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Background and Purpose: Disregarding the increase of relative biological effectiveness (RBE) may raise the risk of acute and late adverse events after proton beam therapy (PBT). This study aims to explore the relationship between variable RBE (above 1.1)-induced normal tissue complication probabilities (NTCP) and patient-specific factors, identify patients at high risk of RBE-induced NTCP increase, and assess risk mitigation by incorporating RBE variability into treatment planning., Materials and Methods: We retrospectively analyzed 105 primary brain tumor patients treated with PBT (RBE = 1.1). We calculated differences in estimated NTCP (ΔNTCP) using a variable RBE-weighted dose (D RBE , Wedenberg model) and a constant RBE-weighted dose (D RBE=1.1 ), across 16 NTCP models. These differences were correlated with patient-specific characteristics. Based on ΔNTCP, patients were classified as high risk (32 %) or low risk (68 %) for adverse events due to RBE-induced NTCP. This classification was compared with alternative classifications based on (a) relevant patient-specific characteristics, (b) D RBE=1.1 , and (c) the difference between D RBE and D RBE=1.1 (ΔD), assessing the balanced accuracy. The potential to reduce RBE-induced NTCP through track-end and linear energy transfer (LET) optimization was evaluated in six example patients., Results: Using a variable RBE instead of a constant one resulted in NTCP increases (up to 32 percentage points). Variable-RBE-induced NTCP increases were strongly negatively correlated with the distance between the clinical target volume (CTV) and the organ at risk (OAR) for most side-effects, and positively correlated with CTV volume for certain side-effects. High increases were associated with (a) specific patient factors, particularly the proximity of the CTV to OARs, (b) D RBE=1.1 , and (c) ΔD, with a balanced accuracy of 0.88, 0.94, and 0.86, respectively. Optimization of track-ends and LET considerably reduced NTCP values, achieving a mean reduction of 31 % for optimized OARs., Conclusion: The risk of variable-RBE-induced NTCP strongly depends on patient-specific factors and the considered side-effect. A small distance between the tumor and OARs notably increases the risk. Integrating biologically-guided objectives into treatment planning can effectively mitigate the risk., Competing Interests: Declaration of competing interest For the present study, the authors received no external financial support, neither for the study design or materials used, nor for the collection, analysis, and interpretation of data, nor for the writing of the publication. OncoRay has a research collaboration with RaySearch Laboratories. Dr. Christian Hahn is employed at RaySearch Laboratories AB. In the past 5 years, Dr. Mechthild Krause received funding for her research projects by Merck KGaA (2014-2018 for preclinical study; 2018-2020 for clinical study), Medipan GmbH (2014-2018). Dr. Mechthild Krause is involved in an ongoing publicly funded (German Federal Ministry of Education and Research) project with the companies Medipan (2019-2022), Attomol GmbH (2019-2022), GA Generic Assays GmbH (2019-2022), Gesellschaft für medizinische und wissenschaftliche genetische Analysen (2019-2022), Lipotype GmbH (2019-2022) and PolyAn GmbH (2019-2022). Dr. Krause confirms that, to the best of their knowledge, none of the above-mentioned funding sources were involved in the preparation of this paper. All other authors have declared no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

This position paper, led by the NRG Oncology Particle Therapy Work Group, focuses on the concept of relative biologic effect (RBE) in clinical proton therapy (PT), with the goal of providing recommendations for the next-generation clinical trials with PT on the best practice of investigating and using RBE, which could deviate from the current standard proton RBE value of 1.1 relative to photons. In part 1, current clinical utilization and practice are reviewed, giving the context and history of RBE. Evidence for variation in RBE is presented along with the concept of linear energy transfer (LET). The intertwined nature of tumor radiobiology, normal tissue constraints, and treatment planning with LET and RBE considerations is then reviewed. Part 2 summarizes current and past clinical data and then suggests the next steps to explore and employ tools for improved dynamic models for RBE. In part 3, approaches and methods for the next generation of prospective clinical trials are explored, with the goal of optimizing RBE to be both more reflective of clinical reality and also deployable in trials to allow clinical validation and interpatient comparisons. These concepts provide the foundation for personalized biologic treatments reviewed in part 4. Finally, we conclude with a summary including short- and long-term scientific focus points for clinical PT. The practicalities and capacity to use RBE in treatment planning are reviewed and considered with more biological data in hand. The intermediate step of LET optimization is summarized and proposed as a potential bridge to the ultimate goal of case-specific RBE planning that can be achieved as a hypothesis-generating tool in near-term proton trials., (Published by Elsevier Inc.)

