The contribution of high-LET track to DNA damage formation and cell death for Monoenergy and SOBP carbon ion irradiation.

Carbon ion radiotherapy (CIRT) is a heavy ion charge particle therapy with 29 years of prominent use. Despite advantages like high relative biological effectiveness (RBE), improved quality of life, and reduced treatment time, challenges persist, especially regarding heavy nuclear fragments. Our research addresses these challenges in horizontal irradiation, aiming to comprehend Monoenergetic and Spread-Out Bragg peak (SOBP) carbon ion beam trajectories using cell survival analysis and visualizing biological effects through DNA damage (γ-H2AX). This reveals repair-related protein foci near the Bragg peak. CR-39, a plastic nuclear track detector, was explored to understand high-linear energy transfer (LET) tracks and radiation quality near the Bragg peak. Findings unveil high-LET DNA damage signatures through aligned γ-H2AX foci, correlating with LET values in SOBP. CR-39 visualized high-LET particle exposure, indicating comet-type etch-pits at the Bragg peak and suggesting carbon ion fragmentation. Unexpectedly, dot-type etch-pits in irradiated and post-Bragg peak regions indicated high-LET neutron production. This investigation highlights the intricate interplay of carbon ion beams, stressing the importance of understanding LET variations, DNA damage patterns, and undesired secondary exposure.

Incorporating variable RBE in IMPT optimization for ependymoma.

PURPOSE: To study the dosimetric impact of incorporating variable relative biological effectiveness (RBE) of protons in optimizing intensity-modulated proton therapy (IMPT) treatment plans and to compare it with conventional constant RBE optimization and linear energy transfer (LET)-based optimization. METHODS: This study included 10 pediatric ependymoma patients with challenging anatomical features for treatment planning. Four plans were generated for each patient according to different optimization strategies: (1) constant RBE optimization (ConstRBEopt) considering standard-of-care dose requirements; (2) LET optimization (LETopt) using a composite cost function simultaneously optimizing dose-averaged LET (LETd ) and dose; (3) variable RBE optimization (VarRBEopt) using a recent phenomenological RBE model developed by McNamara et al.; and (4) hybrid RBE optimization (hRBEopt) assuming constant RBE for the target and variable RBE for organs at risk. By normalizing each plan to obtain the same target coverage in either constant or variable RBE, we compared dose, LETd , LET-weighted dose, and equivalent uniform dose between the different optimization approaches. RESULTS: We found that the LETopt plans consistently achieved increased LET in tumor targets and similar or decreased LET in critical organs compared to other plans. On average, the VarRBEopt plans achieved lower mean and maximum doses with both constant and variable RBE in the brainstem and spinal cord for all 10 patients. To compensate for the underdosing of targets with 1.1 RBE for the VarRBEopt plans, the hRBEopt plans achieved higher physical dose in targets and reduced mean and especially maximum variable RBE doses compared to the ConstRBEopt and LETopt plans. CONCLUSION: We demonstrated the feasibility of directly incorporating variable RBE models in IMPT optimization. A hybrid RBE optimization strategy showed potential for clinical implementation by maintaining all current dose limits and reducing the incidence of high RBE in critical normal tissues in ependymoma patients.

The sensitivity of radiobiological models in carbon ion radiotherapy (CIRT) and its consequences on the clinical treatment plan: Differences between LEM and MKM models.

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.

Up modulation of dose-averaged linear energy transfer by simultaneous integrated boost in carbon-ion radiotherapy for pancreatic carcinoma.

