RBE Values Research Articles

Lower thresholds for lifetime health effects in mammals from high-LET radiation – Comparison with chronic low-LET radiation

Lower threshold dose rates and confidence limits are quantified for lifetime radiation effects in mammalian animals from internally deposited alpha-emitting radionuclides. Extensive datasets on effects from internal alpha-emitters are compiled from the International Radiobiological Archives. In total, the compiled database includes 257 records, which are analyzed by means of non-parametric order statistics. The generic lower threshold for alpha-emitters in mammalian animals (combined datasets) is 6.6·10−5 Gy day−1. Thresholds for individual alpha-emitting elements differ considerably: plutonium and americium - 2.0·10−5 Gy day−1; radium – 2.1·10−4 Gy day−1. Threshold for chronic low-LET radiation is previously estimated at 1·10−3 Gy day−1.For low exposures, the following values of alpha radiation weighting factor wR for internally deposited alpha-emitters in mammals are quantified: wR(α) = 15 as a generic value for the whole group of alpha-emitters; wR(Pu) = 50 for plutonium; wR(Am) = 50 for americium; wR(Ra) = 5 for radium. These values are proposed to serve as radiation weighting factors in calculations of equivalent doses to non-human biota.The lower threshold dose rate for long-lived mammals (dogs) is significantly lower than comparing with the threshold for short-lived mammals (mice): 2.7·10−5 Gy day−1, and 2.0·10−4 Gy day−1, respectively. The difference in thresholds is exactly reflecting the relationship between the natural longevity of these two species.Graded scale of severity in lifetime radiation effects in mammals is developed, based on compiled datasets. Being placed on the severity scale, the effects of internal alpha-emitters are situated in the zones of considerably lower dose rates than effects of the same severity caused by low-LET radiation. RBE values, calculated for effects of equal severity, are found to depend on the intensity of chronic exposure: different RBE values are characteristic for low, moderate, and high lifetime exposures (30, 70, and 13, respectively).The results of the study provide a basis for selecting correct values of radiation weighting factors in dose assessment to non-human biota.

Uveal melanoma clonogenic response to proton beam irradiation

PurposeThe goal of this study was to compare the cellular clonogenic response to proton beam and X‐ray irradiation of uveal melanoma cell line Mel270 and human melanoma cell line BLM.MethodsBLM line was derived from a skin melanoma metastasis to the lung, and Mel270 is a primary uveal melanoma cell line. Cells were irradiated with 1–5 Gy of X ray (300 kVp Phillips, 1 Gy/min) or proton beam (60 MeV) from Proteus C‐235. After irradiation cells were seeded for the clonogenic assay. Two weeks after seeding the number and type of clones were determined. Three types of clones were found: the largest in size holoclones (with the highest potential to proliferate), medium sized meroclones and the smallest paraclones (low potential to proliferate).ResultsThe total number of clones were similar for both cell lines and both types of irradiation. The RBE values calculated for 37% of survival fraction were 1.11 and 1.13 for Mel270 and BLM cells, respectively. Three types of clones seen in untreated cultures imply the heterogeneity of cellular populations. After irradiation the proportion between the three types of clones was changed: the number of holoclones was drastically lower, and the number of paraclones increased. The number of paraclones was lower after proton bean irradiation in comparison to X‐rays in both cell lines.ConclusionsProton beam and X‐ray irradiation differently modify the proliferation potential of melanoma cells.

Neutrons in proton pencil beam scanning: parameterization of energy, quality factors and RBE

