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The choice of appropriate physical quantities to characterize the biological effects of ionizing radiation has evolved over time coupled with advances in scientific understanding. The basic hypothesis in radiation dosimetry is that the energy deposited by ionizing radiation initiates all the consequences of exposure in a biological sample (e.g., DNA damage, reproductive cell death). Physical quantities defined to characterize energy deposition have included dose, a measure of the mean energy imparted per unit mass of the target, and linear energy transfer (LET), a measure of the mean energy deposition per unit distance that charged particles traverse in a medium. The primary advantage of using the "dose and LET" physical system is its relative simplicity, especially for presenting and recording results. Inclusion of additional information such as the energy spectrum of charged particles renders this approach adequate to describe the biological effects of large dose levels from homogeneous sources. The primary disadvantage of this system is that it does not provide a unique description of the stochastic nature of radiation interactions. We and others have used dose-averaged LET (LET d ) as a correlative physical quantity to the relative biological effectiveness (RBE) of proton beams. This approach is based on established experimental findings that proton RBE increases with LET d . However, this approach might not be applicable to intensity-modulated proton therapy or other applications in which the proton energy spectrum is highly heterogeneous. In the current study, we irradiated cancer cells with scanning proton beams with identical LET d (3.4 keV/µm) but arising from two different proton energy/LET spectra (a narrow spectrum in group 1 and a widespread heterogeneous spectrum in group 2). Clonogenic survival after irradiation revealed significant differences in RBE at any cell surviving fraction: e.g., at a surviving fraction of 0.1, the RBE was 0.97 ± 0.03 in group 1 and 1.16 ± 0.04 in group 2 (p≤0.01), validating our hypothesis that LET d alone may not adequately indicate proton RBE. Further analysis showed that microdosimetric spectrum (the probability density function of the stochastic physical quantity lineal energy y) was helpful for interpreting observed differences in biological effects. However, more accurate use of microdosimetric spectrum to quantify RBE requires a cell line-specific mechanistic model., (© 2024. The Author(s).)

Objective. Relative biological effectiveness (RBE) differs between radiation qualities. However, an RBE of 1.0 has been established for photons regardless of the wide range of photon energies used clinically, the lack of reproducibility in radiobiological studies, and outdated reference energies used in the experimental literature. Moreover, due to intrinsic radiosensitivity, different cancer types have different responses to radiation. This study aimed to characterize the RBE of clinically relevant high and low photon energies in vitro for three human cancer cell lines: HCT116 (colon), HeLa (cervix), and PC3 (prostate). Approach. Experiments were conducted following dosimetry protocols provided by the American Association of Physicists in Medicine. Cells were irradiated with 6 MV x-rays, an 192 Ir brachytherapy source, 225 kVp and 50 kVp x-rays. Cell survival post-irradiation was assessed using the clonogenic assay. Survival fractions were fitted using the linear quadratic model, and survival curves were generated for RBE calculations. Main results. Cell killing was more efficient with decreasing photon energy. Using 225 kVp x-rays as the reference, the HCT116 RBE SF0.1 for 6 MV x-rays, 192 Ir, and 50 kVp x-rays were 0.89 ± 0.03, 0.95 ± 0.03, and 1.24 ± 0.04; the HeLa RBE SF0.1 were 0.95 ± 0.04, 0.97 ± 0.05, and 1.09 ± 0.03, and the PC3 RBE SF0.1 were 0.84 ± 0.01, 0.84 ± 0.01, and 1.13 ± 0.02, respectively. HeLa and PC3 cells had varying radiosensitivity when irradiated with 225 and 50 kVp x-rays. Significance. This difference supports the notion that RBE may not be 1.0 for all photons through experimental investigations that employed precise dosimetry. It highlights that different cancer types may not have identical responses to the same irradiation quality. Additionally, the RBE of clinically relevant photons was updated to the reference energy of 225 kVp x-rays., (Creative Commons Attribution license.)

Background: Phenomenological relative biological effectiveness (RBE) models for proton therapy, based on the dose-averaged linear energy transfer (LET), have been developed to address the apparent RBE increase towards the end of the proton range. The results of these phenomenological models substantially differ due to varying empirical assumptions and fitting functions. In contrast, more theory-based approaches are used in carbon ion radiotherapy, such as the microdosimetric kinetic model (MKM). However, implementing microdosimetry-based models in LET-based proton therapy treatment planning systems poses challenges., Purpose: This work presents a LET-based version of the MKM that is practical for clinical use in proton radiotherapy., Methods: At first, we derived an approximation of the Mayo Clinic Florida (MCF) MKM for relatively-sparsely ionizing radiation such as protons. The mathematical formalism of the proposed model is equivalent to the original MKM, but it maintains some key features of the MCF MKM, such as the determination of model parameters from measurable cell characteristics. Subsequently, we carried out Monte Carlo calculations with PHITS in different simulated scenarios to establish a heuristic correlation between microdosimetric quantities and the dose averaged LET of protons., Results: A simple allometric function was found able to describe the relationship between the dose-averaged LET of protons and the dose-mean lineal energy, which includes the contributions of secondary particles. The LET-based MKM was used to model the in vitro clonogenic survival RBE of five human and rodent cell lines (A549, AG01522, CHO, T98G, and U87) exposed to pristine and spread-out Bragg peak (SOBP) proton beams. The results of the LET-based MKM agree well with the biological data in a comparable or better way with respect to the other models included in the study. A sensitivity analysis on the model results was also performed., Conclusions: The LET-based MKM integrates the predictive theoretical framework of the MCF MKM with a straightforward mathematical description of the RBE based on the dose-averaged LET, a physical quantity readily available in modern treatment planning systems for proton therapy., (© 2024 American Association of Physicists in Medicine.)

This study introduces the MKM_B model, an approach derived from the MKM model, designed to evaluate the biological effectiveness of Boron Neutron Capture Therapy (BNCT) in the face of challenges from varying microscopic boron distributions. The model introduces a boron compensation factor, allowing for the assessment of compound Biological Effectiveness (CBE) values for different boron distributions. Utilizing the TOPAS simulation platform, the lineal energy spectrum of particles in BNCT was simulated, and the sensitivity of the MKM_B model to parameter variations and the influence of cell size on the model were thoroughly investigated. The CBE values for 10B-boronphenylalanine (BPA) and 10B-sodium (BSH) were determined to be 3.70 and 1.75, respectively. These calculations were based on using the nucleus radius of 2.5 μm and the cell radius of 5 μm while considering a 50% surviving fraction. It was observed that as cell size decreased, the CBE values for both BPA and BSH increased. Additionally, the model parameter rd was identified as having the most significant impact on CBE, with other parameters showing moderate effects. The development of the MKM_B model enables the accurate prediction of CBE under different boron distributions in BNCT. This model offers a promising approach to optimize treatment planning by providing increased accuracy in biological effectiveness., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Carbon ion radiotherapy (CIRT) for pediatric cancer is currently limited because of the unknown risk of induction of secondary cancers. Medulloblastoma of Ptch1+/- mice offers a unique experimental system for radiation-induced carcinogenesis, in which tumors are classified into spontaneous and radiation-induced subtypes based on their features of loss of heterozygosity (LOH) that affect the wild-type Ptch1 allele. The present study aims to investigate in young Ptch1+/- mice the carcinogenic effect, and its age dependence, of the low-linear energy transfer (LET, ∼13 keV/µm) carbon ions, to which normal tissues in front of the tumor are exposed during therapy. We irradiated Ptch1+/- mice at postnatal day (P) 1, 4, or 10 with 290 MeV/u carbon ions (0.05-0.5 Gy; LET, 13 keV/µm) and monitored them for medulloblastoma development. Loss of heterozygosity of seven genetic markers on chromosome 13 (where Ptch1 resides) was studied to classify the tumors. Carbon ion exposure induced medulloblastoma most effectively at P1. The LOH patterns of tumors were either telomeric or interstitial, the latter occurring almost exclusively in the irradiated groups, allowing the use of interstitial LOH as a biomarker of radiation-induced tumors. Radiation-induced tumors developed during a narrow age window (most strongly at P1 and only moderately at P4, with suppressed tumorigenesis at P10). Calculated using previous results using 137Cs gamma rays, the values for relative biological effectiveness (RBE) regarding radiation-induced tumors were 4.1 (3.4, 4.8) and 4.3 (3.3, 5.2) (mean and 95% confidence interval) for exposure at P1 and 4, respectively. Thus, the RBE of carbon ions for medulloblastoma induction in Ptch1+/- mice was higher than the generally recognized RBE of 1-2 for cell killing, chromosome aberrations, and skin reactions., (© 2024 by Radiation Research Society. All rights of reproduction in any form reserved.)