BACKGROUND: Local recurrence in locally advanced pancreatic cancer (LAPC) after carbon-ion radiotherapy (CIRT) may partly attribute to low dose-averaged linear energy transfer (LETd), despite high CIRT dose. PURPOSE: This study aimed to investigate the approaches to up-modulate the CIRT LETd and to evaluate the corresponding oxygen enhancement ratio (OER) reduction. METHODS: 10 LAPCs that had been irradiated by CIRT with 67.5 Gy (RBE) in 15 fractions were selected. Their original plans were taken as the control plan for the LETd and OER investigations. Our considerations for up-modulating LETd were: (1) to deliver high doses to gross tumor volume core (GTVcore), while keeping dose constraints of the gastrointestinal (GI) tract in tolerance; (2) to put more Bragg-peak (BP) within the modulated targets; (3) to increase the BP density, high doses were necessary; (4) CIRT LETd could be effectively increased to small volumes; and (5) simultaneous integrated boost technique (SIB) could achieve the aforementioned tasks. The LETd and the corresponding OER distributions of each type of SIB plan were evaluated. RESULTS: We delivered up to 100 Gy (RBE) to GTVcore using SIB. The mean LETd of GTV increased significantly by 21.3% from 47.8 to 58.0 keV/µm (p < 0.05). Meanwhile, the mean OER of GTVcore decreased by 6.6%, from 1.51 to 1.41 (p < 0.05). The GI LETdS in all modulated plans were not more than those in the original plans. CONCLUSIONS: SIB could effectively increase CIRT LETd to LAPC, thus producing reduced OER, which may effectively overcome the radioresistance of LAPCs.

RadPhysBio: A Radiobiological Database for the Prediction of Cell Survival upon Exposure to Ionizing Radiation.

Based on the need for radiobiological databases, in this work, we mined experimental ionizing radiation data of human cells treated with X-rays, γ-rays, carbon ions, protons and α-particles, by manually searching the relevant literature in PubMed from 1980 until 2024. In order to calculate normal and tumor cell survival α and ß coefficients of the linear quadratic (LQ) established model, as well as the initial values of the double-strand breaks (DSBs) in DNA, we used WebPlotDigitizer and Python programming language. We also produced complex DNA damage results through the fast Monte Carlo code MCDS in order to complete any missing data. The calculated α/ß values are in good agreement with those valued reported in the literature, where α shows a relatively good association with linear energy transfer (LET), but not ß. In general, a positive correlation between DSBs and LET was observed as far as the experimental values are concerned. Furthermore, we developed a biophysical prediction model by using machine learning, which showed a good performance for α, while it underscored LET as the most important feature for its prediction. In this study, we designed and developed the novel radiobiological 'RadPhysBio' database for the prediction of irradiated cell survival (α and ß coefficients of the LQ model). The incorporation of machine learning and repair models increases the applicability of our results and the spectrum of potential users.

Cumulative Dose from Recurrent CT Scans: Exploring the DNA Damage Response in Human Non-Transformed Cells.

Recurrent computed tomography (CT) examination has become a common diagnostic procedure for several diseases and injuries. Though each singular CT scan exposes individuals at low doses of low linear energy transfer (LET) radiation, the cumulative dose received from recurrent CT scans poses an increasing concern for potential health risks. Here, we evaluated the biological effects of recurrent CT scans on the DNA damage response (DDR) in human fibroblasts and retinal pigment epithelial cells maintained in culture for five months and subjected to four CT scans, one every four weeks. DDR kinetics and eventual accumulation of persistent-radiation-induced foci (P-RIF) were assessed by combined immunofluorescence for γH2AX and 53BP1, i.e., γH2AX/53BP1 foci. We found that CT scan repetitions significantly increased both the number and size of γH2AX/53BP1 foci. In particular, after the third CT scan, we observed the appearance of giant foci that might result from the overlapping of individual small foci and that do not associate with irreversible growth arrest, as shown by DNA replication in the foci-carrying cells. Whether these giant foci represent coalescence of unrepaired DNA damage as reported following single exposition to high doses of high LET radiation is still unclear. However, morphologically, these giant foci resemble the recently described compartmentalization of damaged DNA that should facilitate the repair of DNA double-strand breaks but also increase the risk of chromosomal translocations. Overall, these results indicate that for a correct evaluation of the damage following recurrent CT examinations, it is necessary to consider the size and composition of the foci in addition to their number.

Comparative Analysis of Cystamine and Cysteamine as Radioprotectors and Antioxidants: Insights from Monte Carlo Chemical Modeling under High Linear Energy Transfer Radiation and High Dose Rates.

