Relative Biological Effectiveness Values Research Articles

O43. Estimating the effectiveness of high LET radiations to induce damage to DNA in human lymphocytes and modelling the repair thereof

Introduction Neutron and ion beam irradiations have an increased efficiency in cell killing, resulting from their high linear-energy-transfer (LET) which in turn induces clustered and complex DNA breaks. Similarly, Auger electron irradiations have been shown to a have an increased relative biological effectiveness (RBE) when compared to low-LET radiations. We report on our investigations into the RBE of the DNA incorporated Auger electron emitting 123 I and a model which may estimate the induction and repair of γ -H2AX foci (markers of DNA double strand breaks (DSBs)) in human lymphocytes after exposure to fast neutrons. Materials and methods The RBE of 123 I was determined by comparison of micronuclei inductions in T-lymphocytes using 5-[ 123 I]-iodo-2-deoxyuridine and similar inductions by graded doses of 60 Co γ -rays. Additionally, a theoretical model which describes the time-based repair pathways of DNA DSBs using a set of dependent partial differential equations, was investigated. The validity of the model was assessed by comparing the γ -H2AX foci kinetics predicted by the model to experimental curves observed for lymphocytes exposed to neutrons (20 keV/ μ m) and 60 Co γ -rays. Results The dose-limiting RBE of the DNA incorporated 123 I was found to range from 3 to 11. These observed RBE values relate well to those obtained in studies with 125 I incorporated into rodent cell lines. The higher micronuclei frequencies noted for Auger electrons in the study is indicative of the high-LET nature of these particles. Similar to experimental observations, the theoretical repair model predicted that a larger number of DSBs remain unrepaired after neutron irradiation compared to low-LET γ -irradiation. The model was shown to accurately describe and estimate the kinetics of γ -H2AX foci in human lymphocytes after exposure to fast neutrons and 60 Co γ -rays. Conclusion With respect to their role in radiation therapy and protection, there is a need for investigating and developing models which may predict the induction and repair of high-LET radiation induced DNA damage. Acknowledgement This work was supported by a University Development Cooperation VLIR Own Initiative Programme between Belgium and South Africa.

Radiobiological Effectiveness of Ultrashort Laser-Driven Electron Bunches: Micronucleus Frequency, Telomere Shortening and Cell Viability

Laser-driven electron accelerators are capable of producing high-energy electron bunches in shorter distances than conventional radiofrequency accelerators. To date, our knowledge of the radiobiological effects in cells exposed to electrons using a laser-plasma accelerator is still very limited. In this study, we compared the dose-response curves for micronucleus (MN) frequency and telomere length in peripheral blood lymphocytes exposed to laser-driven electron pulse and X-ray radiations. Additionally, we evaluated the effects on cell survival of in vitro tumor cells after exposure to laser-driven electron pulse compared to electron beams produced by a conventional radiofrequency accelerator used for intraoperative radiation therapy. Blood samples from two different donors were exposed to six radiation doses ranging from 0 to 2 Gy. Relative biological effectiveness (RBE) for micronucleus induction was calculated from the alpha coefficients for electrons compared to X rays (RBE = alpha laser/alpha X rays). Cell viability was monitored in the OVCAR-3 ovarian cancer cell line using trypan blue exclusion assay at day 3, 5 and 7 postirradiation (2, 4, 6, 8 and 10 Gy). The RBE values obtained by comparing the alpha values were 1.3 and 1.2 for the two donors. Mean telomere length was also found to be reduced in a significant dose-dependent manner after irradiation with both electrons and X rays in both donors studied. Our findings showed a radiobiological response as mirrored by the induction of micronuclei and shortening of telomere as well as by the reduction of cell survival in blood samples and cancer cells exposed in vitro to laser-generated electron bunches. Additional studies are needed to improve preclinical validation of the radiobiological characteristics and efficacy of laser-driven electron accelerators in the future.

Rapid RBE-Weighted Proton Radiation Dosimetry Risk Assessment.