Background and Purpose: With proton therapy, the relative biological effectiveness (RBE) accounts for increased DNA damage caused by higher linear energy transfer (LET) compared to photons. However, the LET and hence the RBE varies along the proton range, particularly at the Bragg peak, introducing challenges in proton treatment planning for brain tumors. The aim of this paper is to standardize evaluating and reporting LET and RBE in proton therapy for patients with grade 2 and 3 IDH mutant gliomas among the Dutch proton therapy centers., Materials and Methods: A working group, comprising experts from three Dutch proton therapy centers, conducted nine meetings between 2020 and 2023. A joint literature review supported the standardized evaluation and reporting of LET and RBE. Questionnaires sent out to the three Dutch proton centers in 2020 and 2023 provided input for discussions on clinical practices. Three clinical examples were chosen to illustrate the application of the recommended methodology in treatment planning., Results: Following the literature review, a guideline on evaluation and reporting using the dose averaged LET (LET d ) of primary and secondary protons calculated in water normalized to unit density was established. The McNamara variable RBE model with an α/β value of 2 Gy was selected for reporting., Conclusion: The study presents a harmonization of approaches to evaluating and reporting LET and variable RBE in a guideline for the three Dutch proton therapy centers, providing clarity for future clinical interpretation. Having chosen a single variable RBE model offers practicality, although its accuracy remains a topic of ongoing research., 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 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: Although proton relative biological effectiveness (RBE) depends on factors like linear energy transfer (LET), tissue properties, dose, and biological endpoint, a constant RBE of 1.1 is recommended in clinical practice. This study surveys proton institutions to explore activities using functionalities beyond a constant proton RBE., Methods: Research versions of RayStation integrate functionalities considering variable proton RBE, LET, proton track-ends, and dirty dose. A survey of 19 institutions in Europe and the United States, with these functionalities available, investigated clinical adoption and research prospects using a 25-question online questionnaire., Results: Of the 16 institutions that responded (84% response rate), 13 were clinically active. These clinical institutions prescribe RBE = 1.1 but also employ planning strategies centered around special beam arrangements to address potentially enhanced RBE effects in serially structured organs at risk (OARs). Clinical plan evaluation encompassed beam angles/spot position (69%), dose-averaged LET (LET d ) (46%), and variable RBE distributions (38%). High ratings (discrete scale: 1-5) were reported for the research functionalities using linear LET d -RBE models, LET d , track-end frequency and dirty dose (averages: 4.0-4.8), while LQ-based phenomenological RBE models dependent on LET d scored lower for optimization (average: 2.2) but congruent for evaluation (average: 4.1). The institutions preferred LET reported as LET d (94%), computed in unit-density water (56%), for all protons (63%), and lean toward LET d -based phenomenological RBE models for clinical use (> 50%)., Conclusions: Proton institutions recognize RBE variability but adhere to a constant RBE while actively mitigating potential enhancements, particularly in serially structured OARs. Research efforts focus on planning techniques that utilize functionalities beyond a constant RBE, emphasizing standardized LET and RBE calculations to facilitate their adoption in clinical practice and improve clinical data collection. LET d calculated in unit-density water for all protons as input to adaptable phenomenological RBE models was the most suggested approach, aligning with predominant clinical LET and variable RBE reporting., (© 2024 The Author(s). Journal of Applied Clinical Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

Photon (X-ray) radiotherapy is the most common treatment used in cancer therapy. However, the exposure of normal tissues and organs at risk to ionising radiation often results in a significant incidence of low-grade adverse side effects, whilst high-grade toxicities also occur at concerningly high rates. As an alternative, boron neutron capture therapy (BNCT) aims to create densely ionising helium and lithium ions directly within cancer cells, thus sparing the surrounding normal cells and tissues but also leading to significantly more effective tumour control than X-rays. Although very promising for patients with recurring and highly invasive tumours, BNCT does not currently have widespread use worldwide, in part due to limited and reliable neutron sources for clinical use. Another limitation is devising strategies leading to the selective and optimal accumulation of boron within the cancer cells. Boronophenylalanine (BPA) is currently the major compound used in BNCT which takes advantage of the amino acid transporter LAT1 that is overexpressed in a number of human cancers. Additionally, there is a lack of in-depth knowledge regarding the impact of BNCT on cellular DNA, and the molecular mechanisms that are responsive to the treatment, which are important in developing optimal therapeutic strategies using BNCT, are unclear. In this review, we highlight the current knowledge of the radiobiology of BNCT acquired from in vitro and in vivo studies, particularly in the context of DNA damage and repair, but also present evidence of established and new boron-containing compounds aimed at enhancing the specificity and effectiveness of the treatment.

Liew and Mairani (2024 Phys. Med. Biol . 69 248001) commented on our previous reply to comments on our paper, 'Modeling for predicting survival fraction of cells after ultra-high dose rate irradiation'. We appreciate their comments on the choice of experimental data on DNA damage for cell survival and agree that the estimate of the dose-response curve on cell survival depends on the selection of DNA damage data. As an additional benchmark test, we compared the relative biological effectiveness (RBE) predicted using the recommended DNA damage data measured in normoxia with those reported in our original paper, and confirmed that the difference in RBE was less than 8%. Although our model allows for the estimation of cell survival and RBE under ultra-high dose rate (UHDR) irradiation, we highlight that a further accumulation of experimental data on DNA damage under UHDR irradiation is necessary for the further development of biophysical models concerning the mechanistical estimation of biological effects., (© 2024 Institute of Physics and Engineering in Medicine. All rights, including for text and data mining, AI training, and similar technologies, are reserved.)

Objective. To develop an empirical model to predict carbon ion (C-ion) relative biological effectiveness (RBE). Approach. We used published cell survival data comprising 360 cell line/energy combinations to characterize the linear energy transfer (LET) dependence of cell radiosensitivity parameters describing the dose required to achieve a given survival level, e.g. 5% (D 5% ), which are linearly correlated between photon and C-ion radiations. Based on the LET response of the metrics D 5% and D 37% , we constructed a model containing four free parameters that predicts cells' linear quadratic model (LQM) survival curve parameters for C-ions, α C and β C , from the reference LQM parameters for photons, α X and β X , for a given C-ion LET value. We fit our model's free parameters to the training dataset and assessed its accuracy via leave-one out cross-validation. We further compared our model to the local effect model (LEM) and the microdosimetric kinetic model (MKM) by comparing its predictions against published predictions made with those models for clinically relevant LET values in the range of 23-107 keV μ m -1 . Main Results. Our model predicted C-ion RBE within ±7%-15% depending on cell line and dose which was comparable to LEM and MKM for the same conditions. Significance. Our model offers comparable accuracy to the LEM or MKM but requires fewer input parameters and is less computationally expensive and whose implementation is so simple we provide it coded into a spreadsheet. Thus, our model can serve as a pragmatic alternative to these mechanistic models in cases where cell-specific input parameters cannot be obtained, the models cannot be implemented, or for which their computational efficiency is paramount., (Creative Commons Attribution license.)