Purpose: Our objective was to develop a methodology for assessing the linear energy transfer (LET) and relative biological effectiveness (RBE) in clinical proton and helium ion beams using fluorescent nuclear track detectors (FNTDs)., Methods and Materials: FNTDs were exposed behind solid water to proton and helium ( 4 He) ion spread-out Bragg peaks. Detectors were imaged with a confocal microscope, and the LET spectra were derived from the fluorescence intensity. The track- and dose-averaged LET (LET F and LET D , respectively) were calculated from the LET spectra. LET measurements were used as input on RBE models to estimate the RBE. Human alveolar adenocarcinoma cells (A549) were exposed at the same positions as the FNTDs. The RBE was calculated from the resulting survival curves. All measurements were compared with Monte Carlo simulations., Results: For protons, average relative differences between measurements and simulations were 6% and 19% for LET F and LET D , respectively. For helium ions, the same differences were 11% for both quantities. The position of the experimental LET spectra primary peaks agreed with the simulations within 9% and 14% for protons and helium ions, respectively. For the RBE models using LET D as input, FNTD-based RBE values ranged from 1.02 ± 0.01 to 1.25 ± 0.04 and from 1.08 ± 0.09 to 2.68 ± 1.26 for protons and helium ions, respectively. The average relative differences between these values and simulations were 2% and 4%. For A549 cells, the RBE ranged from 1.05 ± 0.07 to 1.47 ± 0.09 and from 0.89 ± 0.06 to 3.28 ± 0.20 for protons and helium ions, respectively. Regarding the RBE-weighted dose (2.0 Gy at the spread-out Bragg peak), the differences between simulations and measurements were below 0.10 Gy., Conclusions: This study demonstrates for the first time that FNTDs can be used to perform direct LET measurements and to estimate the RBE in clinical proton and helium ion beams., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The relative biological effectiveness is a mathematical quantity first defined in the 1950s. This has resulted in more than 4,000 scientific papers published to date. Yet defining the correct value of the RBE to use in clinical practice remains a challenge. A scientific analysis in the radiation research literature can provide an understanding of how this mathematical quantity has evolved. The purpose of this study is to investigate documents published since 1950 using bibliometric indicators and network visualization. This analysis seeks to provide an assessment of global research activities, key themes, and RBE research within the radiation-related field. It strives to highlight top-performing authors, organizations, and nations that have made major contributions to this research domain, as well as their interactions. The Scopus Collection was searched for articles and reviews pertaining to RBE in radiation research from 1950 through 2023. Scopus and Bibiometrix analytic tools were used to investigate the most productive countries, researchers, collaboration networks, journals, along with the citation analysis of references and keywords. A total of 4,632 documents were retrieved produced by authors originating from 71 countries. Publication trends could be separated in 20-year groupings beginning with slow accrual from 1950 to 1970, an early rise from 1970-1990, followed by a sharp increase in the years 1990s-2010s that matches the development of charged particle therapy in clinics worldwide and opened discussion on the true value of the RBE in proton beam therapy. Since the 2010s, a steady 200 papers, on average, have been published per year. The United States produced the most publications overall (N = 1,378) and Radiation Research was the most likely journal to have published articles related to the RBE (606 publications during this period). J. Debus was the most prolific author (112 contributions, with 2,900 citations). The RBE has captured the research interest of over 7,000 authors in the past decade alone. This study supports that notion that the growth of the body of evidence surrounding the RBE, which started 75 years ago, is far from reaching its end. Applications to medicine have continuously dominated the field, with physics competing with Biochemistry, Genetics and Molecular Biology for second place over the decades. Future research can be predicted to continue., (© 2024 by Radiation Research Society. All rights of reproduction in any form reserved.)

Purpose: To model relative biological effectiveness (RBE) differences found in two studies which used spread-out Bragg-peaks (SOBP) placed at (a) superficial depth and (b) at the maximum range depth. For pencil beam scanning (PBS), RBE at similar points within the SOBP did not change between the two extreme SOBP placement depths; in passively scattered beams (PSB), high RBE values (typically 1.2-1.3) were found within superficially- placed SOBP but reduced to lower values (1-1.07) at similar points within the extreme-depth positioned SOBP. The dose, LET (linear energy transfer) distributions along each SOBP were closely comparable regardless of placement depth, but significant changes in dose rate occurred with depth in the PSB beam., Methods: The equations used allow α and β changes with falling dose rate (the converse to FLASH studies) in PSB, resulting in reduced α/β ratios, compatible with a reduction in micro-volumetric energy transfer (the product of Fluence and LET), with commensurate reductions in RBE. The experimental depth-distances, positions within SOBP, observed dose-rates and radiosensitivity ratios were used to estimate the changes in RBE., Results: RBE values within a 5 % tolerance limit of the experimental results for PSB were found at the deepest SOBP placement. No RBE changes were predicted for PBS beams, as in the published results., Conclusions: Enhanced proton therapy toxicity might occur with PBS when compared with PSB for deeply positioned SOBP due to the maintenance of higher RBE. Scanned pencil beam users need to be vigilant about RBE and further research is indicated., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Associazione Italiana di Fisica Medica e Sanitaria. Published by Elsevier Ltd. All rights reserved.)

Purpose: Recent experimental studies and clinical trial results might indicate that-at least for some indications-continued use of the mechanistic model for relative biological effectiveness (RBE) applied at carbon ion therapy facilities in Europe for several decades (LEM-I) may be unwarranted. We present a novel clinical framework for prostate cancer treatment planning and tumor control probability (TCP) prediction based on the modified microdosimetric kinetic model (mMKM) for particle therapy., Methods and Materials: Treatment plans of 91 patients with prostate tumors (proton: 46, carbon ions: 45) applying 66 GyRBE [RBE = 1.1 for protons and LEM-I, (α/β) x = 2.0 Gy, for carbon ions] in 20 fractions were recalculated using mMKM [(α/β) x = 3.1 Gy]). Based solely on the response data of photon-irradiated patient groups stratified according to risk and usage of androgen deprivation therapy, we derived parameters for an mMKM-based Poisson-TCP model. Subsequently, new carbon and helium ion plans, adhering to prescribed biological dose criteria, were generated. These were systematically compared with the clinical experience of Japanese centers employing an analogous fractionation scheme and existing proton plans., Results: mMKM predictions suggested significant biological dose deviation between the proton and carbon ion arms. Patients irradiated with protons received (3.25 ± 0.08)  GyRBE mMKM /Fx, whereas patients treated with carbon ions received(2.51 ± 0.05)  GyRBE mMKM /Fx. TCP predictions were (86 ± 3)% for protons and (52 ± 4)% for carbon ions, matching the clinical outcome of 85% and 50%. Newly optimized carbon ion plans, guided by the mMKM/TCP model, effectively replicated clinical data from Japanese centers. Using mMKM, helium ions exhibited similar target coverage as proton and carbon ions and improved rectum and bladder sparing compared with proton., Conclusions: Our mMKM-based model for prostate cancer treatment planning and TCP prediction was validated against clinical data for proton and carbon ion therapy, and its application was extended to helium ion therapy. Based on the data presented in this work, mMKM seems to be a good candidate for clinical biological calculations in carbon ion therapy for prostate cancer., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

In the next decade, the International Commission on Radiological Protection (ICRP) will issue the next set of general recommendations, for which evaluation of relative biological effectiveness (RBE) for various types of tissue reactions would be needed. ICRP has recently classified diseases of the circulatory system (DCS) as a tissue reaction, but has not recommended RBE for DCS. We therefore evaluated the mean and uncertainty of RBE for DCS by applying a microdosimetric kinetic model specialized for RBE estimation of tissue reactions. For this purpose, we analyzed several RBE data for DCS determined by past animal experiments and evaluated the radius of the subnuclear domain best fit to each experiment as a single free parameter included in the model. Our analysis suggested that RBE for DCS tends to be lower than that for skin reactions, and their difference was borderline significant due to large variances of the evaluated parameters. We also found that RBE for DCS following mono-energetic neutron irradiation of the human body is much lower than that for skin reactions, particularly at the thermal energy and around 1 MeV. This tendency is considered attributable not only to the intrinsic difference of neutron RBE between skin reactions and DCS but also to the difference in the contributions of secondary γ-rays to the total absorbed doses between their target organs. These findings will help determine RBE by ICRP for preventing tissue reactions., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Objective. While a constant relative biological effectiveness (RBE) of 1.1 forms the basis for clinical proton therapy, variable RBE models are increasingly being used in plan evaluation. However, there is substantial variation across RBE models, and several new in vitro datasets have not yet been included in the existing models. In this study, an updated in vitro proton RBE database was collected and used to examine current RBE model assumptions, and to propose an up-to-date RBE model as a tool for evaluating RBE effects in clinical settings. Approach. A proton database (471 data points) was collected from the literature, almost twice the size of the previously largest model database. Each data point included linear-quadratic model parameters and linear energy transfer (LET). Statistical analyses were performed to test the validity of commonly applied assumptions of phenomenological RBE models, and new model functions were proposed forRBEmaxandRBEmin(RBE at the lower and upper dose limits). Previously published models were refitted to the database and compared to the new model in terms of model performance and RBE estimates. Main results. The statistical analysis indicated that the intercept of theRBEmaxfunction should be a free fitting parameter and RBE estimates were clearly higher for models with free intercept.RBEminincreased with increasing LET, while a dependency ofRBEminon the reference radiation fractionation sensitivity (α/βx) did not significantly improve model performance. Evaluating the models, the new model gave overall lowest RMSE and highest R2 score. RBE estimates in the distal part of a spread-out-Bragg-peak in water (α/βx= 2.1 Gy) were 1.24-1.51 for original models, 1.25-1.49 for refits and 1.42 for the new model. Significance. An updated RBE model based on the currently largest database among published phenomenological models was proposed. Overall, the new model showed better performance compared to refitted published RBE models., (© 2024 Institute of Physics and Engineering in Medicine.)