Proton therapy dose is affected by relative biological effectiveness differently than X-ray therapies. The current clinically accepted weighting factor is 1.1 at all positions along the depth-dose profile. However, the relative biological effectiveness correlates with the linear energy transfer, cell or tissue type, and the dose per fraction causing variation of relative biological effectiveness along the depth-dose profile. In this article, we present a simple relative biological effectiveness-weighted treatment planning risk assessment algorithm in 2-dimensions and compare the results with those derived using the standard relative biological effectiveness of 1.1. The isodose distribution profiles for beams were accomplished using matrices that represent coplanar intersecting beams. These matrices were combined and contoured using MATLAB to achieve the distribution of dose. There are some important differences in dose distribution between the dose profiles resulting from the use of relative biological effectiveness = 1.1 and the empirically derived depth-dependent values of relative biological effectiveness. Significant hot spots of up to twice the intended dose are indicated in some beam configurations. This simple and rapid risk analysis could quickly evaluate the safety of various dose delivery schema.

Relative biological effectiveness in canine osteosarcoma cells irradiated with accelerated charged particles.

Heavy ions, characterized by high linear energy transfer (LET) radiation, have advantages compared with low LET protons and photons in their biological effects. The application of heavy ions within veterinary clinics requires additional background information to determine heavy ion efficacy. In the present study, comparison of the cell-killing effects of photons, protons and heavy ions was investigated in canine osteosarcoma (OSA) cells in vitro. A total of four canine OSA cell lines with various radiosensitivities were irradiated with 137Cs gamma-rays, monoenergetic proton beams, 50 keV/µm carbon ion spread out Bragg peak beams and 200 keV/µm iron ion monoenergetic beams. Clonogenic survival was examined using colony-forming as says, and relative biological effectiveness (RBE) values were calculated relative to gamma-rays using the D10 value, which is determined as the dose (Gy) resulting in 10% survival. For proton irradiation, the RBE values for all four cell lines were 1.0-1.1. For all four cell lines, exposure to carbon ions yielded a decreased cell survival compared with gamma-rays, with the RBE values ranging from 1.56-2.10. Iron ions yielded the lowest cell survival among tested radiation types, with RBE values ranging from 3.51-3.69 observed in the three radioresistant cell lines. The radiosensitive cell line investigated demonstrated similar cell survival for carbon and iron ion irradiation. The results of the present study suggest that heavy ions are more effective for killing radioresistant canine OSA cells when compared with gamma-rays and protons. This markedly increased efficiency of cell killing is an attractive reason for utilizing heavy ions for radioresistant canine OSA.

SU-F-T-682: In-Vivo Simulation of the Relative Biological Effectiveness in Proton Therapy Using a Monte Carlo Method

Purpose: In proton therapy, the relative biological effectiveness (RBE) – compared with conventional photon therapy – is routinely set to 1.1. However, experimental in vitro studies indicate evidence for the variability of the RBE. To clarify the impact on patient treatment, investigation of the RBE in a preclinical case study should be performed. Methods: The Monte Carlo software TOPAS was used to simulate the radiation field of an irradiation setup at the experimental beamline of the proton therapy facility (OncoRay) in Dresden, Germany. Simulations were performed on cone beam CT-data (CBCT) of a xenogeneous mouse with an orthotopic lung carcinoma obtained by an in-house developed small animal image-guided radiotherapy device. A homogeneous physical fraction dose of 1.8Gy was prescribed for the contoured tumor volume. Simulated dose and linear energy transfer distributions were used to estimate RBE values in the mouse based on an RBE model by Wedenberg et al. To characterize radiation sensitivity of normal and tumor tissue, α/β-ratios were taken from the literature for NB1RGB (10.1Gy) and human squamous lung cancer (6.2Gy) cell lines, respectively. Results: Good dose coverage of the target volume was achieved with a spread-out Bragg peak (SOBP). The contra-lateral lung was completely spared from receiving radiation. An increase in RBE towards the distal end of the SOBP from 1.07 to 1.35 and from 1.05 to 1.3 was observed when considering normal tissue and tumor, respectively, with the highest RBE values located distal to the target volume. Conclusion: Modeled RBE values simulated on CBCT for experimental preclinical proton therapy varied with tissue type and depth in a mouse and differed therefore from a constant value of 1.1. Further translational work will include, first, conducting preclinical experiments and, second, analogous RBE studies in patients using experimentally verified simulation settings for our clinically used patient-specific beam conforming technique.