Purpose: One main advantage of proton therapy versus photon therapy is its precise radiation delivery to targets without exit dose, resulting in lower dose to surrounding healthy tissues. This is critical, given the proximity of head and neck tumors to normal structures. However, proton planning requires careful consideration of factors, including air-tissue interface, anatomic uncertainties, surgical artifacts, weight fluctuations, rapid tumor response, and daily variations in setup and anatomy, as these heterogeneities can lead to inaccuracies in targeting and creating unwarranted hotspots to a greater extent than photon radiation. In addition, the elevated relative biological effectiveness at the Bragg peak's distal end can also increase hot spots within and outside the target area., Methods and Materials: The purpose of this study was to evaluate for a difference in positron emission tomography (PET) standard uptake value (SUV) after definitive treatment, between intensity modulated proton therapy (IMPT) and intensity modulated photon therapy (IMRT). In addition, we compared the biologic dose between PET areas of high and low uptake within the clinical target volume-primary of patients treated with IMPT. This work is assuming that the greater SUV may potentially result in greater toxicities. For the purposes of this short communication, we are strictly focusing on the SUV and do not have correlation with toxicity outcomes. To accomplish this, we compared the 3- and 6-month posttreatment fluorodeoxyglucose PET scans for 100 matched patients with oropharyngeal cancer treated definitively without surgery using either IMPT (n = 50) or IMRT (n = 50)., Results: Our study found a significant difference in biologic dose between the high- and low-uptake regions on 3-month posttreatment scans of IMPT. However, this difference did not translate to a significant difference in PET uptake in the clinical target volume-primary at 3 and 6 months' follow-up between patients who received IMPT versus IMRT., Conclusions: Studies have proposed that proton's greater relative biological effectiveness at the Bragg peak could lead to tissue inflammation. Our study did not corroborate these findings. This study's conclusion underscores the need for further investigations with ultimate correlation with clinical toxicity outcomes., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background and Purpose: High linear energy transfer (LET) radiation exhibits stronger tumor-killing effect. However, the correlation between LET and the therapeutic efficacy in Carbon-ion radiotherapy (CIRT) for locally advanced non-small-cell lung cancer (LA-NSCLC) is currently not clear. This study aimed to investigate the relationship between the dose-averaged LET (LET d ) distribution within tumor and local recurrence for LA-NSCLC treated with CIRT., Methods and Materials: An analysis of 62 consecutive patients with LA-NSCLC who underwent CIRT from 2018 to 2022 was conducted. The LET d distribution was calculated based on their treated plans, and the correlation between local recurrence and LET d , relative biological effectiveness (RBE)-weighted doses (D RBE ) and clinical factors was investigated. Receiver operating characteristic (ROC) curve, log-rank test, and Cox regression analysis were performed based on that., Results: 16 patients were defined as local recurrence. Overall survival (OS) and local control (LC) at 24 months were 76.9 % and 73.2 %, respectively. The mean LET d in internal gross tumor volume (iGTV) in the local recurrence group was 48.7 keV/µm, significantly lower than the mean LET d of 53.2 keV/µm in the local control group (p = 0.016). No significant difference was observed in D RBE between the local recurrence and local control groups. ROC curve analysis indicated that a percentage of 88 % of volume in iGTV receiving at least 40 keV/µm (V 40keV/μm ) is the optimal threshold for predicting local recurrence (Area under curve (AUC) = 0.7636). The log-rank test and Cox regression analysis revealed that the LET d value covering 98 % volume of iGTV (LET d 98%) was a significant risk factor for LC (p = 0.020)., Conclusions: Our study revealed an association between LET d distribution and local recurrence in patients with LA-NSCLC. These findings suggest that lower LET d may increase the probability of local recurrence. We suggest that LET d distribution within iGTV should be routinely assessed in CIRT for lung cancer., 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 Elsevier B.V. All rights reserved.)

The advantageous depth dose profile of ion beams together with state of the art beam delivery and treatment planning systems allow for highly conformal tumor treatments in patients. First treatments date back to 1954 at the Lawrence Berkeley Laboratory (LBL) and in Europe, ion beam therapy started in the mid-1990s at the Paul-Scherrer Institute (PSI) with protons and at the Helmholtz Center for Heavy Ion Research (GSI) with carbon ions, followed by the Heidelberg Ion Therapy Center (HIT) in Heidelberg. This review describes the historical development of ion beam therapy in Germany based on the pioneering work at LBL and in the context of simultaneous developments in other countries as well as recent developments.