This study conducts a comparative analysis of cystamine (RSSR), a disulfide, and cysteamine (RSH), its thiol monomer, to evaluate their efficacy as radioprotectors and antioxidants under high linear energy transfer (LET) and high-dose-rate irradiation conditions. It examines their interactions with reactive primary species produced during the radiolysis of the aqueous ferrous sulfate (Fricke) dosimeter, offering insights into the mechanisms of radioprotection and highlighting their potential to enhance the therapeutic index of radiation therapy, particularly in advanced techniques like FLASH radiotherapy. Using Monte Carlo multi-track chemical modeling to simulate the radiolytic oxidation of ferrous to ferric ions in Fricke-cystamine and Fricke-cysteamine solutions, this study assesses the radioprotective and antioxidant properties of these compounds across a variety of irradiation conditions. Concentrations were varied in both aerated (oxygen-rich) and deaerated (hypoxic) environments, simulating conditions akin to healthy tissue and tumors. Both cystamine and cysteamine demonstrate radioprotective and strong antioxidant properties. However, their effectiveness varies significantly depending on the concentration employed, the conditions of irradiation, and whether or not environmental oxygen is present. Specifically, excluding potential in vivo toxicity, cysteamine substantially reduces the adverse effects of ionizing radiation under aerated, low-LET conditions at concentrations above ~1 mM. However, its efficacy is minimal in hypoxic environments, irrespective of the concentration used. Conversely, cystamine consistently offers robust protective effects in both oxygen-rich and oxygen-poor conditions. The distinct protective capacities of cysteamine and cystamine underscore cysteamine's enhanced potential in radiotherapeutic settings aimed at safeguarding healthy tissues from radiation-induced damage while effectively targeting tumor tissues. This differential effectiveness emphasizes the need for personalized radioprotective strategies, tailored to the specific environmental conditions of the tissue involved. Implementing such approaches is crucial for optimizing therapeutic outcomes and minimizing collateral damage in cancer treatment.

NF-κB in the Radiation Response of A549 Non-Small Cell Lung Cancer Cells to X-rays and Carbon Ions under Hypoxia.

Cellular hypoxia, detectable in up to 80% of non-small cell lung carcinoma (NSCLC) tumors, is a known cause of radioresistance. High linear energy transfer (LET) particle radiation might be effective in the treatment of hypoxic solid tumors, including NSCLC. Cellular hypoxia can activate nuclear factor κB (NF-κB), which can modulate radioresistance by influencing cancer cell survival. The effect of high-LET radiation on NF-κB activation in hypoxic NSCLC cells is unclear. Therefore, we compared the effect of low (X-rays)- and high (12C)-LET radiation on NF-κB responsive genes' upregulation, as well as its target cytokines' synthesis in normoxic and hypoxic A549 NSCLC cells. The cells were incubated under normoxia (20% O2) or hypoxia (1% O2) for 48 h, followed by irradiation with 8 Gy X-rays or 12C ions, maintaining the oxygen conditions until fixation or lysis. Regulation of NF-κB responsive genes was evaluated by mRNA sequencing. Secretion of NF-κB target cytokines, IL-6 and IL-8, was quantified by ELISA. A greater fold change increase in expression of NF-κB target genes in A549 cells following exposure to 12C ions compared to X-rays was observed, regardless of oxygenation status. These genes regulate cell migration, cell cycle, and cell survival. A greater number of NF-κB target genes was activated under hypoxia, regardless of irradiation status. These genes regulate cell migration, survival, proliferation, and inflammation. X-ray exposure under hypoxia additionally upregulated NF-κB target genes modulating immunosurveillance and epithelial-mesenchymal transition (EMT). Increased IL-6 and IL-8 secretion under hypoxia confirmed NF-κB-mediated expression of pro-inflammatory genes. Therefore, radiotherapy, particularly with X-rays, may increase tumor invasiveness in surviving hypoxic A549 cells.

Comparison of linear energy transfer measurement for therapeutic carbon beam using CR-39 and TLD.

The measurement of linear energy transfer (LET) is crucial for the evaluation of the radiation effect in heavy ion therapy. As two detectors which are convenient to implant into the phantom, the performance of CR-39 and thermoluminescence detector (TLD) for LET measurement was compared by experiment and simulation in this study. The results confirmed the applicability of both detectors for LET measurements, but also revealed that the CR-39 detector would lead to potential overestimation of dose-averaged LET compared with the simulation by PHITS, while the TLD would have a large uncertainty measuring ions with LET larger than 20 keVµm-1. The results of this study were expected to improve the detection method of LET for therapeutic carbon beam and would finally be benefit to the quality assurance of heavy ion radiotherapy.