SU‐G‐TeP3‐01: A New Approach for Calculating Variable Relative Biological Effectiveness in IMPT Optimization

Purpose:To investigate the impact of a new approach for calculating relative biological effectiveness (RBE) in intensity‐modulated proton therapy (IMPT) optimization on RBE‐weighted dose distributions. This approach includes the nonlinear RBE for the high linear energy transfer (LET) region, which was revealed by recent experiments at our institution. In addition, this approach utilizes RBE data as a function of LET without using dose‐averaged LET in calculating RBE values.Methods:We used a two‐piece function for calculating RBE from LET. Within the Bragg peak, RBE is linearly correlated to LET. Beyond the Bragg peak, we use a nonlinear (quadratic) RBE function of LET based on our experimental. The IMPT optimization was devised to incorporate variable RBE by maximizing biological effect (based on the Linear Quadratic model) in tumor and minimizing biological effect in normal tissues. Three glioblastoma patients were retrospectively selected from our institution in this study. For each patient, three optimized IMPT plans were created based on three RBE resolutions, i.e., fixed RBE of 1.1 (RBE‐1.1), variable RBE based on linear RBE and LET relationship (RBE‐L), and variable RBE based on linear and quadratic relationship (RBE‐LQ). The RBE weighted dose distributions of each optimized plan were evaluated in terms of different RBE values, i.e., RBE‐1.1, RBE‐L and RBE‐LQ.Results:The RBE weighted doses recalculated from RBE‐1.1 based optimized plans demonstrated an increasing pattern from using RBE‐1.1, RBE‐L to RBE‐LQ consistently for all three patients. The variable RBE (RBE‐L and RBE‐LQ) weighted dose distributions recalculated from RBE‐L and RBE‐LQ based optimization were more homogenous within the targets and better spared in the critical structures than the ones recalculated from RBE‐1.1 based optimization.Conclusion:We implemented a new approach for RBE calculation and optimization and demonstrated potential benefits of improving tumor coverage and normal sparing in IMPT planning.

WE‐H‐BRA‐07: Mechanistic Modelling of the Relative Biological Effectiveness of Heavy Charged Particles

Purpose Uncertainty in the Relative Biological Effectiveness (RBE) of heavy charged particles compared to photons remains one of the major uncertainties in particle therapy. As RBEs depend strongly on clinical variables such as tissue type, dose, and radiation quality, more accurate individualised models are needed to fully optimise treatments. MethodsWe have developed a model of DNA damage and repair following X‐ray irradiation in a number of settings, incorporating mechanistic descriptions of DNA repair pathways, geometric effects on DNA repair, cell cycle effects and cell death. Our model has previously been shown to accurately predict a range of biological endpoints including chromosome aberrations, mutations, and cell death. This model was combined with nanodosimetric models of individual ion tracks to calculate the additional probability of lethal damage forming within a single track. These lethal damage probabilities can be used to predict survival and RBE for cells irradiated with ions of different Linear Energy Transfer (LET). ResultsBy combining the X‐ray response model with nanodosimetry information, predictions of RBE can be made without cell‐line specific fitting. The model's RBE predictions were found to agree well with empirical proton RBE models (Mean absolute difference between models of 1.9% and 1.8% for cells with α/β ratios of 9 and 1.4, respectively, for LETs between 0 and 15 keV/µm). The model also accurately recovers the impact of high‐LET carbon ion exposures, showing both the reduced efficacy of ions at extremely high LET, as well as the impact of defects in non‐homologous end joining on RBE values in Chinese Hamster Ovary cells.ConclusionOur model is predicts RBE without the inclusion of empirical LET fitting parameters for a range of experimental conditions. This approach has the potential to deliver improved personalisation of particle therapy, with future developments allowing for the calculation of individualised RBEs.SJM is supported by a Marie Curie International Outgoing Fellowship from the European Commission's FP7 program (EC FP7 MC‐IOF‐623630)

Evaluation of the relative biological effectiveness of spot-scanning proton irradiation in vitro.