To compare biochemical recurrence free survival (BCRFS) and cancer-specific survival (CSS) after brachytherapy using the AUA and the Phoenix definitions. 2634 men with T1-T4N0M0 prostate cancer were treated with brachytherapy with or without neoadjuvant hormonal therapy or external beam radiation therapy. Five, 10, and 15- year BCRFS and CSS were estimated with Kaplan-Meier estimates with log rank. Multivariate analysis of survival was performed with Cox regression analysis. Median age was 66, follow-up was 8.6 years, and prostate specific antigen was 6.9. Overall, 11.1% (n = 293) of patients experienced Phoenix BCR and 17.48% (n = 457) experienced AUA BCR. The rates of AUA BCR and Phoenix BCR were significantly different at 5 and 10-years but not at 15 years. Patients treated with BED ≤ 200 Gy were more likely to experience AUA BCR (22.5% vs. 12.4%, OR 1.44, p < 0.001) and Phoenix BCR (14.3% and 8.3%, OR 1.37, p < 0.001) than patients treated with a BED > 200 Gy. Compared to the Phoenix definition, the AUA definition of BCR after brachytherapy is associated with significantly worse BCRFS for the first 15 years after treatment. Receiving a BED > 200, which cannot be achieved without the addition of brachytherapy, is associated with better BCRFS and CSS. Our findings reaffirm the importance of dose in the management of prostate cancer [ABSTRACT FROM AUTHOR]

The outcome of the exposure of living organisms to ionizing radiation is determined by the distribution of the associated energy deposition at different spatial scales. Radiation proceeds through ionizations and excitations of hit molecules with an ~ nm spacing. Approaches such as nanodosimetry/microdosimetry and Monte Carlo track-structure simulations have been successfully adopted to investigate radiation quality effects: they allow to explore correlations between the spatial clustering of such energy depositions at the scales of DNA or chromosome domains and their biological consequences at the cellular level. Physical features alone, however, are not enough to assess the entity and complexity of radiation-induced DNA damage: this latter is the result of an interplay between radiation track structure and the spatial architecture of chromatin, and further depends on the chromatin dynamic response, affecting the activation and efficiency of the repair machinery. The heterogeneity of radiation energy depositions at the single-cell level affects the trade-off between cell inactivation and induction of viable mutations and hence influences radiation-induced carcinogenesis. In radiation therapy, where the goal is cancer cell inactivation, the delivery of a homogenous dose to the tumour has been the traditional approach in clinical practice. However, evidence is accumulating that introducing heterogeneity with spatially fractionated beams (mini- and microbeam therapy) can lead to significant advantages, particularly in sparing normal tissues. Such findings cannot be explained in merely physical terms, and their interpretation requires considering the scales at play in the underlying biological mechanisms, suggesting a systemic response to radiation. [ABSTRACT FROM AUTHOR]

The relative biological effectiveness (RBE) calculations used during the planning of ion therapy treatments are generally based on the microdosimetric kinetic model (MKM) and the local effect model (LEM). The Mayo Clinic Florida MKM (MCF MKM) was recently developed to overcome the limitations of previous MKMs in reproducing the biological data and to eliminate the need for ion-exposed in vitro data as input for the model calculations. Since we are considering to implement the MCF MKM in clinic, this article presents (a) an extensive benchmark of the MCF MKM predictions against corresponding in vitro clonogenic survival data for 4 rodent and 10 cell lines exposed to ions from 1H to 238U, and (b) a systematic comparison with published results of the latest version of the LEM (LEM IV). Additionally, we introduce a novel approach to derive an approximate value of the MCF MKM model parameters by knowing only the animal species and the mean number of chromosomes. The overall good agreement between MCF MKM predictions and in vitro data suggests the MCF MKM can be reliably used for the RBE calculations. In most cases, a reasonable agreement was found between the MCF MKM and the LEM IV. [ABSTRACT FROM AUTHOR]

Plasmid DNA is useful for investigating the DNA damaging effects of ionizing radiation. In this study, we have explored the feasibility of plasmid DNA-based detectors to assess the DNA damaging effectiveness of two radiotherapy X-ray beam qualities after undergoing return shipment of ~8000 km between two institutions. The detectors consisted of 18   μ L of pBR322 DNA enclosed with an aluminum seal in nine cylindrical cavities drilled into polycarbonate blocks. We shipped them to Toronto, Canada for irradiation with either 100   kVp   or 6   MV   X-ray beams to doses of 10, 20, and 30 Gy in triplicate before being shipped back to San Diego, USA. The Toronto return shipment also included non-irradiated controls and we kept a separate set of controls in San Diego. In San Diego, we quantified DNA single strand breaks (SSBs), double strand breaks (DSBs), and applied Nth and Fpg enzymes to quantify oxidized base damage. The rate of DSBs/Gy/plasmid was 2.8 ± 0.7   greater for the 100 kVp than the 6 MV irradiation. The 100   kVp irradiation also resulted in 5 ± 2 times more DSBs/SSB than the 6   MV beam, demonstrating that the detector is sensitive enough to quantify relative DNA damage effectiveness, even after shipment over thousands of kilometers. [ABSTRACT FROM AUTHOR]

• Translation between European and Japanese RBE modelling for constraint validation. • Potential pitfalls for constraint definition in carbon ion radiotherapy of CNS. • RBE model translation trend outliers and their association with clinical toxicities. • Decision making process based on two RBE models, triggered by CNS toxicities. Carbon ion radiotherapy (CIRT) treatment planning is based on relative biological effectiveness (RBE) weighted dose calculations. A large amount of clinical evidence for CIRT was collected in Japan with RBE estimated by the modified microdosimetric kinetic model (MKM) while all European centres apply the first version of the local effect model (LEM). Japanese schedules have been used in Europe with adapted prescription dose and organs at risk (OAR) dose constraints. Recently, less conservative adapted LEM constraints have been implemented in clinical practice. The aim of this study was to analyse the new set of LEM dose constraints for brain parenchyma, brainstem and optic system considering both RBE models and evaluating early clinical data. 31 patients receiving CIRT at MedAustron were analysed using the RayStation v9A planning system by recalculating clinical LEM-based plans in MKM. Dose statistics (D1cm3, D5cm3, D0.1cm3, D0.7cm3, D10%, D20%) were extracted for relevant critical OARs. Curve fitting for those values was performed, resulting in linear quadratic translation models. Clinical and radiological toxicity was evaluated. Based on derived fits, currently applied LEM constraints matched recommended MKM constraints with deviations between −8% and +3.9%. For particular cases, data did not follow the expected LEM vs MKM trends resulting in outliers. Radiological (asymptomatic) toxicity was detected in two outlier cases. Respecting LEM constraints does not automatically ensure that MKM constraints are met. Constraints for both RBE models need to be fulfilled for future CIRT patients at MedAustron. Careful selection of planning strategies is essential. [ABSTRACT FROM AUTHOR]