Purpose: Neutron capture therapy (NCT) by 10B and 157Gd agents is a unique irradiation-based method which can be used to treat brain tumors. Current study aims to quantitatively evaluate the relative biological effectiveness (RBE) and dose distributions during the combined BNCT and GdNCT modalities through a hybrid Monte Carlo (MC) simulation approach., Methods: Snyder head phantom as well as a cubic hypothetical tumor was at first modeled by Geant4 MC Code. Then, the energy spectra and dose distribution relevant to the released secondary particles during the combined Gd/BNCT were scored for different concentrations of 157Gd and 10B inside tumor volume. Finally, the scored energy spectra were imported to the MCDS code to estimate both RBESSB and RBEDSB values for different 157Gd concentrations., Results: The results showed that combined Gd/BNCT increases the fluence-averaged RBESSB values by about 1.7 times when 157Gd concentration increments from 0 to 2000 µg/g for both considered cell oxygen levels (pO 2  = 10% and 100%). Besides, a reduction of about 26% was found for fluence-averaged RBEDSB values with an increment of 157Gd concentration in tumor volume., Conclusion: From the results, it can be concluded that combined Gd/BNCT technique can improve tumor coverage with higher dose levels but in the expense of RBEDSB reduction which can affect the clinical efficacy of the NCT technique., (© 2024 The Author(s). Journal of Applied Clinical Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

Purpose: Proton relative biological effectiveness (RBE) is a dynamic variable influenced by factors like linear energy transfer (LET), dose, tissue type, and biological endpoint. The standard fixed proton RBE of 1.1, currently used in clinical planning, may not accurately represent the true biological effects of proton therapy (PT) in all cases. This uncertainty can contribute to radiation-induced normal tissue toxicity in patients. In late-responding tissues such as the spinal cord, toxicity can cause devastating complications. This study investigated spinal cord tolerance in mice subjected to proton irradiation and characterized the influence of fractionation on proton- induced myelopathy at entrance (ENT) and Bragg peak (BP) positions., Methods and Materials: Cervical spinal cords of 8-week-old C57BL/6J female mice were irradiated with single- or multi-fractions (18x) using lateral opposed radiation fields at 1 of 2 positions along the Bragg curve: ENT (dose-mean LET = 1.2 keV/μm) and BP (LET = 6.9 keV/μm). Mice were monitored over 1 year for changes in weight, mobility, and general health, with radiation-induced myelopathy as the primary biological endpoint. Calculations of the RBE of the ENT and BP curve (RBE ENT/BP ) were performed., Results: Single-fraction RBE ENT/BP for 50% effect probability (tolerance dose (TD 50 ), grade II paresis, determined using log-logistic model fitting) was 1.10 ± 0.06 (95% CI) and for multifraction treatments it was 1.19 ± 0.05 (95% CI). Higher incidence and faster onset of paralysis were seen in mice treated at the BP compared with ENT., Conclusions: The findings challenge the universally fixed RBE value in PT, indicating up to a 25% mouse spinal cord RBE ENT/BP variation for multifraction treatments. These results highlight the importance of considering fractionation in determining RBE for PT. Robust characterization of proton-induced toxicity, aided by in vivo models, is paramount for refining clinical decision-making and mitigating potential patient side effects., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: Carbon ion radiotherapy (CIRT) relies on relative biological effectiveness (RBE)-weighted dose calculations. Japanese clinics predominantly use the microdosimetric kinetic model (MKM), while European centers utilize the local effect model (LEM). Despite both models estimating RBE-distributions in tissue, their physical and mathematical assumptions differ, leading to significant disparities in RBE-weighted doses. Several European clinics adopted Japanese treatment schedules, necessitating adjustments in dose prescriptions and organ at risk (OAR) constraints. In the context of these two clinically used standards for RBE-weighted dose estimation, the objective of this study was to highlight specific scenarios for which the translations between models diverge, as shortcomings between them can influence clinical decisions., Methods: Our aim was to discuss planning strategies minimizing those discrepancies, ultimately striving for more accurate and robust treatments. Evaluations were conducted in a virtual water phantom and patient CT-geometry, optimizing LEM RBE-weighted dose first and recomputing MKM thereafter. Dose-averaged linear energy transfer (LETd) distributions were also assessed., Results: Results demonstrate how various parameters influence LEM/MKM translation. Similar LEM-dose distributions lead to markedly different MKM-dose distributions and variations in LETd. Generally, a homogeneous LEM RBE-weighted dose aligns with lower MKM values in most of the target volume. Nevertheless, paradoxical MKM hotspots may emerge (at the end of the range), potentially influencing clinical outcomes. Therefore, translation between models requires great caution., Conclusions: Understanding the relationship between these two clinical standards enables combining European and Japanese based experiences. The implementation of optimal planning strategies ensures the safety and acceptability of the clinical plan for both models and therefore enhances plan robustness from the RBE-weighted dose and LETd distribution point of view. This study emphasizes the importance of optimal planning strategies and the need for comprehensive CIRT plan quality assessment tools. In situations where simultaneous LEM and MKM computation capabilities are lacking, it can provide guidance in plan design, ultimately contributing to enhanced CIRT outcomes., (© 2024 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

Very high energy electrons (VHEE) are a potential candidate for radiotherapy applications. This includes tumours in inhomogeneous regions such as lung and prostate cancers, due to the insensitivity of VHEE to inhomogeneities. This study explores how electrons in the VHEE range can be used to perform successful in vitro radiobiological studies. The ARES (accelerator research experiment at SINBAD) facility at DESY, Hamburg, Germany was used to deliver 154 MeV electrons to both prostate (PC3) and lung (A549) cancer cells in suspension. Dose was delivered to samples with repeatability and uniformity, quantified with Gafchromic film. Cell survival in response to VHEE was measured using the clonogenic assay to determine the biological effectiveness of VHEE in cancer cells for the first time using this method. Equivalent experiments were performed using 300 kVp X-rays, to enable VHEE irradiated cells to be compared with conventional photons. VHEE irradiated cancer cell survival was fitted to the linear quadratic (LQ) model (R 2  = 0.96-0.97). The damage from VHEE and X-ray irradiated cells at doses between 1.41 and 6.33 Gy are comparable, suggesting similar relative biological effectiveness (RBE) between the two modalities. This suggests VHEE is as damaging as photon radiotherapy and therefore could be used to successfully damage cancer cells during radiotherapy. The RBE of VHEE was quantified as the relative doses required for 50% (D 0.5 ) and 10% (D 0.1 ) cell survival. Using these values, VHEE RBE was measured as 0.93 (D 0.5 ) and 0.99 (D 0.1 ) for A549 and 0.74 (D 0.5 ) and 0.93 (D 0.1 ) for PC3 cell lines respectively. For the first time, this study has shown that 154 MeV electrons can be used to effectively kill lung and prostate cancer cells, suggesting that VHEE would be a viable radiotherapy modality. Several studies have shown that VHEE has characteristics that would offer significant improvements over conventional photon radiotherapy for example, electrons are relatively easy to steer and can be used to deliver dose rapidly and with high efficiency. Studies have shown improved dose distribution with VHEE in treatment plans, in comparison to VMAT, indicating that VHEE can offer improved and safer treatment plans with reduced side effects. The biological response of cancer cells to VHEE has not been sufficiently studied as of yet, however this initial study provides some initial insights into cell damage. VHEE offers significant benefits over photon radiotherapy and therefore more studies are required to fully understand the biological effectiveness of VHEE., (© 2024. The Author(s).)

Background: The Relative Biological Effectiveness (RBE) of kilovoltage photon beams has been previously investigated in vitro and in silico using analytical methods. The estimated values range from 1.03 to 1.82 depending on the methodology and beam energies examined., Purpose: The focus of this work was to independently estimate RBE values for a range of clinically used kilovoltage beams (70-200 kVp) while investigating the suitability of using TOPAS-nBio for this task., Methods: Previously validated spectra of clinical beams were used to generate secondary electron spectra at several depths in a water tank phantom via TOPAS Monte Carlo (MC) simulations. Cell geometry was irradiated with the secondary electrons in TOPAS-nBio MC simulations. The deposited dose and the calculated number of DNA strand breaks were used to estimate RBE values., Results: Monoenergetic secondary electron simulations revealed the highest direct and indirect double strand break yield at approximately 20 keV. The average RBE value for the kilovoltage beams was calculated to be 1.14., Conclusions: TOPAS-nBio was successfully used to estimate the RBE values for a range of clinical radiotherapy beams. The calculated value was in agreement with previous estimates, providing confidence in its clinical use in the future., (© 2024 The Authors. Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

In addition to the continuous exposure to cosmic rays, astronauts in space are occasionally exposed to Solar Particle Events (SPE), which involve less energetic particles but can deliver much higher doses. The latter can exceed several Gy in a few hours for the most intense SPEs, for which non-stochastic effects are thus a major concern. To identify adequate shielding conditions that would allow respecting the dose limits established by the various space agencies, the absorbed dose in the considered organ/tissue must be multiplied by the corresponding Relative Biological Effectiveness (RBE), which is a complex quantity depending on several factors including particle type and energy, considered biological effect, level of effect (and thus absorbed dose), etc. While in several studies only the particle-type dependence of RBE is taken into account, in this work we developed and applied a new approach where, thanks to an interface between the FLUKA Monte Carlo transport code and the BIANCA biophysical model, the RBE dependence on particle energy and absorbed dose was also considered. Furthermore, we included in the considered SPE spectra primary particles heavier than protons, which in many studies are neglected. This approach was then applied to the October 2003 SPE (the most intense SPE of solar cycle 23, also known as "Halloween event") and the January 2005 event, which was characterized by a lower fluence but a harder spectrum, i.e., with higher-energy particles. The calculation outcomes were then discussed and compared with the current dose limits established for skin and blood forming organs in case of 30-days missions. This work showed that the BIANCA model, if interfaced to a radiation transport code, can be used to calculate the RBE values associated to Solar Particle Events. More generally, this work emphasizes the importance of taking into account the RBE dependence on particle energy and dose when calculating equivalent doses., Competing Interests: Declaration of interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Committee on Space Research (COSPAR). Published by Elsevier B.V. All rights reserved.)