Variations in relative biological effectiveness (RBE) from a fixed value of 1.1 are critical in proton beam therapy. To date, studies estimating RBE at multiple positions relative to the spread-out Bragg peak (SOBP) have been predominantly performed using passive scattering methods, and limited data are available for spot-scanning beams. Thus, to investigate the RBE of spot-scanning beams, Chinese hamster fibroblast V79 cells were irradiated using the beam line at the Hokkaido University Hospital Proton Therapy Center. Cells were placed at six different depths, including the entrance of the proton beam and the proximal and distal part of the SOBP. Surviving cell fractions were analyzed using colony formation assay, and cell survival curves were obtained by the curve fitted using a linear–quadratic model. RBE10 and RBE37 were 1.15 and 1.21 at the center of the SOBP, respectively. In contrast, the distal region showed higher RBE values (1.50 for RBE10 and 1.85 for RBE37). These results are in line with those of previous studies conducted using passive scattering proton beams. Taken together, these data strongly suggest that variations in RBE should be considered during treatment planning for spot-scanning beams as well as for passive scattering proton beams.

SU‐F‐T‐124: Radiation Biological Equivalent Presentations OfLEM‐1 and MKM Approaches in the Carbon‐Ion Radiotherapy

Purpose:To study the correlations of the radiation biological equivalent doses (BED) along depth and lateral distance between LEM‐1 and MKM approaches.Methods:In NIRS‐MKM (Microdosimetric Kinetic Model) approach, the prescribed BED, referred as C‐Eq, doses aims to present the relative biological effectiveness (RBE) for different energies of carbon‐ions on a fixed 10% survival value of HCG cell with respect to convention X‐ray. Instead of a fixed 10% survival, the BED doses of LEM‐1 (Local Effect Model) approach, referred as X‐Eq, aims to present the RBE over the whole survival curve of chordoma‐like cell with alpha/beta ratio of 2.0. The relationship of physical doses as a function of C‐Eq and X‐Eq doses were investigated along depth and lateral distance for various sizes of cubic targets in water irradiated by carbon‐ions.Results:At the center of each cubic target, the trends between physical and C‐Eq or X‐Eq doses can be described by a linear and 2nd order polynomial functions, respectively. Using fit functions can then calculate a scaling factor between C‐Eq and X‐Eq doses to have similar physical doses. With equalized C‐Eq and X‐Eq doses at the depth of target center, over‐ and under‐estimated X‐Eq to C‐Eq are seen for depths before and after the target center, respectively. Near the distal edge along depth, sharp rising of RBE value is observed for X‐Eq, but sharp dropping of RBE value is observed for C‐Eq. For lateral locations near and just outside 50% dose level, sharp raising of RBE value is also seen for X‐Eq, while only minor increasing with fast dropping for C‐Eq.Conclusion:An analytical function to model the differences between the CEq and X‐Eq doses along depth and lateral distance need to further investigated to explain varied clinic outcome of specific cancers using two different approaches to calculated BED doses.

Relative Biological Effectiveness of HZE Particles for Chromosomal Exchanges and Other Surrogate Cancer Risk Endpoints.

The biological effects of high charge and energy (HZE) particle exposures are of interest in space radiation protection of astronauts and cosmonauts, and estimating secondary cancer risks for patients undergoing Hadron therapy for primary cancers. The large number of particles types and energies that makeup primary or secondary radiation in HZE particle exposures precludes tumor induction studies in animal models for all but a few particle types and energies, thus leading to the use of surrogate endpoints to investigate the details of the radiation quality dependence of relative biological effectiveness (RBE) factors. In this report we make detailed RBE predictions of the charge number and energy dependence of RBE’s using a parametric track structure model to represent experimental results for the low dose response for chromosomal exchanges in normal human lymphocyte and fibroblast cells with comparison to published data for neoplastic transformation and gene mutation. RBE’s are evaluated against acute doses of γ-rays for doses near 1 Gy. Models that assume linear or non-targeted effects at low dose are considered. Modest values of RBE (<10) are found for simple exchanges using a linear dose response model, however in the non-targeted effects model for fibroblast cells large RBE values (>10) are predicted at low doses <0.1 Gy. The radiation quality dependence of RBE’s against the effects of acute doses γ-rays found for neoplastic transformation and gene mutation studies are similar to those found for simple exchanges if a linear response is assumed at low HZE particle doses. Comparisons of the resulting model parameters to those used in the NASA radiation quality factor function are discussed.