The quality factor (Q) is formally linked to the stochastic (e.g., carcinogenic) risk of diverse ionizing radiations at low doses and/or low dose rates. Q can be a function of the non-stochastic physical quantity Linear Energy Transfer (LET) or the microdosimetric parameter lineal energy (y). These two physical quantities can be calculated either by Monte Carlo (MC) track-structure simulations or by analytic models. In this work, various generalized analytical models were utilized and combined to determine the proton lineal energy spectra in liquid water spheres of various sizes (i.e., 10–3000 nm diameter) over the proton energy range of 1–250 MeV. The calculated spectra were subsequently used within the Theory of Dual Radiation Action (TDRA) and the ICRU Report 40 microdosimetric methodologies to determine the variation of Q ¯ with proton energy. The results revealed that the LET-based Q values underestimated the microdosimetric-based Q ¯ values for protons with energy below ~100 MeV. At energies relevant to the Bragg peak region (<20–30 MeV), the differences were larger than 20–50%, while reaching 200–500% at ~5 MeV. It was further shown that the microdosimetric-based Q ¯ values for protons below ~100 MeV were sensitive to the sphere size. Finally, condensed-phase effects had a very small (<5%) influence on the calculated microdosimetric-based Q ¯ over the proton energy range considered here. [ABSTRACT FROM AUTHOR]

Purpose: Targeting the prostate-specific membrane antigen (PSMA) using lutetium-177-labeled PSMA-specific tracers has become a very promising novel therapy option for prostate cancer (PCa). The efficacy of this therapy might be further improved by replacing the β-emitting lutetium-177 with the α-emitting actinium-225. Actinium-225 is thought to have a higher therapeutic efficacy due to the high linear energy transfer (LET) of the emitted α-particles, which can increase the amount and complexity of the therapy induced DNA double strand breaks (DSBs). Here we evaluated the relative biological effectiveness of [225Ac]Ac-PSMA-I&T and [177Lu]Lu-PSMA-I&T by assessing in vitro binding characteristics, dosimetry, and therapeutic efficacy. Methods and results: The PSMA-expressing PCa cell line PC3-PIP was used for all in vitro assays. First, binding and displacement assays were performed, which revealed similar binding characteristics between [225Ac]Ac-PSMA-I&T and [177Lu]Lu-PSMA-I&T. Next, the assessment of the number of 53BP1 foci, a marker for the number of DNA double strand breaks (DSBs), showed that cells treated with [225Ac]Ac-PSMA-I&T had slower DSB repair kinetics compared to cells treated with [177Lu]Lu-PSMA-I&T. Additionally, clonogenic survival assays showed that specific targeting with [225Ac]Ac-PSMA-I&T and [177Lu]Lu-PSMA-I&T caused a dose-dependent decrease in survival. Lastly, after dosimetric assessment, the relative biological effectiveness (RBE) of [225Ac]Ac-PSMA-I&T was found to be 4.2 times higher compared to [177Lu]Lu-PSMA-I&T. Conclusion: We found that labeling of PSMA-I&T with lutetium-177 or actinium-225 resulted in similar in vitro binding characteristics, indicating that the distinct biological effects observed in this study are not caused by a difference in uptake of the two tracers. The slower repair kinetics of [225Ac]Ac-PSMA-I&T compared to [177Lu]Lu-PSMA-I&T correlates to the assumption that irradiation with actinium-225 causes more complex, more difficult to repair DSBs compared to lutetium-177 irradiation. Furthermore, the higher RBE of [225Ac]Ac-PSMA-I&T compared to [177Lu]Lu-PSMA-I&T underlines the therapeutic potential for the treatment of PCa. [ABSTRACT FROM AUTHOR]

Background: Proton relative biological effectiveness (RBE) is known to depend on physical factors of the proton beam, such as its linear energy transfer (LET), as well as on cell‐line specific biological factors, such as their ability to repair DNA damage. However, in a clinical setting, proton RBE is still considered to have a fixed value of 1.1 despite the existence of several empirical models that can predict proton RBE based on how a cell's survival curve (linear‐quadratic model [LQM]) parameters α and β vary with the LET of the proton beam. Part of the hesitation to incorporate variable RBE models in the clinic is due to the great noise in the biological datasets on which these models are trained, often making it unclear which model, if any, provides sufficiently accurate RBE predictions to warrant a departure from RBE = 1.1. Purpose: Here, we introduce a novel model of proton RBE based on how a cell's intrinsic radiosensitivity varies with LET, rather than its LQM parameters. Methods and materials: We performed clonogenic cell survival assays for eight cell lines exposed to 6 MV x‐rays and 1.2, 2.6, or 9.9 keV/µm protons, and combined our measurements with published survival data (n = 397 total cell line/LET combinations). We characterized how radiosensitivity metrics of the form DSF%, (the dose required to achieve survival fraction [SF], e.g., D10%) varied with proton LET, and calculated the Bayesian information criteria associated with different LET‐dependent functions to determine which functions best described the underlying trends. This allowed us to construct a six‐parameter model that predicts cells' proton survival curves based on the LET dependence of their radiosensitivity, rather than the LET dependence of the LQM parameters themselves. We compared the accuracy of our model to previously established empirical proton RBE models, and implemented our model within a clinical treatment plan evaluation workflow to demonstrate its feasibility in a clinical setting. Results: Our analyses of the trends in the data show that DSF% is linearly correlated between x‐rays and protons, regardless of the choice of the survival level (e.g., D10%, D37%, or D50% are similarly correlated), and that the slope and intercept of these correlations vary with proton LET. The model we constructed based on these trends predicts proton RBE within 15%–30% at the 68.3% confidence level and offers a more accurate general description of the experimental data than previously published empirical models. In the context of a clinical treatment plan, our model generally predicted higher RBE‐weighted doses than the other empirical models, with RBE‐weighted doses in the distal portion of the field being up to 50.7% higher than the planned RBE‐weighted doses (RBE = 1.1) to the tumor. Conclusions: We established a new empirical proton RBE model that is more accurate than previous empirical models, and that predicts much higher RBE values in the distal edge of clinical proton beams. [ABSTRACT FROM AUTHOR]