Purpose: Determination of the value of relative biological effectiveness (RBE) of heavy charged ions in vivo is an important task for their optimal use in particle radiotherapy. The aim of this study was to determine the RBE value of a beam of carbon ions with an energy of 450 MeV/nucleon in different regions of the Bragg curve in irradiation of mice at low, medium, and high doses in comparison with X-ray radiation., Materials and Methods: SHK mice ( n  = 330) were irradiated in three regions of the Bragg curve in the dose range of 0-1.5 Gy for cytogenetic damage detection and at a dose of 6.5 Gy for determination of 30-day survival. For irradiation of mice in the Bragg peak, two widths of a spread-out Bragg peak (SOBP) were used: 10 mm (LET ∼100 keV/µm) and 30 mm (LET ∼39 keV/µm)., Results: The RBE value was 0.8-0.9 before the Bragg peak (LET ∼15 keV/µm) and 0.8 after the peak (LET ∼5 keV/µm), and did not depend on the determination method, despite the differences in LET values. The RBE value determined by the micronucleus test was 1.1-1.7 for the 10-mm-wide SOBP and 1.0-1.3 for the 30-mm-wide SOBP, with the highest RBE value obtained in the low-dose region upon irradiation of mice in the 10-mm-wide Bragg peak. The RBE values in the high-dose region determined by the 30-day survival test lay in the range from 1.4 to 2.6 depending on the width of the Bragg peak and the chosen criterion for calculating the value. The RBE values in the 10-mm-wide Bragg peak (LET ∼100 keV/µm) were higher than those in the 30-mm-wide Bragg peak (LET ∼39 keV/µm) at all used criteria., Conclusions: The present findings suggest that there is the complex relationship between LET and organism response to accelerated charged particle radiation, and the contribution of specific factors and mechanisms must be further considered.

Introduction: The need for accurate relative biological effectiveness (RBE) estimation for low energy therapeutic X-rays (corresponding to 50 kV nominal energy of a commercial low-energy IORT system (INTRABEAM)) is a crucial issue due to increased radiobiological effects, respect to high energy photons. Modeling of radiation-induced DNA damage through Monte Carlo (MC) simulation approaches can give useful information. Hence, this study aimed to evaluate and compare RBE of low energy therapeutic X-rays using Geant4-DNA toolkit and Monte Carlo damage simulation (MCDS) code., Materials and Methods: RBE calculations were performed considering the emitted secondary electron spectra through interactions of low energy X-rays inside the medium. In Geant4-DNA, the DNA strand breaks were obtained by employing a B-DNA model in physical stage with 10.79 eV energy-threshold and the probability of hydroxyl radical's chemical reactions of about 0.13%. Furthermore, RBE estimations by MCDS code were performed under fully aerobic conditions., Results: Acquired results by two considered MC codes showed that the same trend is found for RBE DSB and RBE SSB variations. Totally, a reasonable agreement between the calculated RBE values (both RBE SSB and RBE DSB ) existed between the two considered MC codes. The mean differences of 9.2% and 1.8% were obtained between the estimated RBE SSB and RBE DSB values by two codes, respectively., Conclusion: Based on the obtained results, it can be concluded that a tolerable accordance is found between the calculated RBE DSB values through MCDS and Geant4-DNA, a fact which appropriates both codes for RBE evaluations of low energy therapeutic X-rays, especially in the case of RBE DSB where lethal damages are regarded.

In the framework of the MUNES project, a prototype accelerator-based thermal neutron source was developed and installed at the Legnaro National Laboratories of INFN. The microdosimetric characterization of this radiation field was performed with a Tissue-Equivalent Proportional Counter with interchangeable cathode walls, either doped with 100 ppm of 10B or without boron doping. A suitable subtraction procedure allowed to discriminate the gamma, neutron and BNC dose components (Selva et al., 2022, Appl. Radiat. Isot. 182, 110144). The measured microdosimetric spectra can be weighted with a biological weighting function to estimate the Relative Biological Effectiveness of the radiation field, for the purpose of intercomparison between different thermal neutron sources. This work compares, therefore, the biological doses resulting from four different weighting functions applied to the same initial microdosimetric spectrum, discussing strengths and limitations of each of them., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Purpose: This work aims to simulate clustered DNA damage from ionizing radiation and estimate the relative biological effectiveness (RBE) for radionuclide (rBT)- and electronic (eBT)-based surface brachytherapy through a hybrid Monte Carlo (MC) approach, using realistic models of the sources and applicators., Methods: Damage from ionizing radiation has been studied using the Monte Carlo Damage Simulation algorithm using as input the primary electron fluence simulated using a state-of-the-art MC code, PENELOPE-2018. Two 192 Ir rBT applicators, Valencia and Leipzig, one 60 Co source with a Freiburg Flap applicator (reference source), and two eBT systems, Esteya and INTRABEAM, have been included in this study implementing full realizations of their geometries as disclosed by the manufacturer. The role played by filtration and tube kilovoltage has also been addressed., Results: For rBT, an RBE value of about 1.01 has been found for the applicators and phantoms considered. In the case of eBT, RBE values for the Esteya system show an almost constant RBE value of about 1.06 for all depths and materials. For INTRABEAM, variations in the range of 1.12-1.06 are reported depending on phantom composition and depth. Modifications in the Esteya system, filtration, and tube kilovoltage give rise to variations in the same range., Conclusions: Current clinical practice does not incorporate biological effects in surface brachytherapy. Therefore, the same absorbed dose is administered to the patients independently on the particularities of the rBT or eBT system considered. The almost constant RBE values reported for rBT support that assumption regardless of the details of the patient geometry, the presence of a flattening filter in the applicator design, or even significant modifications in the photon energy spectra above 300 keV. That is not the case for eBT, where a clear dependence on the eBT system and the characteristics of the patient geometry are reported. A complete study specific for each eBT system, including detailed applicator characteristics (size, shape, filtering, among others) and common anatomical locations, should be performed before adopting an existing RBE value., (© 2022 American Association of Physicists in Medicine.)

The MUNES project (MUltidisciplinary NEutron Source) aims at the realization of an intense accelerator-based source of thermal neutrons, suitable for Boron Neutron Capture Therapy (BNCT). This exploits the interaction of 5 MeV protons onto a beryllium target, producing a fast neutron spectrum, which is moderated to the thermal range by a large assembly made of a Polytetrafluoroethylene (PTFE) tank filled with heavy water, surrounded by graphite blocks. The thermal neutron field is extracted through a bismuth beam port. The microdosimetric characterization of this field was performed using a cylindrical avalanche-confinement Tissue Equivalent Proportional Counter (TEPC) equipped with interchangeable cathode walls, positioned in front of the beam port. Measurements were taken both with a boron-doped wall and with an undoped one. The comparison of the two microdosimetric distributions allows to distinguish the relative dose contribution due to alpha particles and lithium ions from the BNC reaction from that of photons and other particles from neutron interactions on the cathode walls. The Relative Biological Effectiveness (RBE) was also calculated from the convolution of the measured spectra with a biological weighting function. This paper describes the experimental microdosimetric approach and the results of measurements with a boron-loaded cathode performed for the first time at an accelerator-based BNCT source., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Theoretical evaluations indicate the radiation weighting factor for thermal neutrons differs from the current International Commission on Radiological Protection (ICRP) recommended value of 2.5, which has radiation protection implications for high-energy radiotherapy, inside spacecraft, on the lunar or Martian surface, and in nuclear reactor workplaces. We examined the relative biological effectiveness (RBE) of DNA damage generated by thermal neutrons compared to gamma radiation. Whole blood was irradiated by 64 meV thermal neutrons from the National Research Universal reactor. DNA damage and erroneous DNA double-strand break repair was evaluated by dicentric chromosome assay (DCA) and cytokinesis-block micronucleus (CBMN) assay with low doses ranging 6-85 mGy. Linear dose responses were observed. Significant DNA aberration clustering was found indicative of high ionizing density radiation. When the dose contribution of both the 14 N(n,p) 14 C and 1 H(n,γ) 2 H capture reactions were considered, the DCA and the CBMN assays generated similar maximum RBE values of 11.3 ± 1.6 and 9.0 ± 1.1, respectively. Consequently, thermal neutron RBE is approximately four times higher than the current ICRP radiation weighting factor value of 2.5. This lends support to bimodal peaks in the quality factor for RBE neutron energy response, underlining the importance of radiological protection against thermal neutron exposures.

This paper estimates the yields of DNA double-strand breaks (DSBs) induced by ultrasoft X-rays and uses the DSB yields and the repair outcomes to evaluate the relative biological effectiveness ( RBE ) of ultrasoft X-rays. We simulated the yields of DSB induction and predicted them in the presence and absence of oxygen, using a Monte Carlo damage simulation (MCDS) software, to calculate the RBE . Monte Carlo excision repair (MCER) simulations were also performed to calculate the repair outcomes (correct repairs, mutations, and DSB conversions). Compared to 60 Co γ-rays, the RBE values for ultrasoft X-rays (titanium K-shell, aluminum K-shell, copper L-shell, and carbon K-shell) for DSB induction were respectively 1.3, 1.9, 2.3, and 2.6 under aerobic conditions and 1.3, 2.1, 2.5, and 2.9 under a hypoxic condition (2% O 2 ). The RBE values for enzymatic DSBs were 1.6, 2.1, 2.3, and 2.4, respectively, indicating that the enzymatic DSB yields are comparable to the yields of DSB induction. The synergistic effects of DSB induction and enzymatic DSB formation further facilitate cell killing and the advantage in cancer treatment.

Chromosome aberrations are widely considered among the best biomarkers of radiation health risk due to their relationship with late cancer incidence. In particular, aberrations in peripheral blood lymphocytes (PBL) can be regarded as indicators of hematologic toxicity, which is a major limiting factor of radiotherapy total dose. In this framework, a radiobiological database describing the induction of PBL dicentrics as a function of ion type and energy was developed by means of the BIANCA (BIophysical ANalysis of Cell death and chromosome Aberrations) biophysical model, which has been previously applied to predict the effectiveness of therapeutic-like ion beams at killing tumour cells. This database was then read by the FLUKA Monte Carlo transport code, thus allowing us to calculate the Relative Biological Effectiveness (RBE) for dicentric induction along therapeutic C-ion beams. A comparison with previous results showed that, while in the higher-dose regions (e.g., the Spread-Out Bragg Peak, SOBP), the RBE for dicentrics was lower than that for cell survival. In the lower-dose regions (e.g., the fragmentation tail), the opposite trend was observed. This work suggests that, at least for some irradiation scenarios, calculating the biological effectiveness of a hadrontherapy beam solely based on the RBE for cell survival may lead to an underestimation of the risk of (late) damage to healthy tissues. More generally, following this work, BIANCA has gained the capability of providing RBE predictions not only for cell killing, but also for healthy tissue damage.