The biological effectiveness of neutrons produced during proton therapy in inducing cancer is unknown, but potentially large. In particular, since neutron biological effectiveness is energy dependent, it is necessary to estimate, besides the dose, also the energy spectra, in order to obtain quantities which could be a measure of the biological effectiveness and test current models and new approaches against epidemiological studies on cancer induction after proton therapy. For patients treated with proton pencil beam scanning, this work aims to predict the spatially localized neutron energies, the effective quality factor, the weighting factor according to ICRP, and two RBE values, the first obtained from the saturation corrected dose mean lineal energy and the second from DSB cluster induction.A proton pencil beam was Monte Carlo simulated using GEANT. Based on the simulated neutron spectra for three different proton beam energies a parameterization of energy, quality factors and RBE was calculated. The pencil beam algorithm used for treatment planning at PSI has been extended using the developed parameterizations in order to calculate the spatially localized neutron energy, quality factors and RBE for each treated patient.The parameterization represents the simple quantification of neutron energy in two energy bins and the quality factors and RBE with a satisfying precision up to 85 cm away from the proton pencil beam when compared to the results based on 3D Monte Carlo simulations. The root mean square error of the energy estimate between Monte Carlo simulation based results and the parameterization is 3.9%. For the quality factors and RBE estimates it is smaller than 0.9%. The model was successfully integrated into the PSI treatment planning system.It was found that the parameterizations for neutron energy, quality factors and RBE were independent of proton energy in the investigated energy range of interest for proton therapy. The pencil beam algorithm has been extended using the developed parameterizations in order to calculate the neutron energy, quality factor and RBE.

SU‐C‐204‐04: Irradiation of Human Cell Lines Using Various Ions

Purpose:The purpose of this study is to investigate and quantify the biological effects of ion radiation using several human cell lines. We aim to answer the question of whether carbon ion the most ideal ion species for heavy ion radiotherapy.Methods:The cells were irradiated at different positions along the pristine Bragg peak of several ions with different atomic number. The biological effectiveness was evaluated using the clonogenic cell survival assay. Irradiation of three human lung cancer cell lines and a fibroblast cell line were undertaken using the charged particle beam at the NASA Space Radiation Laboratory at Brookhaven National Lab. Four mono‐energetic ion beams (carbon, oxygen, helium and lithium) were used to irradiate the cells. Water or media‐filled T25 flasks were lined up along the beam line so that the cell‐containing surfaces of the flasks were placed at a specific depth along the pristine Bragg curve. Four depths along the curve, representing entrance point, rising peak, peak and distal fall off, were selected to determine biological effectiveness. Gaf‐chromic films were placed between the flasks to monitor the irradiation as soon as it was finished.Results:For all ion radiations, the maximum cell killing effect occurs at either peak or distal fall off, depending on the cell lines. For instance, for the fibroblast cell line AGO1522, RBEs of 1.4, 1.2, 1.4 and 1.9 were observed at the Bragg peak for Helium, Lithium, Carbon and Oxygen ions. Comparing positions, RBEs of 0.9, 1.2, 1.4 and 1.8 were observed for carbon irradiation of AGO‐1522 cells positions corresponding to entrance, rising peak, peak and distal fall off.Conclusion:RBE values differ with position in the Bragg peak, ion species and cell line. Ions other than carbon may prove more effective in certain irradiation conditions and may contribute to optimized heavy ion therapy.