Purpose: We assessed whether adding sodium borocaptate (BSH) or 4‐borono‐l‐phenylalanine (BPA) to cells irradiated with proton beams influenced the biological effectiveness of those beams against prostate cancer cells to investigate if the alpha particles generated through proton–boron nuclear reactions would be sufficient to enhance the biological effectiveness of the proton beams. Methods: We measured clonogenic survival in DU145 cells treated with 80.4‐ppm BSH or 86.9‐ppm BPA, or their respective vehicles, after irradiation with 6‐MV X‐rays, 1.2‐keV/μm (low linear energy transfer [LET]) protons, or 9.9‐keV/μm (high‐LET) protons. We also measured γH2AX and 53BP1 foci in treated cells at 1 and 24 h after irradiation with the same conditions. Results: We found that BSH radiosensitized DU145 cells across all radiation types. However, no difference was found in relative radiosensitization, characterized by the sensitization enhancement ratio or the relative biological effectiveness, for vehicle‐ versus BSH‐treated cells. No differences were found in numbers of γH2AX or 53BP1 foci or γH2AX/53BP1 colocalized foci for vehicle‐ versus BSH‐treated cells across radiation types. BPA did not radiosensitize DU145 cells nor induced any significant differences when comparing vehicle‐ versus BPA‐treated cells for clonogenic cell survival or γH2AX and 53BP1 foci or γH2AX/53BP1 colocalized foci. Conclusions: Treatment with 11B, at concentrations of 80.4 ppm from BSH or 86.9 ppm from BPA, had no effect on the biological effectiveness of proton beams in DU145 prostate cancer cells. Our results agree with published theoretical calculations indicating that the contribution of alpha particles from such reactions to the total absorbed dose and biological effectiveness is negligible. We also found that BSH radiosensitized DU145 cells to X‐rays, low‐LET protons, and high‐LET protons but that the radiosensitization was not related to DNA damage. [ABSTRACT FROM AUTHOR]

In this review article, we review the 3 important aspects of linear-energy-transfer (LET) in intensity-modulated proton therapy (IMPT) for head and neck (H&N) cancer management. Accurate LET calculation methods are essential for LET-guided plan evaluation and optimization, which can be calculated either by analytical methods or by Monte Carlo (MC) simulations. Recently, some new 3D analytical approaches to calculate LET accurately and efficiently have been proposed. On the other hand, several fast MC codes have also been developed to speed up the MC simulation by simplifying nonessential physics models and/or using the graphics processor unit (GPU)– acceleration approach. Some concepts related to LET are also briefly summarized including (1) dose-weighted versus fluence-weighted LET; (2) restricted versus unrestricted LET; and (3) microdosimetry versus macrodosimetry. LET-guided plan evaluation has been clinically done in some proton centers. Recently, more and more studies using patient outcomes as the biological endpoint have shown a positive correlation between high LET and adverse events sites, indicating the importance of LET-guided plan evaluation in proton clinics. Various LET-guided plan optimization methods have been proposed to generate proton plans to achieve biologically optimized IMPT plans. Different optimization frameworks were used, including 2-step optimization, 1-step optimization, and worst-case robust optimization. They either indirectly or directly optimize the LET distribution in patients while trying to maintain the same dose distribution and plan robustness. It is important to consider the impact of uncertainties in LET-guided optimization (ie, LET-guided robust optimization) in IMPT, since IMPT is sensitive to uncertainties including both the dose and LET distributions. We believe that the advancement of the LET-guided plan evaluation and optimization will help us exploit the unique biological characteristics of proton beams to improve the therapeutic ratio of IMPT to treat H&N and other cancers.

A thin diamond membrane energy-dispersive dosimeter 50 μm thick was fabricated for estimating clinical dose distribution. In contrast to conventional semiconductors, diamond wide-bandgap semiconductors are expected to have excellent radiation tolerance and biological compatibility based on the linear relationship of stopping power ratio for clinical carbon particles. Linear energy transfer (LET) spectra were obtained along with the Bragg curve for a clinical carbon beam generated at Gunma University Heavy Ion Medical Center. The relative biological effectiveness (RBE) distributions were estimated from the LET spectra for both the mono-energy and spread-out Bragg peak irradiation configurations. The diamond detector was also used as a solid ionization chamber to obtain the radiation-induced current (RIC) distribution, which represents the physical dose distribution. The clinical dose distribution was estimated from the RIC and RBE distributions as proof of concept for the clinical carbon beam therapy field with a single-chip diamond energy-dispersive dosimeter. [ABSTRACT FROM AUTHOR]