Purpose: Uncertainties in relative biological effectiveness (RBE) constitute a major pitfall of the use of protons in clinics. An RBE value of 1.1, which is based on cell culture and animal models, is currently used in clinical proton planning. The purpose of this study was to determine RBE for temporal lobe radiographic changes using long-term follow-up data from patients with nasopharyngeal carcinoma., Methods and Materials: Five hundred sixty-six patients with newly diagnosed nasopharyngeal carcinoma received double-scattering proton therapy or intensity modulated radiation therapy at our institutions. The 2 treatment cohorts were well matched. Proton dose distributions were simulated using Monte Carlo and compared with those obtained from the proton clinical treatment planning system. Late treatment effect was defined as development of enhancement of temporal lobe on T1-weighted magnetic resonance imaging, with or without accompanying clinical symptoms. The tolerance dose was calculated with receiving operator characteristic analysis and the Youden index. Tolerance curves, expressed as a cumulative dose-volume histogram, were generated using the cutoff points., Results: With a median follow-up period >5 years for both cohorts, 10% of proton patients and 4% of patients undergoing intensity modulated radiation therapy developed temporal lobe enhancement in unilateral temporal lobe. There was no significant difference in dose distributions between the Monte Carlo method and treatment planning system. The tolerance dose-volume levels were V10 (26.1%), V20 (21.9%), V30 (14.0%), V40 (7.7%), V50 (4.8%), and V60 (3.3%) for proton therapy (P < .03). Comparison of the two tolerance curves revealed that tolerance doses of proton treatments were lower than that of photon treatments at all dose levels. The dose tolerance at D1% was 58.56 Gy for protons and 69.07 Gy for photons. The RBE for temporal lobe enhancement from proton treatments were calculated to be 1.18., Conclusions: Using long-term clinical outcome of patients with nasopharyngeal carcinoma, our data suggest that the RBE for temporal lobe enhancement is 1.18 at D1%. A prospective study in a large cohort would be necessary to confirm these findings., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The effect of proton pencil beam scanning in the dose range of 4.5-15 Gy on the radiosensitivity of mice under irradiation in two regions of the Bragg curve was studied according to the criteria of 30-day survival, dynamics of death, and average lifespan of mice. The relative biological effectiveness (RBE) value of protons relative to X-ray radiation before and at the Bragg peak determined by the LD 50/30 index was 0.86 and 0.94, respectively, and by the criterion of 30-day survival at a dose of 6.5 Gy it was 0.83 and 0.84, respectively. With similar RBE values for protons in different regions of the Bragg curve, significant differences in the dynamics of the course of radiation sickness were revealed, which indicates different damage to critical systems and organs of animals and the induction of compensatory mechanisms involved in the formation of stress responses at the organismal level., (© 2021. Pleiades Publishing, Ltd.)

Objective: To determine whether biological effective dose (BED) was predictive of obliteration after stereotactic radiosurgery (SRS) for cerebral arteriovenous malformations (AVMs)., Patients and Methods: We studied patients undergoing single-session AVM SRS between January 1, 1990, and December 31, 2014, with at least 2 years of imaging follow-up. Excluded were patients with syndromic AVM, previous SRS or embolization, and patients treated with volume-staged SRS. Biological effective dose was calculated using a mono-exponential model described by Jones and Hopewell. The primary outcome was likelihood of total obliteration defined by digital subtraction angiography or magnetic resonance imaging (MRI). Variables were analyzed as continuous and dichotomous variables based on the maximum value of (sensitivity-[1-specificity])., Results: This study included 352 patients (360 AVM, median follow-up, 5.9 years). The median margin dose prescribed was 18.75 Gy (interquartile range [IQR]: 18 to 20 Gy). Two hundred fifty-nine patients (71.9%) had obliteration shown by angiography (n=176) or MRI (n=83) at a median of 36 months after SRS (IQR: 26 to 44 months). Higher BED was associated with increased likelihood of obliteration in univariate Cox regression analyses, when treated as either a dichotomous (≥133 Gy; hazard ratio [HR],1.52; 95% confidence interval [CI], 1.19 to 1.95; P<.001) or continuous variable (HR, 1.00, 95% CI, 1.0002 to 1.005; P=.04). In multivariable analyses including dichotomized BED and location, BED remained associated with obliteration (P=.001)., Conclusion: Biological effective dose ≥133 Gy was predictive of AVM obliteration after single-session SRS within the prescribed margin dose range 15 to 25 Gy. Further study is warranted to determine whether BED optimization should be considered as well as treatment dose for AVM SRS planning., (Copyright © 2020 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Background: Hypopituitarism is the most frequent complication after pituitary adenoma stereotactic radiosurgery (SRS) and is correlated with increasing radiation to the pituitary gland. Biological effective dose (BED) is a dosimetric parameter that incorporates a time component to adjust for mechanisms of deoxyribonucleic acid repair activated during treatment., Objective: To assess mean gland BED as a predictor of post-SRS hypopituitarism, as compared to mean gland dose, in a contemporary cohort study of patients undergoing single-fraction SRS for pituitary adenoma., Methods: Cohort study of 97 patients undergoing single-fraction SRS from 2007 to 2014. Eligible patients had no prior pituitary irradiation, normal pre-SRS endocrine function, and >24 mo of endocrine follow-up. Cox proportional hazards analysis was used to assess mean gland dose and BED as predictors of new post-SRS hypopituitarism., Results: Median post-SRS follow-up was 48 mo (interquartile range [IQR], 34-68). A total of 27 patients (28%) developed new hypopituitarism at a median 22 mo (IQR, 12-36). Actuarial rates of new endocrinopathy were 17% at 2 yr (95% CI 10%-25%) and 31% at 5 yr (95% CI 20%-42%). On univariate analysis, sex (P = .02), gland volume (P = .03), mean gland dose (P < .0001), and BED significantly predicted new hypopituitarism (P < .0001). After adjusting for sex and gland volume, BED > 45 Gy2.47 and mean gland dose > 10 Gy were significantly associated increased risk of hypopituitarism (hazard ratio [HR] = 14.32, 95% CI = 4.26-89.0, P < .0001; HR = 11.91, 95% CI = 3.54-74.0, P < .0001)., Conclusion: BED predicted hypopituitarism more reliably than mean gland dose after pituitary adenoma SRS, but additional studies are needed to confirm these results., (© Congress of Neurological Surgeons 2021.)

Uncertainties in the relative biological effectiveness (RBE) of protons remains a major barrier to the biological optimisation of proton therapy. While a constant value of 1.1 is widely used in treatment planning, extensive preclinical in vitro and in vivo data suggests that proton RBE is variable, depending on proton energy, target tissue, and endpoint. A number of phenomenological models have been developed to try and explain this variation, but agreement between these models is often poor. This has been attributed to both the models' underlying assumptions and the data to which they are fit. In this brief note, we investigate the underlying trends in these models by comparing their predictions as a function of relevant biological and physical parameters, to determine where models are in conceptual agreement or disagreement. By doing this, it can be seen that the primary differences between models arise from how they handle biological parameters (i.e. [Formula: see text] and [Formula: see text] from the linear-quadratic model for photon exposures). By contrast, when specifically explored for linear energy transfer-dependence, all models show extremely good correlation. These observations suggest that there is a pressing need for more systematic exploration of biological variation in RBE across different cells in well-controlled conditions to help distinguish between these different models and identify the true behaviour.

A practical neutron energy dependent RBE model has been developed, based on the relationship between a mono-energetic neutron energy and its likely recoil proton energy. Essentially, the linear energy transfer (LET) values of the most appropriate recoil proton energies are then used to modify the linear quadratic model radiosensitivities (α and β) from their reference LET radiation values to provide the RBE estimates. Experimental neutron studies published by Hall (including some mono-energetic beams ranging from 0.2 to 15 MeV), Broerse, Berry, and data from the Clatterbridge and Detroit clinical neutron beams, which all contain some data from a spectrum of neutron energies, are used to derive single effective neutron energies (NE eff ) for each spectral beam. These energies yield a recoil proton spectrum, but with an effective mean proton energy (being around 50% of NE eff ). The fractional increase in LET is given by the recoil proton LET divided by the proton (LET U ) value which provides the highest RBE. This ratio is then used to determine the change in the linear-quadratic model α and β parameters, from those of the reference radiation, to estimate the RBE. The predicted proton recoil RBE is then reasonably close to the experimental neutron RBE values found when taking into account the variation inherent in biological experiments. The work has some important consequences. The data of Hall et al (1975 Radiat. Res. 64 245-55) shows that the highest RBE values are found with neutron energies around 0.3-0.4 MeV, but this energy cannot possibly generate recoil proton energies which are higher, as necessary for a 0.68 MeV proton with a 30.5 keV μm -1 LET U (the LET value which provides the maximum obtainable RBE for a specified ion). For 0.4 MeV neutrons with proton recoil energies of around 0.2 MeV, the latter have a LET of around 62.88 keV μm -1 . This could have an impact on proton beam RBE modelling. However, this is compensated by finding that the maximum radiosensitivity for mono-energetic neutrons was around 1.7 times larger than previously suggested from experimental ion beam studies, probably due to the necessary spreading out of Bragg peaks for ion beam experimental purposes, sampling errors and particle range considerations. This semi-empirical model can be used with minimal computer support and could have applications in ionic beams and in radioprotection.