Protons for Prostate: Seeking Benefit via Anterior Beam Angles

For prostate treatments, robust evidence regarding the superiority of either IMRT or proton therapy is currently lacking. Some studies find that IMRT is better able to minimize high-dose regions in the bladder and rectal wall than standard bilateral proton beams, whilst others report the opposite. Here, we investigated whether a combination of anterior oblique (AO) beam angles, in vivo range verification, and state-of-the-art IMPT might substantially advance proton dose distributions relative to IMRT. The impact of uncertainty surrounding proton RBE was assessed. Eight patients were considered, all prescribed 79.2 Gy(E) to the prostate and 50.4 Gy(E) to the proximal 5-15 mm of seminal vesicles; IMRT and IMPT plans were created using MCO-based systems. The IMPT plans utilized AO beam angles (±35deg) with in-air spot sigma values of 12 mm at 60 MeV to 4.6 mm at 230MeV. Vowelized dose and LET distributions were simulated using Monte Carlo (TOPAS), and RBE was calculated according to three different models (Carabe 2012, Wedenberg 2013, McNamara 2015). The IMPT planning strategy (i) limited rectal toxicity with a 1 cm3 constraint of 81.58 Gy(E) and α/β = 3, and (ii) maximized dose to tumor to reduce under-dosage if true LET/RBE effects in vivo were lower than predicted. Table 1 shows that for all patients IMRT was able to adequately cover the CTV79.2 whilst meeting the rectal constraint. Typically, for AO IMPT it was not possible to find a plan that simultaneously met tumor and rectal constraints for fixed and variable RBE (vRBE) models, respectively. The tabulated vRBE data considers the median model.ePoster Abstracts 1144; Table 1Mean value across 8 patients (range)IMRTAO IMPT, RBE = 1.1AO IMPT, vRBE α/β = 3Dose received by 95% of CTV79.279.5 (79.3-79.8)77.8 (74.8-79.6)85.7 (82.7-87.5)Mean bladder dose16.4 (10.6-23.1)13.4 (7.5-18.7)14.1 (8.1-19.6)Mean penile bulb dose16.8 (8.8-25.1)14.2 (6.2-17.8)18.2 (8.6-22.4)Max rectal wall dose (1 cm3)79.6 (76.9-81.3)61.6 (60.7-63.8)81.4 (81.4-81.5) Open table in a new tab The question of whether improvements over IMRT can be gained using AO IMPT rests upon the validity of published LET/RBE models. If either the fixed RBE value of 1.1 or a vRBE model could be validated in vivo (via analysis of patient outcome data) then it would always be possible to use AO IMPT to dose-boost the prostate / improve normal tissue sparing relative to IMRT; however, simultaneously considering the two worst cases, fixed RBE for the tumor and vRBE for normal tissues, it is typically not possible to find an AO IMPT plan that meets both rectum and target constraints. This study 1) underlines the importance of resolving the question of proton RBE and 2) highlights that without further LET/RBE model validation, great care must be taken if AO proton fields are to be considered for prostate treatments.

SU‐E‐T‐547: Modeling Biological Response to Proton Irradiation and Evaluating Its Potential Clinical Consequences

Purpose:In addition to physical uncertainties, proton therapy may also be associated with biologic uncertainties. Currently a generic RBE value of 1.1 is used for treatment planning. In this work the effects of variable RBE, in comparison to a fixed RBE, were evaluated by calculating the effective dose for proton treatments.Methods:The repair misrepair fixation (RMF) model was used to calculate variable proton RBEs. The RBE weighted spread‐out Bragg peak (SOBP) dose in water phantom was calculated using Monte Carlo simulation and compared to 1.1 weighted SOBP dose. A head and neck proton treatment was used to evaluate the potential effects, by comparing the head and neck treatment plan computed with a commercial treatment planning system that incorporates fixed RBE of 1.1 and a Monte Carlo treatment planning system that incorporates variable RBE.Results:RBE calculations along the depth of SOBP showed that the RBE at the entrance is approximately 1 and reaches 1.1 near the center of the SOBP. However, in distal regions the RBE rises to higher values (up to 3.5 depending on the cell type). Comparison of commercial treatment plans using a fixed RBE of 1.1 and Monte Carlo using variable RBE showed noticeable differences in the effective dose distributions.Conclusion:The comparison of the treatment planning with fixed and variable RBE shows that using commercial treatment planning systems that incorporate fixed RBE (1.1) could Result in overestimation of the effective dose to part of head and neck target volumes, while underestimating the effective dose to the normal tissue beyond the tumor. The accurate variable RBE as a function of proton beam energy in patient should be incorporated in treatment planning to improve the accuracy of effective dose calculation.

TU‐CD‐303‐00: In Memoriam of Warren Sinclair: Physics Applications for New Radiobiology