Calculating Variations in Biological Effectiveness for a 62 MeV Proton Beam.

A biophysical model of radiation-induced cell death and chromosome aberrations [called BIophysical ANalysis of Cell death and chromosome Aberrations (BIANCA)] was further developed and applied to therapeutic protons. The model assumes a pivotal role of DNA cluster damage, which can lead to clonogenic cell death following three main steps: (i) a DNA “cluster lesion” (CL) produces two independent chromosome fragments; (ii) fragment mis-rejoining within a threshold distance d gives rise to chromosome aberrations; (iii) certain aberration types (dicentrics, rings, and large deletions) lead to clonogenic inactivation. The yield of CLs and the probability, f, that a chromosome fragment remains un-rejoined even if other fragment(s) are present within d, were adjustable parameters. The model, implemented as a MC code providing simulated dose–responses directly comparable with experimental data, was applied to pristine and modulated Bragg peaks of the proton beam used to treat eye melanoma at INFN-LNS in Catania, Italy. Experimental survival curves for AG01522 cells exposed to the Catania beam were reproduced, supporting the model assumptions. Furthermore, cell death and chromosome aberrations at different depths along a spread-out Bragg peak (SOBP) dose profile were predicted. Both endpoints showed an increase along the plateau, and high levels of damage were found also beyond the distal dose fall-off, due to low-energy protons. Cell death and chromosome aberrations were also predicted for V79 cells, in the same irradiation scenario as that used for AG01522 cells. In line with other studies, this work indicated that assuming a constant relative biological effectiveness (RBE) along a proton SOBP may be sub-optimal. Furthermore, it provided qualitative and quantitative evaluations of the dependence of the beam effectiveness on the considered endpoint and dose. More generally, this work represents an example of therapeutic beam characterization avoiding the use of experimental RBE values, which can be source of uncertainties.

The Effect of X-Ray and Heavy Ions Radiations on Chemotherapy Refractory Tumor Cells.

The purpose of this study is to link both numeric and structural chromosomal aberrations to the effectiveness of radiotherapy in chemotherapy refractory tumor cells. Neuroblastoma (LAN-1) and 79HF6 glioblastoma cells derived from patients and their chemoresistant sublines were artificially cultured as neurospheres and irradiated by X-rays and heavy ions sources. All the cell lines were irradiated by Carbon-SIS with LET of 100 keV/μm. However, 79HF6 cells and LAN-1 cells were also irradiated by Carbon-UNILAC with LET of 168 keV/μm and Nickel ions with LET of 174 keV/μm, respectively. The effect of radiation on the survival and proliferation of cells was addressed by standard clonogenic assays. In order to analyze cell karyotype standard Giemsa staining, multicolor fluorescence in situ hybridization (mFISH) and multicolor banding (mBAND) techniques were applied. Relative biological effectiveness values of heavy ion beams relative to X-rays at the D10 values were found between 2.3 and 2.6 with Carbon-SIS and Nickel for LAN-1 and between 2.5 and 3.4 with Carbon-SIS and Carbon-UNILAC for 79HF6 cells. Chemorefractory LAN-1(RETO) cells were found more radioresistant than untreated LAN-1(WT) cells. 79HF6(RETO) glioblastoma cells were found more radiosensitive than cytostatic sensitive cells 79HF6(WT). Sphere formation assay showed that LAN-1(RETO) cells were able to form spheres in serum-free culture, whereas 79HF6 cells could not. Most of 79HF6(WT) cells revealed a number of 71-90 chromosomes, whereas 79HF6(RETO) revealed a number of 52-83 chromosomes. The majority of LAN-1(WT) cells revealed a number of 40-44 chromosomes. mFISH analysis showed some stable aberrations, especially on chromosome 10 as judged by the impossibility to label this region with specific probes. This was corroborated using mBAND analysis. Heavy ion irradiation was more effective than X-ray in both cytostatic naive cancer and chemoresistant cell lines. LAN-1(RETO) chemoresistant neuroblastoma cells were found to be more radioresistant than the cytostatic naive cells (LAN-1(WT)), whereas this effect was not found in 79HF6 cells.