Purpose: To evaluate the effect of dose heterogeneity in the treatment target on biologically effective dose (BED) for frequently used hypofractionation regimens in stereotactic body radiation therapy (SBRT)., Methods: In the case of non-uniform target dose, BED in the planning target volume (PTV) is determined by using the linear-quadratic model. An expression for BED is obtained for an arbitrary dose distribution in the PTV in the case of small variance of the target dose. Another analytical expression for BED is obtained by assuming a Gaussian dose distribution in the target., Results: Analytical expressions for BED as a function of the variance of the target dose have been derived. It is shown that a relatively small dose inhomogeneity (<5%-6%) can cause a significant reduction (i.e. >10%) in the corresponding BED and equivalent uniform dose (EUD) compared to the case of uniform target dose., Conclusions: Small variations in the absorbed dose can significantly reduce BED and EUD in the PTV. The effect of dose non-uniformity on BED increases with increasing dose per fraction. The observed reduction in BED compared to that for uniform target dose can be several times greater for SBRT than for standard fractionation with dose per fraction varying between 1.8 and 2 Gy.

Purpose: In the modern era of radiotherapy, use of conventional radiation modalities (based on γ-rays) is being replaced by high-energy linear accelerator-based X-rays. As a result of mishandling of equipment or mechanical errors, health workers can be exposed to these high-energy X-rays. Especially in the absence of personnel monitoring devices, biodosimetry with a lower energy X-ray calibration curve may not provide an acceptable dose estimate. Moreover, the relative biological effectiveness (RBE) value assigned for X-rays is the same (ONE) regardless of beam energy (V), employed in diagnosis, interventional medicine, and radiotherapy. Therefore, the purpose of the study is to examine the induced biological effects, measured through micronucleus (MN) formation, of X-rays of different energies (3 and 6 MV X-rays), and to investigate the RBE relative to 225 kVp X-rays., Materials and Methods: Peripheral blood lymphocytes (PBLs) from healthy donors ( n  = 6), were irradiated with 225 kVp, 3 MV, and 6 MV energy X-rays and induced biological damage was quantified as MN formation using the cytokinesis blocked MN (CBMN) assay., Results: The MN per cell in the X-irradiated samples for the three different X-ray energies showed a significant ( p <.0001) dose-dependent increase, when compared to unexposed samples. Aberration frequencies obtained at the same dose for the three different energies showed significant ( p <.05) difference for the MN per cell among the energy levels; however, the in vitro dose-response curve parameters (slope, intercept, and coefficient) did not show any significant differences. The estimated dose in the blinded sample was within the 95% confidence intervals of each of the calibration curves. However, overall, the 6 MV dose-response curve coefficients yielded the closest dose estimate to that of the true dose. The calculated RBE values at 5% induced MN for 3 and 6 MV LINAC X-rays were 2.0 ± 0.04 and 0.70 ± 0.01, respectively, and the average RBE for the complete dose-response curves were 1.13 ± 0.04 and 0.80 ± 0.02 relative to 225 kVp X-rays as standard radiation., Conclusion: The established dose-response curves obtained for PBL exposed to different energy levels of X-rays of 225 kVp, 3 MV, and 6 MV are ready to use for biological dosimetry purposes. The calculated RBE values for the higher energies of X-rays relative to 225 kVp X-rays in this study suggest that RBE of X-rays may not be equal to one, with the true value dependent on the beam energy, the dose and dose rate, and the endpoint investigated.

Proton beams are widely used worldwide to treat localized tumours, the lower entrance dose and no exit dose, thus sparing surrounding normal tissues, being the main advantage of this treatment modality compared to conventional photon techniques. Clinical proton beam therapy treatment planning is based on the use of a general relative biological effectiveness (RBE) of 1.1 along the whole beam penetration depth, without taking into account the documented increase in RBE at the end of the depth dose profile, in the Bragg peak and beyond. However, an inaccurate estimation of the RBE can cause both underdose or overdose, in particular it can cause the unfavourable situation of underdosing the tumour and overdosing the normal tissue just beyond the tumour, which limits the treatment success and increases the risk of complications. In view of a more precise dose delivery that takes into account the variation of RBE, experimental microdosimetry offers valuable tools for the quality assurance of LET or RBE-based treatment planning systems. The purpose of this work is to compare the response of two different microdosimetry systems: the mini-TEPC and the MicroPlus-Bridge detector. Microdosimetric spectra were measured across the 62 MeV spread out Bragg peak of CATANA with the mini-TEPC and with the Bridge microdosimeter. The frequency and dose distributions of lineal energy were compared and the different contributions to the spectra were analysed, discussing the effects of different site sizes and chord length distributions. The shape of the lineal energy distributions measured with the two detectors are markedly different, due to the different water-equivalent sizes of the sensitive volumes: 0.85 μm for the TEPC and 17.3 μm for the silicon detector. When the Loncol's biological weighting function is applied to calculate the microdosimetric assessment of the RBE, both detectors lead to results that are consistent with biological survival data for glioma U87 cells. Both the mini-TEPC and the MicroPlus-Bridge detector can be used to assess the RBE variation of a 62 MeV modulated proton beam along its penetration depth. The microdosimetric assessment of the RBE based on the Loncol's weighting function is in good agreement with radiobiological results when the 10% biological uncertainty is taken into account.

An improved biological weighting function (IBWF) is proposed to phenomenologically relate microdosimetric lineal energy probability density distributions with the relative biological effectiveness (RBE) for the in vitro clonogenic cell survival (surviving fraction = 10%) of the most commonly used mammalian cell line, i.e. the Chinese hamster lung fibroblasts (V79). The IBWF, intended as a simple and robust tool for a fast RBE assessment to compare different exposure conditions in particle therapy beams, was determined through an iterative global-fitting process aimed to minimize the average relative deviation between RBE calculations and literature in vitro data in case of exposure to various types of ions from 1 H to 238 U. By using a single particle- and energy- independent function, it was possible to establish an univocal correlation between lineal energy and clonogenic cell survival for particles spanning over an unrestricted linear energy transfer range of almost five orders of magnitude (0.2 keV µm -1 to 15 000 keV µm -1 in liquid water). The average deviation between IBWF-derived RBE values and the published in vitro data was ∼14%. The IBWF results were also compared with corresponding calculations (in vitro RBE 10 for the V79 cell line) performed using the modified microdosimetric kinetic model (modified MKM). Furthermore, RBE values computed with the reference biological weighting function (BWF) for the in vivo early intestine tolerance in mice were included for comparison and to further explore potential correlations between the BWF results and the in vitro RBE as reported in previous studies. The results suggest that the modified MKM possess limitations in reproducing the experimental in vitro RBE 10 for the V79 cell line in case of ions heavier than 20 Ne. Furthermore, due to the different modelled endpoint, marked deviations were found between the RBE values assessed using the reference BWF and the IBWF for ions heavier than 2 H. Finally, the IBWF was unchangingly applied to calculate RBE values by processing lineal energy density distributions experimentally measured with eight different microdosimeters in 19 1 H and 12 C beams at ten different facilities (eight clinical and two research ones). Despite the differences between the detectors, irradiation facilities, beam profiles (pristine or spread out Bragg peak), maximum beam energy, beam delivery (passive or active scanning), energy degradation system (water, PMMA, polyamide or low-density polyethylene), the obtained IBWF-based RBE trends were found to be in good agreement with the corresponding ones in case of computer-simulated microdosimetric spectra (average relative deviation equal to 0.8% and 5.7% for 1 H and 12 C ions respectively).

Introduction: Low-kV IORT (Low kilovoltage intraoperative radiotherapy) using INTRABEAM machine and dedicated spherical applicators is a candidate modality for breast cancer treatment. The current study aims to quantify the RBE (relative biologic effectiveness) variations of emitted X-rays from the surface of different spherical applicators and bare probe through a hybrid Monte Carlo (MC) simulation approach., Materials and Methods: A validated MC model of INTRABEAM machine and different applicator diameters, based on GEANT4 Toolkit, was employed for RBE evaluation. To doing so, scored X-ray energy spectra at the surface of each applicator diameter/bare probe were used to calculate the corresponding secondary electron energy spectra at various distances inside the water and breast tissue. Then, MCDS (Monte Carlo damage simulation) code was used to calculate the RBE values according to the calculated electron spectra., Results: Presence of spherical applicators can increase the RBE of emitted X-rays from the bare probe by about 22.3%. In return, changing the applicator diameter has a minimal impact (about 3.2%) on RBE variation of emitted X-rays from each applicator surface. By increasing the distance from applicator surface, the RBE increments too, so that its value enhances by about 10% with moving from 2 to 10 mm distance. Calculated RBE values within the breast tissue were higher than those of water by about 4% maximum value., Conclusion: Ball section of spherical IORT applicators can affect the RBE value of the emitted X-rays from INTRABEAM machine. Increased RBE of breast tissue can reduce the prescribed dose for breast irradiation if INTRABEAM machine has been calibrated inside the water., (Copyright © 2020 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.)