The Medical Physics and Radiation Protection communities lost one of their true pioneers in May, 2014 with the passing of Warren K. Sinclair, Ph.D. He received his Doctorate in Physics at the University of London, U.K. He was a fellow of the Institute of Physics and a Certified Health Physicist. After a number of posts at Hospitals and Universities in the U.K. and New Zealand, he became the Head, Physics Department at the M.D. Anderson Hospital, Houston, TX. He held a number of academic physics positions with the University of Texas, Austin at the main campus and at the Postgraduate School of Medicine, Houston. He later served as a Senior Biophysicist, Division Director, and then Associate Laboratory Director for Biomedical Division Director, and then Associate Laboratory Director for Biomedical and Environmental Research at the Argonne National Laboratory, IL. He had additional academic appointments at the University of California, Berkeley; Northern Illinois University; the University of Illinois (Chicago Circle Campus); and the University of Chicago.Warren was a charter member of the AAPM and a leader in many communities: President of the AAPM from 1960 to 1961 and the Journal Editor from 1964 to 1969, the 2nd President of the NCRP from 1977 to 1991, and the President of the Radiation Research Society from 1978 to 1979. His many awards included the William D. Coolidge Award in 1986. Even this barely scratches the surface of the many other organizations he served with and influenced including the ICRP, IOP, RSNA, SNM, and UNSCEAR. His research interests resulted in publications from 1948 to the 1990s in many aspects (physical and biological) of radiotherapy and the effects of ionizing radiation in general, leading to early definitions of RBE values for megavoltage radiotherapy as well as contributing to the development of the modern framework for radiation protection worldwide.Warren was not a retiring person and even after moving to NCRP President Emeritus status continued to provide advice and comments on publications and to mentor others until the time of his passing. Sadly, Warren's long‐time wife Joy passed away in December, 2014 but he is survived by his son Bruce and daughter Roslyn, 2 grandchildren and 4 great‐grandchildren.

TU‐CD‐303‐01: Memorial to Warren Sinclair ‐ Memorial Lecturer

The Medical Physics and Radiation Protection communities lost one of their true pioneers in May, 2014 with the passing of Warren K. Sinclair, Ph.D. He received his Doctorate in Physics at the University of London, U.K. He was a fellow of the Institute of Physics and a Certified Health Physicist. After a number of posts at Hospitals and Universities in the U.K. and New Zealand, he became the Head, Physics Department at the M.D. Anderson Hospital, Houston, TX. He held a number of academic physics positions with the University of Texas, Austin at the main campus and at the Postgraduate School of Medicine, Houston. He later served as a Senior Biophysicist, Division Director, and then Associate Laboratory Director for Biomedical Division Director, and then Associate Laboratory Director for Biomedical and Environmental Research at the Argonne National Laboratory, IL. He had additional academic appointments at the University of California, Berkeley; Northern Illinois University; the University of Illinois (Chicago Circle Campus); and the University of Chicago.Warren was a charter member of the AAPM and a leader in many communities: President of the AAPM from 1960 to 1961 and the Journal Editor from 1964 to 1969, the 2nd President of the NCRP from 1977 to 1991, and the President of the Radiation Research Society from 1978 to 1979. His many awards included the William D. Coolidge Award in 1986. Even this barely scratches the surface of the many other organizations he served with and influenced including the ICRP, IOP, RSNA, SNM, and UNSCEAR. His research interests resulted in publications from 1948 to the 1990s in many aspects (physical and biological) of radiotherapy and the effects of ionizing radiation in general, leading to early definitions of RBE values for megavoltage radiotherapy as well as contributing to the development of the modern framework for radiation protection worldwide.Warren was not a retiring person and even after moving to NCRP President Emeritus status continued to provide advice and comments on publications and to mentor others until the time of his passing. Sadly, Warren's long‐time wife Joy passed away in December, 2014 but he is survived by his son Bruce and daughter Roslyn, 2 grandchildren and 4 great‐grandchildren.

Nanodosimetry and RBE values in radiotherapy.

In a recent paper, the authors reported that the dose mean lineal energy, [Formula: see text] in a volume of about 10-15 nm is approximately proportional to the α-parameter in the linear-quadratic relation used in fractionated radiotherapy in both low- and high-LET beams. This was concluded after analyses of reported radiation weighting factors, WisoE (clinical RBE values), and [Formula: see text] values in a large range of volumes. Usually, microdosimetry measurements in the nanometer range are difficult; therefore, model calculations become necessary. In this paper, the authors discuss the calculation method. A combination of condensed history Monte Carlo and track structure techniques for calculation of mean lineal energy values turned out to be quite useful. Briefly, the method consists in weighting the relative dose fractions of the primary and secondary charged particles with their respective energy-dependent dose mean lineal energies. The latter were obtained using a large database of Monte Carlo track structure calculations.