DOSE-RESPONSE STUDY USING MICRONUCLEUS CYTOME ASSAY: A TOOL FOR BIODOSIMETRY APPLICATION.

The present study is aimed at obtaining in vitro dose-response data for the induction of micronucleus (MN) and nucleoplasmic bridges (NPBs) in human lymphocytes using 60Co-gamma rays and 8 MeV pulsed electron beam. An attempt was made to validate the possibility of applying NPBs as new biodosimetry endpoint in the dose range of 0-6 Gy. A total of 1000 binucleated cells (BNCs) per dose point were evaluated for the frequency of MN and NPBs. From the study, it is clear that the dose-response increase of MN and NPBs is linear quadratic in nature. The study provides linear and quadratic parameter for biodosimetry application. The relative biological effectiveness value of the 8 MeV electron beam was estimated using slope values and is found to be 1.18 ± 0.01 for MN/BNCs, 1.27 ± 0.02 for the fraction of BNCs with MN, 1.16 ± 0.13 for MN/(BNCs with MN) and 1.09±0.01 for NPBs.

The Radiation Enhancement of 15 nm Citrate-Capped Gold Nanoparticles Exposed to 70 keV/μm Carbon Ions.

Radiotherapy is an important modality for tumor treatment. The central goal of radiotherapy is to deliver a therapeutic dose to the tumor as much as possible whilst sparing the surrounding normal tissues. On one hand, heavy ion radiation induces maximum damage at the end of the track (called the Bragg Peak). Hadron therapy based on heavy ions is considered superior to conventional X-rays and γ-rays radiations for tumors sited in sensitive tissues, childhood cases and radioresistant cancers. On the other hand, radiation sensitizers enhanced the radiation effects in tumors by increasing the dose specifically to the tumor cells. Recently, the use of gold nanoparticles as potential tumor selective radio-sensitizers has been proposed as a breakthrough in radiotherapy with conventional radiations. The enhanced radiation effect of heavy ions in tumor by using gold nanoparticles as radio-sensitizer may provide alternative in hadron therapy. In this study, we investigated the radiosensitizing effects of carbon ions with a linear energy transfer of 70 keV/μm in the presence of 15 nm citrate-capped AuNPs. The existing of AuNPs resulted in 5.5-fold enhancement in hydroxyl radical production and 24.5% increment in relative biological effectiveness (RBE) values for carbon-ion-irradiated HeLa cells. The study indicated gold nanoparticles can be used as potential radio-sensitizer in carbon ions therapy.

Effect of oxygen pressure during incubation with a 10B-carrier on 10B uptake capacity of cultured p53 wild-type and mutated tumor cells: dependency on p53 status of tumor cells and types of 10B-carriers

Purpose To evaluate the effect of oxygen pressure during incubation with a 10B-carrier on 10B uptake capacity of cultured p53 wild-type and mutated tumor cells.Materials and methods Cultured human head and neck squamous cell carcinoma cell line transfected with mutant TP53 (SAS/mp53), or with a neo vector as a control (SAS/neo) was incubated with L-para-boronophenylalanine-10B (BPA) or sodium mercaptoundecahydrododecaborate-10B (BSH) as a 10B-carrier at the 10B concentration of 60 ppm for 24 h under aerobic (20.7% of oxygen) or hypoxic (0.28% of oxygen) conditions. Immediately after incubation, cultured tumor cells received reactor thermal neutron beams, and a cell survival assay was performed. 10B concentration of cultured SAS/neo or SAS/mp53 cells incubated under aerobic or hypoxic conditions was determined with a thermal neutron guide tube.Results Hypoxic incubation significantly decreased 10B concentration of cultured cells with a clearer tendency observed following BPA than BSH treatment in both SAS/neo and SAS/mp53 cells. Following neutron beam irradiation, SAS/mp53 cells showed significantly higher relative biological effectiveness values than SAS/neo cells because of the significantly lower radiosensitivity of SAS/mp53 to γ-rays than SAS/neo cells.Conclusion Oxygen pressure during incubation with a 10B-carrier had a critical impact on 10B uptake of cultured tumor cells.

Theoretical substantiation of biological efficacy enhancement for β-delayed particle decay (9)C beam: A Monte Carlo study in combination with analysis with the local effect model approach.