Health Effects of Ionizing Radiation on the Human Body.

Radioactivity is a process in which the nuclei of unstable atoms spontaneously decay, producing other nuclei and releasing energy in the form of ionizing radiation in the form of alpha (α) and beta (ß) particles as well as the emission of gamma (γ) electromagnetic waves. People may be exposed to radiation in various forms, as casualties of nuclear accidents, workers in power plants, or while working and using different radiation sources in medicine and health care. Acute radiation syndrome (ARS) occurs in subjects exposed to a very high dose of radiation in a very short period of time. Each form of radiation has a unique pathophysiological effect. Unfortunately, higher organisms-human beings-in the course of evolution have not acquired receptors for the direct "capture" of radiation energy, which is transferred at the level of DNA, cells, tissues, and organs. Radiation in biological systems depends on the amount of absorbed energy and its spatial distribution, particularly depending on the linear energy transfer (LET). Photon radiation with low LET leads to homogeneous energy deposition in the entire tissue volume. On the other hand, radiation with a high LET produces a fast Bragg peak, which generates a low input dose, whereby the penetration depth into the tissue increases with the radiation energy. The consequences are mutations, apoptosis, the development of cancer, and cell death. The most sensitive cells are those that divide intensively-bone marrow cells, digestive tract cells, reproductive cells, and skin cells. The health care system and the public should raise awareness of the consequences of ionizing radiation. Therefore, our aim is to identify the consequences of ARS taking into account radiation damage to the respiratory system, nervous system, hematopoietic system, gastrointestinal tract, and skin.

High-LET charged particles: radiobiology and application for new approaches in radiotherapy.

The number of patients treated with charged-particle radiotherapy as well as the number of treatment centers is increasing worldwide, particularly regarding protons. However, high-linear energy transfer (LET) particles, mainly carbon ions, are of special interest for application in radiotherapy, as their special physical features result in high precision and hence lower toxicity, and at the same time in increased efficiency in cell inactivation in the target region, i.e., the tumor. The radiobiology of high-LET particles differs with respect to DNA damage repair, cytogenetic damage, and cell death type, and their increased LET can tackle cells' resistance to hypoxia. Recent developments and perspectives, e.g., the return of high-LET particle therapy to the US with a center planned at Mayo clinics, the application of carbon ion radiotherapy using cost-reducing cyclotrons and the application of helium is foreseen to increase the interest in this type of radiotherapy. However, further preclinical research is needed to better understand the differential radiobiological mechanisms as opposed to photon radiotherapy, which will help to guide future clinical studies for optimal exploitation of high-LET particle therapy, in particular related to new concepts and innovative approaches. Herein, we summarize the basics and recent progress in high-LET particle radiobiology with a focus on carbon ions and discuss the implications of current knowledge for charged-particle radiotherapy. We emphasize the potential of high-LET particles with respect to immunogenicity and especially their combination with immunotherapy.

Modeling of ionizing radiation-induced chromosome aberration and tumor prevalence based on two classes of DNA double-strand breaks clustering in chromatin domains.

There has been some controversy over the use of radiobiological models when modeling the dose-response curves of ionizing radiation (IR)-induced chromosome aberration and tumor prevalence, as those curves usually show obvious non-targeted effects (NTEs) at low doses of high linear energy transfer (LET) radiation. The lack of understanding the contribution of NTEs to IR-induced carcinogenesis can lead to distinct deviations of relative biological effectiveness (RBE) estimations of carcinogenic potential, which are widely used in radiation risk assessment and radiation protection. In this work, based on the initial pattern of two classes of IR-induced DNA double-strand breaks (DSBs) clustering in chromatin domains and the subsequent incorrect repair processes, we proposed a novel radiobiological model to describe the dose-response curves of two carcinogenic-related endpoints within the same theoretical framework. The representative experimental data was used to verify the consistency and validity of the present model. The fitting results indicated that, compared with targeted effect (TE) and NTE models, the current model has better fitting ability when dealing with the experimental data of chromosome aberration and tumor prevalence induced by multiple types of IR with different LETs. Notably, the present model without introducing an NTE term was adequate to describe the dose-response curves of IR-induced chromosome aberration and tumor prevalence with NTEs in low-dose regions. Based on the fitting parameters, the LET-dependent RBE values were calculated for three given low doses. Our results showed that the RBE values predicted by the current model gradually decrease with the increase of doses for the endpoints of chromosome aberration and tumor prevalence. In addition, the calculated RBE was also compared with those evaluated from other models. These analyses show that the proposed model can be used as an alternative tool to well describe dose-response curves of multiple carcinogenic-related endpoints and effectively estimate RBE in low-dose regions.