The effectiveness of the high-LET radiations from the boron neutron capture [10B(n,α) 7Li] reaction determined for induction of chromosome aberrations and apoptosis in lymphocytes of human blood samples.

Provided that a selective accumulation of (10)B-containing compounds is introduced in tumor cells, following irradiation by thermal neutrons produces high-LET alpha-particles ((4)He) and recoiling lithium-7 ((7)Li) nuclei emitted during the capture of thermalized neutrons (0.025eV) from (10)B. To estimate the biological effectiveness of this boron neutron capture [(10)B(n,α)(7)Li] reaction, the chromosome aberration assay and the flow cytometry apoptosis assay were applied. At the presence of the clinically used compounds BSH (sodium borocaptate) and BPA (p-boronophenylalanine), human lymphocytes were irradiated by sub-thermal neutrons. For analyzing chromosome aberrations, human lymphocytes were exposed to thermally equivalent neutron fluences of 1.82×10(11) cm(-2) or 7.30×10(11) cm(-2) (corresponding to thermal neutron doses of 0.062 and 0.248Gy, respectively) in the presence of 0, 10, 20, and 30ppm of BSH or BPA. Since the kerma coefficient of blood increased by 0.864×10(-12)Gycm(2) per 10ppm of (10)B, the kerma coefficients in blood increase from 0.34×10(-12) cm(2) (blood without BSH or BPA) up to 2.93×10(-12) Gycm(2) in the presence of 30ppm of (10)B. For the (10)B(n, α)(7)Li reaction, linear dose-response relations for dicentrics with coefficients α=0.0546±0.0081Gy(-1) for BSH and α=0.0654±0.0075Gy(-1) for BPA were obtained at 0.062Gy as well as α=0.0985±0.0284Gy(-1) for BSH and α=0.1293±0.0419Gy(-1) for BPA at 0.248Gy. At both doses, the corresponding (10)B(n, α)(7)Li reactions from BSH and BPA are not significantly different. A linear dose-response relation for dicentrics also was obtained for the induction of apoptosis by the (10)B(n, α)(7)Li reaction at 0.248Gy. The linear coefficients α=0.0249±0.0119Gy(-1) for BSH and α=0.0334±0.0064Gy(-1) for BPA are not significantly different. Independently of the applied thermal neutron doses of 0.062Gy or 0.248Gy, the (10)B(n, α)(7)Li reaction from 30ppm BSH or BPA induced an apparent RBE of about 2.2 for the production of dicentrics as compared to exposure to thermal neutrons alone. Since the apparent RBE value is defined as the product of the RBE of a thermal neutron dose alone times a boron localization factor which depends on the concentration of a (10)B-containing compound, this localization factor determines the biological effectiveness of the (10)B(n, α)(7)Li reaction.

Simulation of ultrasoft X-rays induced DNA damage using the Geant4 Monte Carlo toolkit

In this study, the total yields of SSB and DSB induced by monoenergetic electrons with energies of 0.28–4.55keV, corresponding to ultrasoft X-rays energies, have been calculated in Charlton and Humm volume model using the Geant4-DNA toolkit and compared with theoretical and experimental data. A reasonable agreement between the obtained results in the present study and experimental and theoretical data of previous studies showed the efficiency of this model in estimating the total yield of strand breaks in spite of its simplicity. Also, it has been found that in the low energy region, the yield of the total SSB remains nearly constant while the DSB yield increases with decreasing energy. Moreover, a direct dependency between DSB induction, RBE value and the mean lineal energy as a microdosimetry quantity has been observed. In addition, it has become clear that the use of the threshold energy of 10.79eV to calculate the total strand breaks yields results in a better agreement with the experiments, while the threshold of 17.5eV shows a big difference.