To improve the efficacy of heavy ion therapy, β-delayed particle decay (9)C beam as a double irradiation source for cancer therapy has been proposed. The authors' previous experiment showed that relative biological effectiveness (RBE) values at the depths around the Bragg peak of a (9)C beam were enhanced and compared to its stable counterpart (12)C beam. The purpose of this study was to explore the nature of the biological efficacy enhancement theoretically. A Monte Carlo simulation study was conducted in this study. First a simplified cell model was established so as to form a tumor tissue. Subsequently, the tumor tissue was imported into the Monte Carlo simulation software package gate and then the tumor cells were virtually irradiated with comparable (9)C and (12)C beams, respectively, in the simulations. The transportation and particle deposition data of the (9)C and (12)C beams, derived from the gate simulations, were analyzed with the authors' local effect model implementation so as to deduce cell survival fractions. The particles emitted from the decay process of deposited (9)C particles around a cell nucleus increased the dose delivered to the nucleus and elicited clustered damages around the secondary particles' trajectories. Therefore, compared to the (12)C beam, the RBE value of the (9)C beam increased at the depths around their Bragg peaks. Collectively, the increased local doses and clustered damages due to the decayed particles emitted from deposited (9)C particles led to the RBE enhancement in contrast with the (12)C beam. Thus, the enhanced RBE effect of a (9)C beam for a simplified tumor model was shown theoretically in this study.

Comparisons of longitudinal and lateral dose profiles and relative biological effectiveness for DNA double strand breaks among 1H, 4He and 12C beams

Monte Carlo FLUKA and MCDS codes were used to study 1H, 4He and 12C ion beams with similar ranges in water phantom. The longitudinal and lateral dose profiles and the relative biological effectiveness (RBE) were investigated. Simulations were performed with particular emphasis in the vicinity of the Bragg peak (BP). The impact of individual nuclear fragments created by the primary beams was examined. Comparisons were made for the BP width, lateral dose profile width, and RBE value at different depths in the phantom. RBE values for the induction of DNA double-strand breaks were estimated, particularly in the vicinity of the BP. Results showed that 12C beam had the narrowest BP width, smallest lateral dose profile, and largest RBE value, followed by 4He and 1H beams. However, the differences between 4He and 12C were smaller than those between 1H and 4He. It also showed that the influence of nuclear fragments was significant for 12C beam, moderate for 4H beam, and minor for 1H beam. This influence was important for 12C at depths beyond the BP. Our results suggest that 4He beam is also a promising option for cancer therapy.

59 - NanoxTM: A new multiscale theoretical framework to predict cell survival in the context of particle therapy

The number of facilities that offer tumor treatment with particle therapy has been increasing substantially over the past decades. The dose distribution deposited by ions, and for the heaviest, their higher biological effectiveness, make them more interesting to destroy localized tumors while sparing healthy tissues. Such an effectiveness is quantified through the RBE (relative biological effectiveness), which is a complex function of multiple parameters like cell line, cell cycle stage, radiation quality and irradiation conditions. Therefore, determining the value of RBE for every scenario is a challenging task that requires modeling to comply with the demands of a clinical environment. Several solutions have already been developed and a few are currently used in treatment planning [1-4]. Nevertheless, despite the progress these models have allowed, they present some shortcomings [5-7] that may limit their improvement. We present thereby a new approach that gathers some principles of the existing ones and addresses some of their weaknesses. The innovative features of NanoxTM are that it is fully based on statistical physics, taking in particular into account the fluctuations in energy deposition at multiple scales, and that it introduces the concept of a chemical dose. The latter is chosen as a parameter defined at the cell scale to represent the induction of cell death by “non-local” events as the accumulation of cellular oxidative stress or sublethal lesions induced by the produced radical species. Such “non-local” events are complementary to the so-called “local” events, which take place at a very localized (nanometric) scale. The “local” events are considered as lethal since a single event can cause cell death. The cell survival predicted by NanoxTM for V79 cell line was compared with experimental results for photons, protons and carbon ions, and even others like neon and argon ions. A good agreement was found in all cases. In particular, the model is able to describe the effectiveness of ions, including the overkill effect at higher LET values. Moreover, NanoxTM can reproduce the typical shoulder in cell survival curves. This was possible due to the introduction of the “non-local” events, through the chemical dose, which varies with LET. It is worthwhile to note that such results were obtained through the adjustment of a reduced number of free parameters. The first results of NanoxTM, obtained for V79 cell line, give us confidence that this model has potential for application in a clinical scenario in the context of particle therapy. Although it requires the tuning of only a few free parameters, NanoxTM is based on solid principles and a thorough mathematical implementation, which renders this approach simple but reliable for application in clinical practice.