Treatment-planning approaches to intensity modulated proton therapy and the impact on dose-weighted linear energy transfer.

PURPOSE: We quantified the effect of various forward-based treatment-planning strategies in proton therapy on dose-weighted linear energy transfer (LETd). By maintaining the dosimetric quality at a clinically acceptable level, we aimed to evaluate the differences in LETd among various treatment-planning approaches and their practicality in minimizing biologic uncertainties associated with LETd. METHOD: Eight treatment-planning strategies that are achievable in commercial treatment-planning systems were applied on a cylindrical water phantom and four pediatric brain tumor cases. Each planning strategy was compared to either an opposed lateral plan (phantom study) or original clinical plan (patient study). Deviations in mean and maximum LETd from clinically acceptable dose distributions were compared. RESULTS: In the phantom study, using a range shifter and altering the robust scenarios during optimization had the largest effect on the mean clinical target volume LETd, which was reduced from 4.5 to 3.9 keV/µm in both cases. Variations in the intersection angle between beams had the largest effect on LETd in a ring defined 3 to 5 mm outside the target. When beam intersection angles were reduced from opposed laterals (180°) to 120°, 90°, and 60°, corresponding maximum LETd increased from 7.9 to 8.9, 10.9, and 12.2 keV/µm, respectively. A clear trend in mean and maximum LETd variations in the clinical cases could not be established, though spatial distribution of LETd suggested a strong dependence on patient anatomy and treatment geometry. CONCLUSION: Changes in LETd from treatment-plan setup follow intuitive trends in a controlled phantom experiment. Anatomical and other patient-specific considerations, however, can preclude generalizable strategies in clinical cases. For pediatric cranial radiation therapy, we recommend using opposed lateral treatment fields to treat midline targets.

Calculating dose-averaged linear energy transfer in an analytical treatment planning system for carbon-ion radiotherapy.

BACKGROUND: Compelling evidence shows the association between the relative biological effectiveness (RBE) of carbon-ion radiotherapy (CIRT) and the dose averaged linear energy transfer (LETd). However, the ability to calculate the LETd in commercially available treatment planning systems (TPS) is lacking. PURPOSE: This study aims to develop a method of calculating the LETd of CIRT plans that could be robustly carried out in RayStation (V10B, Raysearch, Sweden). METHODS: The calculation used the fragment spectra in RayStation for the CIRT treatment planning. The dose-weighted averaging procedure was supported by the microdosimetric kinetic model (MKM). The MKM-based pencil beam dose engine (PBA, v4.2) for calculating RBE-weighted doses was reformulated to become a LET-weighted calculating engine. A separate module was then configured to inversely calculate the LETd from the absorbed dose of a plan and the associated fragment spectra. In this study, the ion and energy-specific LET table in the LETd module was further matched with the values decoded from the baseline data of the Syngo TPS (V13C, Siemens, Germany). The LETd distributions of several monoenergetic and modulated beams were calculated and validated against the values derived from the Syngo TPS and the published data. RESULTS: The differences in LETds of the monoenergetic beams between the new method and the traditional method were within 3% in the entrance and Bragg-peak regions. However, a larger difference was observed in the distal region. The results of the modulated beams were in good agreement with the works from the published literature. CONCLUSIONS: The method presented herein reformulates the MKM dose engine in the RayStation TPS to inversely calculate LETds. The robustness and accuracy were demonstrated.

Effect of Linear Energy Transfer on Cystamine's Radioprotective Activity: A Study Using the Fricke Dosimeter with 6-500 MeV per Nucleon Carbon Ions-Implication for Carbon Ion Hadrontherapy.