A Reusable Proton Range Compensator and Verification of Its Functionality

changes (STC) following PRT and investigated any correlation with Monte Carlo (MC) calculated LET and RBE values. Materials/Methods: We performed a retrospective review of 111 medulloblastoma patients treated with craniospinal passive scattering PRT followed by posterior fossa (PF) or involved field boost at our institution between 2002 and 2011. The locations of STC consistent with possible radiation injury were documented on magnetic resonance image scans of symptomatic patients and, after image registration, contoured on the original planning computed tomography scans. Dose and LET distributions were calculated using MC (TOPAS) for patient and beam geometry of the treated plans. RBE values were estimated by two models, based on LET and dose distributions: the first (Wilkens) highlights relative RBE variations, given an a-priori defined average RBE value; the second (Carabe) estimates absolute RBE values. Results: At median follow up of 4 years, the 5-year cumulative incidence of STC was 4%. A total of 10 STC areas were found in 4 patients, involving the brainstem(3), resection cavity(1), cervical spine(1), cerebellum (2) and inner acoustic canal(1). 8 STC areas had higher LET value than the target, with average LET value of all STC areas being 2.7 versus 2.4 keV/mm in the PF boost area (paired student t-test p-value Z 0.05). Carabe model estimated an average RBE value of 1.202 for the STC areas versus 1.185 for the target (p-value Z 0.06). Conclusions: Cumulative incidence of STC for in patients treated for medulloblastoma with PRTwas comparable to that reported for photon RT. The brainstem was the most common site. Although STC areas had higher LET values, the corresponding RBE difference was less than 2%. Similar variations were present in all treatment plans including patients that did not develop STC. The etiology of RT changes is likely dependent upon other contributing and unknown factors, such as biological and genetic differences in our patients. Author Disclosure: D. Giantsoudi: None. R.V. Sethi: None. B. Yeap: None. T.I. Yock: None. N.J. Tarbell: None. H. Paganetti: None. S.M. MacDonald: None.

Cluster pattern analysis of energy deposition sites for the brachytherapy sources 103Pd, 125I, 192Ir, 137Cs, and 60Co

Analysing the pattern of energy depositions may help elucidate differences in the severity of radiation-induced DNA strand breakage for different radiation qualities. It is often claimed that energy deposition (ED) sites from photon radiation form a uniform random pattern, but there is indication of differences in RBE values among different photon sources used in brachytherapy. The aim of this work is to analyse the spatial patterns of EDs from 103Pd, 125I, 192Ir, 137Cs sources commonly used in brachytherapy and a 60Co source as a reference radiation. The results suggest that there is both a non-uniform and a uniform random component to the frequency distribution of distances to the nearest neighbour ED. The closest neighbouring EDs show high spatial correlation for all investigated radiation qualities, whilst the uniform random component dominates for neighbours with longer distances for the three higher mean photon energy sources (192Ir, 137Cs, and 60Co). The two lower energy photon emitters (103Pd and 125I) present a very small uniform random component. The ratio of frequencies of clusters with respect to 60Co differs up to 15% for the lower energy sources and less than 2% for the higher energy sources when the maximum distance between each pair of EDs is 2 nm. At distances relevant to DNA damage, cluster patterns can be differentiated between the lower and higher energy sources. This may be part of the explanation to the reported difference in RBE values with initial DSB yields as an endpoint for these brachytherapy sources.

Micronucleus formation in human keratinocytes is dependent on radiation quality and tissue architecture.

The cytokinesis-block micronucleus (MN) assay was used to assess the genotoxicity of low doses of different types of space radiation. Normal human primary keratinocytes and immortalized keratinocytes grown in 2D monolayers each were exposed to graded doses of 0.3 or 1.0 GeV/n silicon ions or similar energies of iron ions. The frequencies of induced MN were determined and compared to γ-ray data. RBE(max) values ranged from 1.6 to 3.9 for primary keratinocytes and from 2.4 to 6.3 for immortalized keratinocytes. At low radiation doses ≤ 0.4 Gy, 0.3 GeV/n iron ions were the most effective at inducing MN in normal keratinocytes. An "over-kill effect" was observed for 0.3 GeV/n iron ions at higher doses, wherein 1.0 GeV/n iron ions were most efficient in inducing MN. In immortalized keratinocytes, 0.3 GeV/n iron ions produced MN with greater frequency than 1.0 GeV/n iron ions, except at the highest dose tested. MN formation was higher in immortalized keratinocytes than in normal keratinocytes for all doses and radiation qualities investigated. MN induction was also assessed in human keratinocytes cultured in 3D to simulate the complex architecture of human skin. RBE values for MN formation in 3D were reduced for normal keratinocytes exposed to iron ions, but were elevated for immortalized keratinocytes. Overall, MN induction was significantly lower in keratinocytes cultured in 3D than in 2D. Together, the results suggest that tissue architecture and immortalization status modulate the genotoxic response to space radiation, perhaps via alterations in DNA repair fidelity.

