created for three generic prostate cancer cases. Three BED3Gy equivalent schedules were studied, 78, 57.2, and 42.8Gy in 39, 15, and 7 fractions, respectively. The proton plans were optimized assuming a constant RBE of 1.1. By using the Monte Carlo calculated dose-averaged LET (LETd ) distribution and assuming α/β values on voxel level, three variable RBE models were applied to the proton dose plans. The impact of the variable RBE was studied in the plan comparison, which was based on the dose distribution, DVHs, and normal tissue complication probabilities (NTCP) for the rectum. Subsequently, the physical proton dose was reoptimized for each proton plan based on the LETd distribution, to achieve a homogeneous RBE-weighted target dose when applying a specific RBE model and still fulfill the clinical goals for the rectum and bladder. All the photon and proton plans assuming RBE=1.1 met the clinical goals with similar target coverage. The proton plans fulfilled the robustness criteria in terms of range and setup uncertainty. Applying the variable RBE models generally resulted in higher target doses and rectum NTCP compared to the photon plans. The increase was most pronounced for the fractionation dose of 2Gy(RBE), whereas it was of less magnitude and more dependent on model and α/β assumption for the hypofractionated schedules. The reoptimized proton plans proved to be robust and showed similar target coverage and doses to the organs at risk as the proton plans optimized with a constant RBE. Model predicted RBE values may differ substantially from 1.1. This is most pronounced for fractionation doses of around 2Gy(RBE) with higher doses to the target and the OARs, whereas the effect seems to be of less importance for the hypofractionated schedules. This could result in misleading conclusions when comparing proton plans to photon plans. By accounting for a variable RBE in the optimization process, robust and clinically acceptable dose plans, with the potential of lowering rectal NTCP, may be generated by reoptimizing the physical dose. However, the direction and magnitude of the changes in the physical proton dose to the prostate are dependent on RBE model and α/β assumptions and should therefore be used conservatively.