(1) Background: Radioprotective agents have garnered considerable interest due to their prospective applications in radiotherapy, public health medicine, and situations of large-scale accidental radiation exposure or impending radiological emergencies. Cystamine, an organic diamino-disulfide compound, is recognized for its radiation-protective and antioxidant properties. This study aims to utilize the aqueous ferrous sulfate (Fricke) dosimeter to measure the free-radical scavenging capabilities of cystamine during irradiation by fast carbon ions. This analysis spans an energy range from 6 to 500 MeV per nucleon, which correlates with "linear energy transfer" (LET) values ranging from approximately 248 keV/µm down to 9.3 keV/µm. (2) Methods: Monte Carlo track chemistry calculations were used to simulate the radiation-induced chemistry of aerated Fricke-cystamine solutions across a broad spectrum of cystamine concentrations, ranging from 10-6 to 1 M. (3) Results: In irradiated Fricke solutions containing cystamine, cystamine is observed to hinder the oxidation of Fe2+ ions, an effect triggered by oxidizing agents from the radiolysis of acidic water, resulting in reduced Fe3+ ion production. Our simulations, conducted both with and without accounting for the multiple ionization of water, confirm cystamine's ability to capture free radicals, highlighting its strong antioxidant properties. Aligning with prior research, our simulations also indicate that the protective and antioxidant efficiency of cystamine diminishes with increasing LET of the radiation. This result can be attributed to the changes in the geometry of the track structures when transitioning from lower to higher LETs. (4) Conclusions: If we can apply these fundamental research findings to biological systems at a physiological pH, the use of cystamine alongside carbon-ion hadrontherapy could present a promising approach to further improve the therapeutic ratio in cancer treatments.

Biological effectiveness and relative biological effectiveness of ion beams for in-vitro cell irradiation.

Biological effectiveness and relative biological effectiveness are critical for proton and ion beam radiotherapy. However, the relationship between the two quantities and physical character of ion beams is not well established. By analyzing 1188 sets of in-vitro cell irradiation experiments using ion beams ranging from protons to 238 U, compiled by the Particle Irradiation Data Ensemble (PIDE) project, the biological effectiveness of the ion beams, with cell survival fractionation (SF) as the endpoint, was found to be dependent on the fluence and linear energy transfer (LET) of the ion beam. Consequently, the relative biological effectiveness of the ion beam to photon beam was also established as a function of LET. A common form of relationship among SF, fluence, and LET was found to be valid for all ion beam experiments. The close form relationship could be used for proton and ion beam radiotherapy applications.

Key biological mechanisms involved in high-LET radiation therapies with a focus on DNA damage and repair.

DNA damage and repair studies are at the core of the radiation biology field and represent also the fundamental principles informing radiation therapy (RT). DNA damage levels are a function of radiation dose, whereas the type of damage and biological effects such as DNA damage complexity, depend on radiation quality that is linear energy transfer (LET). Both levels and types of DNA damage determine cell fate, which can include necrosis, apoptosis, senescence or autophagy. Herein, we present an overview of current RT modalities in the light of DNA damage and repair with emphasis on medium to high-LET radiation. Proton radiation is discussed along with its new adaptation of FLASH RT. RT based on α-particles includes brachytherapy and nuclear-RT, that is proton-boron capture therapy (PBCT) and boron-neutron capture therapy (BNCT). We also discuss carbon ion therapy along with combinatorial immune-based therapies and high-LET RT. For each RT modality, we summarise relevant DNA damage studies. Finally, we provide an update of the role of DNA repair in high-LET RT and we explore the biological responses triggered by differential LET and dose.

Towards harmonizing clinical linear energy transfer (LET) reporting in proton radiotherapy: a European multi-centric study.