SU-E-T-375: Passive Scattering to Pencil-Beam-Scanning Comparison for Medulloblastoma Proton Therapy: LET Distributions and Radiobiological Implications

Purpose: To compare the linear energy transfer (LET) distributions between passive scattering and pencil beam scanning proton radiation therapy techniques for medulloblastoma patients and study the potential radiobiological implications. Methods: A group of medulloblastoma patients, previously treated with passive scattering (PS) proton craniospinal irradiation followed by prosterior fossa or involved field boost, were selected from the patient database of our institution. Using the beam geometry and planning computed tomography (CT) image sets of the original treatment plans, pencil beam scanning (PBS) treatment plans were generated for the cranial treatment for each patient, with average beam spot size of 8mm (sigma in air at isocenter). 3-dimensional dose and LET distributions were calculated by Monte Carlo methods (TOPAS) both for the original passive scattering and new pencil beam scanning treatment plans. LET volume histograms were calculated for the target and OARs and compared for the two delivery methods. Variable RBE weighted dose distributions and volume histograms were also calculated using a variable dose and LET-based model. Results: Better dose conformity was achieved with PBS planning compared to PS, leading to increased dose coverage for the boost target area and decreased average dose to the structures adjacent to it and critical structures outside the whole brain treatment field. LET values for the target were lower for PBS plans. Elevated LET values for OARs close to the boosted target areas were noticed, due to end of range of proton beams falling inside these structures, resulting in higher RBE weighted dose for these structures compared to the clinical RBE value of 1.1. Conclusion: Transitioning from passive scattering to pencil beam scanning proton radiation treatment can be dosimetrically beneficial for medulloblastoma patients. LET–guided treatment planning could contribute to better decision making for these cases, especially for critical structures at close proximity to the boosted target area.

Dose estimation of animal experiments at the THOR BNCT beam by NCTPlan and Xplan

Dose estimation of animal experiments affects many subsequent derived quantities, such as RBE and CBE values. It is important to ensure the trustiness of calculated dose of the irradiated animals. However, the dose estimation was normally calculated using simplified geometries and tissue compositions, which led to rough results. This paper introduces the use of treatment planning systems NCTplan and Xplan for the dose estimation. A mouse was taken as an example and it was brought to hospital for micro-PET/CT scan. It was found that the critical organ doses of an irradiated mouse calculated by simplified model were unreliable in comparison to Xplan voxel model. The difference could reach the extent of several tenths percent. It is recommended that a treatment planning system should be introduced to future animal experiments to upgrade the data quality.

Microdosimetric measurements in the thermal neutron irradiation facility of LENA reactor

A twin TEPC with electric-field guard tubes has been constructed to be used to characterize the BNCT field of the irradiation facility of LENA reactor. One of the two mini TEPC was doped with 50ppm of 10B in order to simulate the BNC events occurring in BNCT. By properly processing the two microdosimetric spectra, the gamma, neutron and BNC spectral components can be derived with good precision (~6%). However, direct measurements of 10B in some doped plastic samples, which were used for constructing the cathode walls, point out the scarce accuracy of the nominal 10B concentration value. The influence of the Boral® door, which closes the irradiation channel, has been measured. The gamma dose increases significantly (+51%) when the Boral® door is closed. The crypt-cell-regeneration weighting function has been used to measure the quality, namely the RBEµ value, of the radiation field in different conditions. The measured RBEµ values are only partially consistent with the RBE values of other BNCT facilities.