Purpose: Present-day treatment planning in carbon ion therapy is conducted with assumptions for a limited number of tissue types and models for effective dose. Here, we comprehensively assess relative biological effectiveness (RBE) in carbon ion therapy and associated models toward the modernization of current clinical practice in effective dose calculation., Methods: Using 2 human (A549, H460) and 2 mouse (B16, Renca) tumor cell lines, clonogenic cell survival assay was performed for examination of changes in RBE along the full range of clinical-like spread-out Bragg peak (SOBP) fields. Prediction power of the local effect model (LEM1 and LEM4) and the modified microdosimetric kinetic model (mMKM) was assessed. Experimentation and analysis were carried out in the frame of a multidimensional end point study for clinically relevant ranges of physical dose (D), dose-averaged linear energy transfer (LET d ), and base-line photon radio-sensitivity (α/β) x . Additionally, predictions were compared against previously reported RBE measurements in vivo and surveyed in patient cases., Results: RBE model prediction performance varied among the investigated perspectives, with mMKM prediction exhibiting superior agreement with measurements both in vitro and in vivo across the 3 investigated end points. LEM1 and LEM4 performed their best in the highest LET conditions but yielded overestimations and underestimations in low/midrange LET conditions, respectively, as demonstrated by comparison with measurements. Additionally, the analysis of patient treatment plans revealed substantial variability across the investigated models (±20%-30% uncertainty), largely dependent on the selected model and absolute values for input tissue parameters α x and β x ., Conclusion: RBE dependencies in vitro, in vivo, and in silico were investigated with respect to various clinically relevant end points in the context of tumor-specific tissue radio-sensitivity assignment and accurate RBE modeling. Discovered model trends and performances advocate upgrading current treatment planning schemes in carbon ion therapy and call for verification via clinical outcome analysis with large patient cohorts., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Accurate dosimetry and determination of the biological effectiveness of boron neutron capture therapy (BNCT) is challenging because of the mix of different types and energies of radiation at the cellular and subcellular levels. In this paper, we present a computational, multiscale system of models to better assess the relative biological effectiveness (RBE) and compound biological effectiveness (CBE) of several neutron sources as applied to BNCT using boronophenylalanine (BPA) and a potential monoclonal antibody (mAb) that targets HER-2-positive cells with Trastuzumab. The multiscale model is tested against published in vitro and in vivo measurements of cell survival with and without boron. The combined dosimetric and radiobiological model includes an analytical formulation that accounts for the type of neutron source, the tissue- or cancer-specific dose-response characteristics, and the microdistribution of boron. Tests of the model against results from published experiments with and without boron show good agreement between modeled and experimentally determined cell survival for neutrons alone and in combination with boron. The system of models developed in this work is potentially useful as an aid for the optimization and individualization of BNCT for HER-2-positive cancers, as well as other cancers, that can be targeted with mAb or a conventional BPA compound.

Trinity was the first test of a nuclear fission device. The test took place in south-central New Mexico at the Alamogordo Bombing and Gunnery Range at 05:29 AM on 16 July 1945. This article provides detailed information on the methods that were used in this work to estimate the radiation doses that were received by the population that resided in New Mexico in 1945. The 721 voting precincts of New Mexico were classified according to ecozone (plains, mountains, or mixture of plains and mountains), and size of resident population (urban or rural). Methods were developed to prepare estimates of absorbed doses from a range of 63 radionuclides to five organs or tissues (thyroid, active marrow, stomach, colon, and lung) for representative individuals of each voting precinct selected according to ethnicity (Hispanic, White, Native American, and African American) and age group in 1945 (in utero, newborn, 1-2 y, 3-7 y, 8-12 y, 13-17 y, and adult). Three pathways of human exposure were included: (1) external irradiation from the radionuclides deposited on the ground; (2) inhalation of radionuclide-contaminated air during the passage of the radioactive cloud and, thereafter, of radionuclides transferred (resuspended) from soil to air; and (3) ingestion of contaminated water and foodstuffs. Within the ingestion pathway, 13 types of foods and sources of water were considered. Well established models were used for estimation of doses resulting from the three pathways using parameter values developed from extensive literature review. Because previous experience and calculations have shown that the annual dose delivered during the year following a nuclear test is much greater than the doses received in the years after that first year, the time period that was considered is limited to the first year following the day of the test (16 July 1945). Numerical estimates of absorbed doses, based on the methods described in this article, are presented in a separate article in this issue.

Purpose: To study the potential consequences of differences in the evaluation of variable versus uniform relative biological effectiveness calculations in proton radiotherapy for prostate cancer., Methods and Material: Experimental data with proton beams suggest that relative biological effectiveness increases with linear energy transfer. This relation also depends on the α / β ratio, characteristic of a tissue and a considered endpoint. Three phenomenological models (Carabe et al., Wedenberg et al. and McNamara et al.) are compared to a mechanistic model based on microdosimetry (microdosimetric kinetic model) and to the current assumption of uniform relative biological effectiveness equal to 1.1 in a prostate case., Results and Conclusions: Phenomenological models clearly predict higher relative biological effectiveness values compared to microdosimetric kinetic model, that seems to approach to the constant value of 1.1 adopted in the clinics, at least for low linear energy transfer values achieved in typical prostate proton plans. All models predict a higher increase of the relative biological effectiveness-weighted dose for the prostate tumor than for the rest of structures involved due to its lower α / β ratio, even when linear energy transfer is, in general, lower in the tumor than on the surroundings tissues. Prostate cancer is, therefore, a good candidate to take advantage of variable relative biological effectiveness, especially if linear energy transfer is enhanced within the tumor. However, the discrepancies among models hinder the clinical implementation of variable relative biological effectiveness.

The experimental determination of the relative biological effectiveness of thermal neutron factors is fundamental in Boron Neutron Capture Therapy. The present values have been obtained while using mixed beams that consist of both neutrons and photons of various energies. A common weighting factor has been used for both thermal and fast neutron doses, although such an approach has been questioned. At the nuclear reactor of the Institut Laue-Langevin a pure low-energy neutron beam has been used to determine thermal neutron relative biological effectiveness factors. Different cancer cell lines, which correspond to glioblastoma, melanoma, and head and neck squamous cell carcinoma, and non-tumor cell lines (lung fibroblast and embryonic kidney), have been irradiated while using an experimental arrangement designed to minimize neutron-induced secondary gamma radiation. Additionally, the cells were irradiated with photons at a medical linear accelerator, providing reference data for comparison with that from neutron irradiation. The survival and proliferation were studied after irradiation, yielding the Relative Biological Effectiveness that corresponds to the damage of thermal neutrons for the different tissue types.

In this work, we developed a DNA dosimeter, consisting of 4-kb DNA strands attached to magnetic streptavidin beads and labeled with fluorescein, to detect double-strand breaks (DSBs). The purpose here was to evaluate whether the DNA dosimeter readings reflect the relative biological effects of 160 kVp and 6 MV X rays. AVarian 600 C/D linac (6 MV) and a Faxitron cabinet X-ray system (160 kVp), both calibrated using traceable methods, were used to deliver high- and low-energy photons, respectively, to DNA dosimeters and multiple cell lines (mNs-5, HT-22 and Daoy). The responses were fit versus dose, and were used to quantify the dose of low-energy photons that produced the same response as that of the high-energy photons, at doses of 3, 6 and 9 Gy. The equivalent doses were utilized to calculate the relative biological effectiveness (RBEDSB and RBEcell survival). Additionally, a neutral comet assay was performed to measure the amount of intracellular DNA DSB, and ultimately the RBEcomet assay. The results of this work showed 160-kVp photon RBE values and 95% confidence intervals of 1.12 ± 0.04 (mNS-5), 1.16 ± 0.06 (HT-22), 1.25 ± 0.09 (Daoy) and 1.21 ± 0.24 (DNA dosimeter) at 9 Gy and 1.32 ± 0.16 (comet assay) at 3 Gy. Within the current error, the DNA dosimeter measured RBEDSB values in agreement with the RBEcell survival and assay from the cell survival and comet assay RBEcomet measurements. These results suggest that the DNA dosimeter can measure the changes in the radiobiological effects from different energy photons., (©2020 by Radiation Research Society. All rights of reproduction in any form reserved.)

Many experimental studies are carried out to compare biological effectiveness of high dose rate (HDR) with that of low dose rate (LDR). The rational for this is the uncertainty regarding the value of the dose rate effectiveness factor (DREF) used in radiological protection. While a LDR is defined as 0.1 mGy/min or lower, anything above that is seen as HDR. In cell and animal experiments, a dose rate around 1 Gy/min is usually used as representative for HDR. However, atomic bomb survivors, the reference cohort for radiological protection, were exposed to tens of Gy/min. The important question is whether gamma radiation delivered at very high dose rate (VHDR-several Gy/min) is more effective in inducing DNA damage than that delivered at HDR. The aim of this investigation was to compare the biological effectiveness of gamma radiation delivered at VHDR (8.25 Gy/min) with that of HDR (0.38 Gy/min or 0.79 Gy/min). Experiments were carried out with human peripheral mononuclear cells (PBMC) and the human osteosarcoma cell line U2OS. Endpoints related to DNA damage response were analysed. The results show that in PBMC, VHDR is more effective than HDR in inducing gene expression and micronuclei. In U2OS cells, the repair of 53BP1 foci was delayed after VHDR indicating a higher level of damage complexity, but no VHDR effect was observed at the level of micronuclei and clonogenic cell survival. We suggest that the DREF value may be underestimated when the biological effectiveness of HDR and LDR is compared.

Purpose: To identify the relative positions of the ultimate RBE, at a LET value of LET U (where the LET-RBE turnover point occurs independently of dose), and of the maximum LET (LET M ) for a range of ions from protons to Iron ions., Methods: For a range of relativistic velocities (β), the kinetic energies, LET values and ranges for each ion are obtained using SRIM software. For protons and helium ions, the LET changes with β are plotted and LET M is compared with LET U. For all the ions studied the residual ranges of particles at LET U and LET M are subtracted to provide the physical separation (S) between LET U and LET M ., Results: Graphical methods are used to show the above parameters for protons and helium ions. For all the ions studied, LET U occurs at kinetic energies which are higher than those at LET M , so the ultimate maximal RBE occurs proximal to the Bragg peak for individual particles and not beyond it, as is commonly supposed. The distance S, between LET U and LET M , appears to increase linearly with the atomic charge value Z., Conclusions: For the lighter elements, from protons to carbon ions, S is sufficiently small (less than the tolerance/accuracy of radiation treatments) and so will probably not influence therapeutic decisions or outcomes. For higher Z numbers such as Argon and Iron, larger S values of several centimetres occur, which may have implications not only in any proposed therapeutic beams but also at very low doses encountered in radiation protection where the few cells that are irradiated will typically be traversed by a single particle.