The Influence of C-Ions and X-rays on Human Umbilical Vein Endothelial Cells.

Damage to the endothelium of blood vessels, which may occur during radiotherapy, is discussed as a potential precursor to the development of cardiovascular disease. We thus chose human umbilical vein endothelial cells as a model system to examine the effect of low- and high-linear energy transfer (LET) radiation. Cells were exposed to 250 kV X-rays or carbon ions (C-ions) with the energies of either 9.8 MeV/u (LET = 170 keV/μm) or 91 MeV/u (LET = 28 keV/μm). Subculture of cells was performed regularly up to 46 days (~22 population doublings) post-irradiation. Immediately after exposure, cells were seeded for the colony forming assay. Additionally, at regular intervals, mitochondrial membrane potential (MMP) (JC-1 staining) and cellular senescence (senescence-associated β-galactosidase staining) were assessed. Cytogenetic damage was investigated by the micronucleus assay and the high-resolution multiplex fluorescence in situ hybridization (mFISH) technique. Analysis of radiation-induced damage shortly after exposure showed that C-ions are more effective than X-rays with respect to cell inactivation or the induction of cytogenetic damage (micronucleus assay) as observed in other cell systems. For 9.8 and 91 MeV/u C-ions, relative biological effectiveness values of 2.4 and 1.5 were obtained for cell inactivation. At the subsequent time points, the number of micronucleated cells decreased to the control level. Analysis of chromosomal damage by mFISH technique revealed aberrations frequently involving chromosome 13 irrespective of dose or radiation quality. Disruption of the MMP was seen only a few days after exposure to X-rays or C-ions. Cellular senescence was not altered by radiation at any time point investigated. Altogether, our data indicate that shortly after exposure C-ions were more effective in damaging endothelial cells than X-rays. However, late damage to endothelial cells was not found for the applied conditions and endpoints.

Spot Scanning and Passive Scattering Proton Therapy: Relative Biological Effectiveness and Oxygen Enhancement Ratio in Cultured Cells

To determine the relative biological effectiveness (RBE), oxygen enhancement ratio (OER), and contribution of the indirect effect of spot scanning proton beams, passive scattering proton beams, or both in cultured cells in comparison with clinically used photons. The RBE of passive scattering proton beams at the center of the spread-out Bragg peak (SOBP) was determined from dose-survival curves in 4 cell lines using 6-MV X rays as controls. Survival of 2 cell lines after spot scanning and passive scattering proton irradiation was then compared. Biological effects at the distal end region of the SOBP were also investigated. The OER of passive scattering proton beams and 6 MX X rays were investigated in 2 cell lines. The RBE and OER values were estimated at a 10% cell survival level. The maximum degree of protection of radiation effects by dimethyl sulfoxide was determined to estimate the contribution of the indirect effect against DNA damage. All experiments comparing protons and X rays were made under the same biological conditions. The RBE values of passive scattering proton beams in the 4 cell lines examined were 1.01 to 1.22 (average, 1.14) and were almost identical to those of spot scanning beams. Biological effects increased at the distal end of the SOBP. In the 2 cell lines examined, the OER was 2.74 (95% confidence interval, 2.56-2.80) and 3.08 (2.84-3.11), respectively, for X rays, and 2.39 (2.38-2.43) and 2.72 (2.69-2.75), respectively, for protons (P<.05 for both cells between X rays and protons). The maximum degree of protection was significantly higher for X rays than for proton beams (P<.05). The RBE values of spot scanning and passive scattering proton beams were almost identical. The OER was lower for protons than for X rays. The lower contribution of the indirect effect may partly account for the lower OER of protons.