BACKGROUND: Clinical data suggest that the relative biological effectiveness (RBE) in proton therapy (PT) varies with linear energy transfer (LET). However, LET calculations are neither standardized nor available in clinical routine. Here, the status of LET calculations among European PT institutions and their comparability are assessed. MATERIALS AND METHODS: Eight European PT institutions used suitable treatment planning systems with their center-specific beam model to create treatment plans in a water phantom covering different field arrangements and fulfilling commonly agreed dose objectives. They employed their locally established LET simulation environments and procedures to determine the corresponding LET distributions. Dose distributions D1.1 and DRBE assuming constant and variable RBE, respectively, and LET were compared among the institutions. Inter-center variability was assessed based on dose- and LET-volume-histogram parameters. RESULTS: Treatment plans from six institutions fulfilled all clinical goals and were eligible for common analysis. D1.1 distributions in the target volume were comparable among PT institutions. However, corresponding LET values varied substantially between institutions for all field arrangements, primarily due to differences in LET averaging technique and considered secondary particle spectra. Consequently, DRBE using non-harmonized LET calculations increased inter-center dose variations substantially compared to D1.1 and significantly in mean dose to the target volume of perpendicular and opposing field arrangements (p < 0.05). Harmonizing LET reporting (dose-averaging, all protons, LET to water or to unit density tissue) reduced the inter-center variability in LET to the order of 10-15% within and outside the target volume for all beam arrangements. Consequentially, inter-institutional variability in DRBE decreased to that observed for D1.1. CONCLUSION: Harmonizing the reported LET among PT centers is feasible and allows for consistent multi-centric analysis and reporting of tumor control and toxicity in view of a variable RBE. It may serve as basis for harmonized variable RBE dose prescription in PT.

Development of modified microdosimetric kinetic model for relative biological effectiveness in proton therapy.

To predict the biological effects of ionising radiation, the quantity of biological dose is introduced instead of the physical absorbed dose. In proton therapy, a constant relative biological effectiveness (RBE) of 1.1 is usually applied clinically as recommended by the International Commission of Radiation Units and Measurements. This study presents a new model, based on the modified microdosimetric kinetic model (MMKM), for calculating variable RBE values based on experimental data on the induction of DNA double-strand breaks (DSBs) within cells. The MMKM was proposed based on experimental data for the yield of DSBs in mammalian cells, which allows modification of the yield of primary lesions in the MKM. In this approach, a unique function named f(LET), which describes the relation between RBE and linear energy transfer (LET), was considered for charged particles. In the presented model (DMMKM), the MMKM approach was developed further by considering different f(LET)s for different relevant ions involved in energy deposition events in proton therapy. Although experimental data represent the dependence of the yield of primary lesions on the ion species, the DSB yield (assumed as the main primary lesion) is assumed independent of the ion species in the MMKM. In the DMMKM, by considering the yield of primary lesions as a function of the ion species, the α and ß values are in better agreement with the experimental data as compared to those of the MKM and MMKM approaches. The biological dose in the DMMKM is predicted to be lower than that in the MMKM. Further, in the proposed model, the variation of the ß parameter is higher than the constant value assumed in the MKM, at the distal end of the spread-out Bragg peak (SOBP). Moreover, the level of cell death estimated by the MMKM at the SOBP region is higher than that obtained based on the DMMKM. It is concluded that considering modified f(LET)s in the model developed here is more consistent with experimental results than when MMKM and MKM approaches are considered. The DMMKM examines the biological effects with full detail and will, therefore, be effective in improving proton therapy.

Scripted spot removal in PBS proton therapy planning.

BACKGROUND: It is well known in proton therapy that the relative biological effectiveness (RBE) is not constant across the entire Bragg peak, with higher RBE at the distal end of the Bragg peak due to higher linear energy transfer (LET). Treatment planning systems are moving toward LET optimization to mitigate this potentially higher biological impact at a track end. However, using a simple script, proton users can begin to simulate this process by deleting spots from critical structures during optimization. In most cases, nominal target coverage and plan robustness remain satisfactory. METHODS: In our clinic, we developed a script that allows the user to delete spots in all organs at risk (OARs) of interest for one or more treatment beams. The purpose of this script is to potentially reduce side effects by eliminating Bragg peaks within OARs. The script was first used for prostate patients where spots in the rectum and sigmoid, outside of the overlap with the target, were deleted. We then began to use the script for head and neck (H&N) and breast/chestwall patients to reduce acute side effects of the skin by removing spots in a 0.5-cm skin rind. CONCLUSIONS: By utilizing a simple script for deleting spots in critical structures, we have seen excellent clinical results thus far. We have noted reduced skin reactions for nearly all H&N and breast patients.