A comparative study of the biological effectiveness of 14-MeV neutron pulse and continuous radiation using mouse melanoma B-16 cells

The study was carried out using compact neutron generators with a sealed tube operating in pulsed (neutron generator ING-031) and continuous (NG-14) modes. Neutron radiation was formed due to reaction T(d,n)(4)He. The average flow of 14-MeV neutrons was 6.6×10(9) ns(-1) for ING-031 and 1.2-1.6×10(10) n s(-1) for NG-14. Duration of an impulse was ∼1 ms and pulse frequency of 50 Hz. The gamma rays of (60)Со source with an average energy of 1.25 MeV were standard radiation. Biological efficacy was estimated using the clonogenic activity of mice melanoma B-16 cells. Comparison of biological effects of neutron irradiation in pulse and continuous modes showed no significant difference between them. RBE values of pulse (ING-031) and continuous (NG-14) neutron radiation were equal-in the range of 2.4-2.6. According to the clonogenic activity of melanoma B-16 cells no dose rate effect was observed within the studied range of neutrons doses and dose rates.

A Model of Radiation-Induced Cell Killing: Insights into Mechanisms and Applications for Hadron Therapy

A mechanism-based, two-parameter biophysical model of cell killing was developed with the aim of elucidating the mechanisms underlying radiation-induced cell death and predicting cell killing by different radiation types, including protons and carbon ions at energies and doses of interest for cancer therapy. The model assumed that certain chromosome aberrations (dicentrics, rings and large deletions, called "lethal aberrations") lead to clonogenic inactivation, and that aberrations derive from μm-scale misrejoining of chromatin fragments, which in turn are produced by "dirty" double-strand breaks called "cluster lesions" (CLs). The average numbers of CLs per Gy per cell were left as a semi-free parameter and the threshold distance for chromatin-fragment rejoining was defined the second parameter. The model was "translated" into Monte Carlo code and provided simulated survival curves, which were compared with survival data on V79 cells exposed to protons, carbon ions and X rays. The agreement was good between simulations and survival data and supported the assumptions of the model at least for doses up to a few Gy. Dicentrics, rings and large deletions were found to be lethal not only for AG1522 cells exposed to X rays, as already reported by others, but also for V79 cells exposed to protons and carbon ions of different energies. Furthermore, the derived CL yields suggest that the critical DNA lesions leading to clonogenic inactivation are more complex than "clean" DSBs. After initial validation, the model was applied to characterize the particle and LET dependence of proton and carbon cell killing. Consistent with the proton data, the predicted fraction of inactivated cells after 2 Gy protons was 40-50% below 7.7 keV/μm, increased by a factor ∼1.6 between 7.7-30.5 keV/μm, and decreased by a factor ∼1.1 between 30.5-34.6 keV/μm. These LET values correspond to proton energies below a few MeV, which are always present in the distal region of hadron therapy spread-out Bragg peaks (SOBP). Consistent with the carbon data, the predicted fraction of inactivated cells after 2 Gy carbon was 40-50% between 13.7-32.4 keV/μm, it increased by a factor ∼1.7 between 32.4-153.5 keV/μm, and decreased by a factor ∼1.1 between 153.5-339.1 keV/μm. Finally, we applied the model to predict cell death at different depths along a carbon SOBP used for preclinical experiments at HIMAC in Chiba, Japan. The predicted fraction of inactivated cells was found to be roughly constant (less than 10%) along the SOBP, suggesting that this approach may be applied to predict cell killing of therapeutic carbon beams and that, more generally, dicentrics, rings and deletions at the first mitosis may be regarded as a biological dose for these beams. This study advanced our understanding of the mechanisms of radiation-induced cell death and characterized the particle and LET dependence of proton and carbon cell killing along a carbon SOBP. The model does not use RBE values, which can be a source of uncertainty. More generally, this model is a mechanism-based tool that in minutes can predict cell inactivation by protons or carbon ions of a given energy and dose, based on an experimental photon curve and in principle, a single (experimental) survival point for the considered ion type and energy.

The more important heavy charged particle radiotherapy of the future is more likely to be with heavy ions rather than protons

The more important heavy charged particle radiotherapy of the future is more likely to be with heavy ions rather than protons