Objective: To evaluate the biological effectiveness of dose associated with interruption time; and propose the dose compensation method based on biological effectiveness when an interruption occurs during photon radiation therapy., Methods: The lineal energy distribution for human salivary gland tumor was calculated by Monte Carlo simulation using a photon beam. The biological dose (D bio ) was estimated using the microdosimetric kinetic model. The dose compensating factor with the physical dose for the difference of the D bio with and without interruption (Δ) was derived. The interruption time (τ) was varied to 0.1, 0.2, 0.3, 0.4, 0.5, 1, 2, 3, 4, 5, 10, 20, 30, 40, 50, 75, and 120 min. The dose per fraction and dose rate varied from 2 to 8 Gy and 0.1 to 24 Gy/min, respectively., Results: The maximum Δ with 1 Gy/min occurred when the interruption occurred at half the dose. The Δ with 1 Gy/min at half of the dose was over 3% for τ >= 20 min for 2 Gy, τ = 10 min for 5 Gy, and τ = 10 min for 8 Gy. The maximum difference of the Δ due to the dose rate was within 3% for 2 and 5 Gy, and achieving values of 4.0% for 8 Gy. The dose compensating factor was larger with a high dose per fraction and high-dose rate beams., Conclusion: A loss of biological effectiveness occurs due to interruption. Our proposal method could correct for the unexpected decrease of the biological effectiveness caused by interruption time., Advances in Knowledge: For photon radiotherapy, the interruption causes the sublethal damage repair. The current study proposed the dose compensation method for the decrease of the biological effect by the interruption.

Purpose: Late radiation-induced contrast-enhancing brain lesions (CEBLs) on magnetic resonance imaging (MRI) after proton therapy of brain tumors have been observed to occur frequently in regions of high linear energy transfer (LET) and in proximity to the ventricular system. We analyzed 110 patients with low-grade glioma treated with proton therapy to determine whether the risk for CEBLs is increased in proximity to the ventricular system and if there is a relationship between relative biological effectiveness (RBE) and LET., Methods and Materials: We contoured CEBLs identified on follow-up T1-MRI scans and computed dose and dose-averaged LET (LET d ) distributions for all patients using the Monte Carlo method. We then performed cross-validated voxel-level logistic regression to predict local risks for image change and to extract model parameters, such as the RBE. From the voxel-level model, we derived a model for patient-level risk prediction based on the treatment plan., Results: Of 110 patients, 23 exhibited 1 or several CEBLs on follow-up MRI scans. The voxel-level logistic model has an accuracy as follows: area under the curve of 0.94 and Brier score of 2.6 × 10 -5 . Model predictions are a 3-fold increased risk in the 4 mm region around the ventricular system and an LET d -dependent RBE of, for example, 1.20 for LET d = 2 keV/μm and 1.50 for LET d = 5 keV/μm. The patient-level risk model has an accuracy as follows: area under the curve of 0.78 and Brier score of 0.13., Conclusions: Our findings present clinical evidence for an increased risk in ventricular proximity and for a proton RBE that increases significantly with increasing LET. We present a voxel-level model that accurately predicts the localization of late MRI contrast change and extrapolate a patient-level model that allows treatment plan-based risk prediction., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: Exposure to ionizing radiation increases risk of breast cancer. Although proton radiation is encountered in outer space and in medicine, we do not fully understand breast cancer risks from protons owing to limited in vivo data. The purpose of this study was to comparatively assess the effects of γ-rays and protons on mammary tumorigenesis in APC Min/+ mice., Methods and Materials: Female APC Min/+ mice were exposed to 1 GeV protons (1.88 or 4.71 Gy) and 137 Cs γ-rays (2 or 5 Gy). Mice were euthanized 100 to 110 days after irradiation, at which point mammary tumors were scored, tumor grades were assessed, and relative biological effectiveness was calculated. Molecular phenotypes were determined by assessing estrogen receptor α (ERα) and human epidermal growth factor receptor 2 (HER2) status. ERα downstream signaling was assessed by immunohistochemistry., Results: Exposure to proton radiation led to increased mammary tumor frequency at both proton radiation doses compared with γ-rays. The calculated relative biological effectiveness for proton radiation-induced mammary tumorigenesis was 3.11 for all tumors and >5 for malignant tumors relative to γ-rays. Tumor frequency per unit of radiation was higher at the lower dose, suggesting a saturation effect at the higher dose. Protons induced more adenocarcinomas relative to γ-rays, and proton-induced tumors show greater ERα and HER2 positivity and higher activation of the ERα downstream PI3K/Akt and cyclin D1 pathways relative to γ-rays., Conclusions: Our data demonstrate that protons pose a higher risk of mammary tumorigenesis relative to γ-rays. We also show that proton radiation-induced tumors in APC Min/+ mice are ERα- and HER2-positive, which is consistent with our previous data on radiation-induced estrogenic response in wild-type mice. Although this study establishes APC Min/+ as a model with adequate signal-to-noise ratio for space radiation-induced mammary tumorigenesis, further studies will be required to address the uncertainties in space radiation-induced breast cancer risk estimation., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: While a large amount of experimental data suggest that the proton relative biological effectiveness (RBE) varies with both physical and biological parameters, current commercial treatment planning systems (TPS) use the constant RBE instead of variable RBE models, neglecting the dependence of RBE on the linear energy transfer (LET). To conduct as accurate a clinical evaluation as possible in this circumstance, it is desirable that the dosimetric parameters derived by TPS ( D RBE = 1.1 ) are close to the "true" values derived with the variable RBE models ( D v RBE ). As such, in this study, the closeness of D RBE = 1.1 to D v RBE was compared between planning target volume (PTV)-based and robust plans., Methods: Intensity-modulated proton therapy (IMPT) treatment plans for two Radiation Therapy Oncology Group (RTOG) phantom cases and four nasopharyngeal cases were created using the PTV-based and robust optimizations, under the assumption of a constant RBE of 1.1. First, the physical dose and dose-averaged LET (LET d ) distributions were obtained using the analytical calculation method, based on the pencil beam algorithm. Next, D v RBE was calculated using three different RBE models. The deviation of D v RBE from D RBE = 1.1 was evaluated with D 99 and D max , which have been used as the evaluation indices for clinical target volume (CTV) and organs at risk (OARs), respectively. The influence of the distance between the OAR and CTV on the results was also investigated. As a measure of distance, the closest distance and the overlapped volume histogram were used for the RTOG phantom and nasopharyngeal cases, respectively., Results: As for the OAR, the deviations of D max v RBE from D max RBE = 1.1 were always smaller in robust plans than in PTV-based plans in all RBE models. The deviation would tend to increase as the OAR was located closer to the CTV in both optimization techniques. As for the CTV, the deviations of D 99 v RBE from D 99 RBE = 1.1 were comparable between the two optimization techniques, regardless of the distance between the CTV and the OAR., Conclusion: Robust optimization was found to be more favorable than PTV-based optimization in that the results presented by TPS were closer to the "true" values and that the clinical evaluation based on TPS was more reliable., (© 2020 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.)

Clinical parameters and empirical evidence are the primary determinants for current treatment planning in radiation oncology. Personalized medicine in radiation oncology is only at the very beginning to take the genetic background of a tumor entity into consideration to define an individual treatment regimen, the total dose or the combination with a specific anticancer agent. Likewise, stratification of patients towards proton radiotherapy is linked to its physical advantageous energy deposition at the tumor site with minimal healthy tissue being co-irradiated distal to the target volume. Hence, the fact that photon and proton irradiation also induce different qualities of DNA damages, which require differential DNA damage repair mechanisms has been completely neglected so far. These subtle differences could be efficiently exploited in a personalized treatment approach and could be integrated into personalized treatment planning. A differential requirement of the two major DNA double-strand break repair pathways, homologous recombination and non-homologous end joining, was recently identified in response to proton and photon irradiation, respectively, and subsequently influence the mode of ionizing radiation-induced cell death and susceptibility of tumor cells with defects in DNA repair machineries to either quality of ionizing radiation.This review focuses on the differential DNA-damage responses and subsequent biological processes induced by photon and proton irradiation in dependence of the genetic background and discusses their impact on the unicellular level and in the tumor microenvironment and their implications for combined treatment modalities.

Purpose: The purpose is to verify experimentally whether application of magnetic fields longitudinal and perpendicular to a proton beam alters the biological effectiveness of the radiation., Methods and Materials: Proton beams with linear energy transfer of 1.1 and 3.3 keV/μm irradiated human cancer and normal cells under a longitudinal (perpendicular) magnetic field of B L (B P ) = 0, 0.3, or 0.6 T. Cell survival curves were constructed to evaluate the effects of the magnetic fields on the biological effectiveness. The ratio of dose that would result in a survival fraction of 10% without the magnetic field D wo to the dose with the magnetic field D w , R 10 = D wo /D w , was determined for each cell line and magnetic field., Results: For cancer cells exposed to the 1.1- (3.3-) keV/μm proton beams, R 10 s were increased to 1.10 ± 0.07 (1.11 ± 0.07) and 1.11 ± 0.07 (1.12 ± 0.07) by the longitudinal magnetic fields of B L = 0.3 and 0.6 T, respectively. For normal cells, R 10 s were increased to 1.13 ± 0.06 (1.17 ± 0.06) and 1.17 ± 0.06 (1.30 ± 0.06) by the B L s. In contrast, R 10 s were not changed significantly from 1 by the perpendicular magnetic fields of B P = 0.3 and 0.6 T for both cancer and normal cells exposed to 1.1- and 3.3-keV/μm proton beams., Conclusions: The biological effectiveness of proton beams was significantly enhanced by longitudinal magnetic fields of B L = 0.3 and 0.6 T, whereas the biological effectiveness was not altered by perpendicular magnetic fields of the same strengths. This enhancement effect should be taken into account in magnetic resonance imaging guided proton therapy with a longitudinal magnetic field., (Copyright © 2019 Elsevier Inc. All rights reserved.)