Background: The effectiveness of ionizing radiation regarding DNA damage induction depends on its spatial energy deposition pattern. For electrons an increased effectiveness is observed at low kinetic energies due to the enhanced density of energy deposition events at electron track ends. Purpose: A model is presented, which enables the calculation of the double‐strand‐break (DSB) yield and the relative biological effectiveness (RBE) for DSB induction of electrons. Methods: The model applies the mean free path between two ionizations and the assumption that two ionizations within a certain threshold distance are necessary to potentially lead to a DSB. Next to an expression for the electron RBE according to its common definition, a local RBE is determined, which describes the electrons' local effectiveness at a defined point on their track. Results: This local RBE allows a better understanding of microscopic processes resulting from radiation and can be used, for instance, to describe the mean effectiveness of the mixed electron radiation field as a function of the radial distance to the center of an ion track. Conclusions: The presented model reflects the experimentally observed increased effectiveness of low‐energetic electrons. It will be used in a future work to improve RBE predictions for ions performed with the local effect model. [ABSTRACT FROM AUTHOR]

Background: Ion beam therapy allows for substantial sparing of normal tissues. Besides deterministic normal‐tissue complications, stochastic long‐term effects like secondary cancer (SC) induction are of importance when comparing different treatment modalities. Purpose: To develop a modeling approach for comparison of SC risk in proton and carbon ion therapy. Methods and Materials: The local effect model (LEM) is used to predict the relative biological effectiveness (RBE) of SC induction after particle therapy. A key feature of the new approach is the double use of the LEM, reflecting the competition between the two processes of mutation induction (leading to cancer development) and cell inactivation (leading to suppression of cancer development). Based on previous investigations, treatment plans were in this work analyzed for an idealized geometry in order to assess the underlying systematic dependencies of cancer induction. In a further step, relative SC risks were predicted for proton and carbon ion treatment plans prepared for 10 prostate cancer patients. Results: We investigated the impact of factors such as treatment plan geometry, fractionation scheme, and tissue radiosensitivity to photon irradiation on the ion beam SC risk. Our model studies do not result in a clear preference for either protons or carbon ions, but rather indicate a complex interplay of different aspects. Reduced lateral scattering leads to a lower SC risk for carbon ions compared to protons at the lateral field margins in the entrance channel, while an increased risk was found closely behind the tumor due to projectile fragmentation. The fractionation scheme had little impact on the expected risk ratio. With respect to sensitivity parameters, those characterizing RBE for cell killing of potentially cancerous cells as well as of the primary tumor had the most significant impact. The observed general systematic dependencies are in agreement with results from previous model studies. The prostate patient study reveals reduced SC risks predictions for skin and bones for carbon ions as compared to protons, but higher mean risks for bladder and rectum. Conclusion: The methods established in this work provide a basis for further investigating treatment optimizing strategies for ion beam therapy with regard to SC risk comparisons. [ABSTRACT FROM AUTHOR]

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 192Ir rBT applicators, Valencia and Leipzig, one 60Co 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. [ABSTRACT FROM AUTHOR]

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 β 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 β 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. [ABSTRACT FROM AUTHOR]

Experimental microdosimetry along with the microdosimetric kinetic (MK) model can be utilized to predict the biological effects of ions. To predict the relative biological effectiveness (RBE) of ions and the survival fraction (SF) of human salivary gland tumour (HSGc-C5) cells, microdosimetric quantities measured by a silicon-on-insulator (SOI) MicroPlus-mushroom microdosimeter along the spread-out Bragg peak (SOBP) delivered by pencil beam scanning of 4He, 12C, 16O, and 20Ne ions were used. The MK model parameters of HSGc-C5 cells were obtained from the best fit of the calculated SF for the different linear energy transfer (LET) of these ions and the formerly reported in vitro SF for the same LET and ions used for calculations. For a cube-shaped target of 10 × 10 × 6 cm3, treatment plans for 4He, 12C, 16O, and 20Ne ions were produced with proprietary treatment planning software (TPS) aiming for 10% SF of HSGc-C5 cells over the target volume and were delivered to a polymethyl methacrylate (PMMA) phantom. Afterwards, the saturation-corrected dose-mean lineal energy derived based on the measured microdosimetry spectra, along with the physical dose at various depths in PMMA phantoms, was used for the estimation of the SF, RBE, and RBE-weighted dose using the MK model. The predicted SF, RBE, and the RBE-weighted dose agreed with what was planned by the TPS within 3% at most depths for these ions. [ABSTRACT FROM AUTHOR]

Although clinical studies with carbon ions have been conducted successfully in Japan and Europe, the limited radiobiological information about charged particles that are heavier than protons remains a significant impediment to exploiting the full potential of particle therapy. There is growing interest in the U.S. to build a cancer treatment facility that utilizes charged particles heavier than protons. Therefore, it is essential that additional radiobiological knowledge be obtained using state-of-the-art technologies and biological models and end points relevant to clinical outcome. Currently, most such ion radiotherapy-related research is being conducted outside the U.S. This article addresses the substantial contributions to that research that are possible at the NASA Space Radiation Laboratory (NSRL) at Brookhaven National Laboratory (BNL), which is the only facility in the U.S. at this time where heavy-ion radiobiology research with the ion species and energies of interest for therapy can be done. Here, we briefly discuss the relevant facilities at NSRL and how selected charged particle biology research gaps could be addressed using those facilities.

Increased cancer risk remains a primary concern for travel into deep space and may preclude manned missions to Mars due to large uncertainties that currently exist in estimating cancer risk from the spectrum of radiations found in space with the very limited available human epidemiological radiation-induced cancer data. Existing data on human risk of cancer from X-ray and gamma-ray exposure must be scaled to the many types and fluences of radiations found in space using radiation quality factors and dose-rate modification factors, and assuming linearity of response since the shapes of the dose responses at low doses below 100 mSv are unknown. The goal of this work was to reduce uncertainties in the relative biological effect (RBE) and linear energy transfer (LET) relationship for space-relevant doses of charged-particle radiation-induced carcinogenesis. The historical data from the studies of Fry et al. and Alpen et al. for Harderian gland (HG) tumors in the female CB6F1 strain of mouse represent the most complete set of experimental observations, including dose dependence, available on a specific radiation-induced tumor in an experimental animal using heavy ion beams that are found in the cosmic radiation spectrum. However, these data lack complete information on low-dose responses below 0.1 Gy, and for chronic low-dose-rate exposures, and there are gaps in the LET region between 25 and 190 keV/μm. In this study, we used the historical HG tumorigenesis data as reference, and obtained HG tumor data for 260 MeV/u silicon (LET ∼70 keV/μm) and 1,000 MeV/u titanium (LET ∼100 keV/μm) to fill existing gaps of data in this LET range to improve our understanding of the dose-response curve at low doses, to test for deviations from linearity and to provide RBE estimates. Animals were also exposed to five daily fractions of 0.026 or 0.052 Gy of 1,000 MeV/u titanium ions to simulate chronic exposure, and HG tumorigenesis from this fractionated study were compared to the results from single 0.13 or 0.26 Gy acute titanium exposures. Theoretical modeling of the data show that a nontargeted effect model provides a better fit than the targeted effect model, providing important information at space-relevant doses of heavy ions.

We report the effects of gold nanoparticles (GNP) on the enhancement of the dose effect and double-strand break (DSB) induction for X-ray monoenergies (10 keV–2 MeV). The overall relative biological effectiveness (RBE) was defined as the product of dose and DSB enhancement. The cellular doses and energy spectra were computed using the PENELOPE (PENetration and Energy LOss of Positrons and Electrons) code. The DNA damage yields were estimated using the MCDS (Monte Carlo damage simulation) code. Considering the production of Auger electrons induced by 7mg/ml GNP, we found that dose enhancement at the 30 keV was ~4.0 for cells with radius $4~\mu \text{m}$ . The DSB induction increased as GNP concentrations increased and was dependent on X-ray energy. These findings demonstrated that the maximum RBE was attained at 30–40 keV and therefore this energy range would be more efficient in cancer cell killing.

Purpose: To retrospectively investigate empirical relative biological effectiveness (RBE) for mandible osteoradionecrosis (ORN) in head and neck (H&N) cancer patients treated with pencil-beam-scanning proton therapy (PBSPT). Methods: We included 1,266 H&N cancer patients, of which, 931 patients were treated with volumetric-modulated arc therapy (VMAT) and 335 were treated with PBSPT. Among them, 26 VMAT and 9 PBSPT patients experienced mandible ORN (ORN group), while all others were included in the control group. To minimize the impact of the possible imbalance in clinical factors between VMAT and PBSPT patients in the dosimetric comparison between these two modalities and the resulting RBE quantification, we formed a 1:1 case-matched patient cohort (335 VMAT patients and 335 PBSPT patients including both the ORN and control groups) using the greedy nearest neighbor matching of propensity scores. Mandible dosimetric metrics were extracted from the case-matched patient cohort and statistically tested to evaluate the association with mandibular ORN to derive dose volume constraints (DVCs) for VMAT and PBSPT, respectively. We sought the equivalent constraint doses for VMAT so that the critical volumes of VMAT were equal to those of PBSPT at different physical doses. Empirical RBEs of PBSPT for ORN were obtained by calculating the ratio between the derived equivalent constraint doses and physical doses of PBSPT. Bootstrapping was further used to get the confidence intervals. Results: Clinical variables of age, gender, tumor stage, prescription dose, chemotherapy, hypertension or diabetes, dental extraction, smoking history, or current smoker were not statistically related to the incidence of ORN in the overall patient cohort. Smoking history was found to be significantly associated with the ORN incidence in PBSPT patients only. V40Gy[RBE], V50Gy[RBE], and V60Gy[RBE] were statistically different (p <0.05) between the ORN and control group for VMAT and PBSPT. Empirical RBEs of 1.58(95%CI: 1.34-1.64), 1.34(95%CI: 1.23-1.40), and 1.24(95%: 1.15-1.26) were obtained for proton dose at 40 Gy[RBE=1.1], 50 Gy[RBE=1.1] and 60 Gy[RBE=1.1], respectively. Conclusions: Our study suggested that RBEs were larger than 1.1 at moderate doses (between 40 and 60 Gy[RBE=1.1]) with high LET for mandible ORN. RBEs are underestimated in current clinical practice in PBSPT. The derived DVCs can be used for PBSPT plan evaluation and optimization to minimize the incidence rate of mandible ORN. [ABSTRACT FROM AUTHOR]

PurposeTo retrospectively investigate empirical relative biological effectiveness (RBE) for mandible osteoradionecrosis (ORN) in head and neck (H&N) cancer patients treated with pencil-beam-scanning proton therapy (PBSPT).MethodsWe included 1,266 H&N cancer patients, of which, 931 patients were treated with volumetric-modulated arc therapy (VMAT) and 335 were treated with PBSPT. Among them, 26 VMAT and 9 PBSPT patients experienced mandible ORN (ORN group), while all others were included in the control group. To minimize the impact of the possible imbalance in clinical factors between VMAT and PBSPT patients in the dosimetric comparison between these two modalities and the resulting RBE quantification, we formed a 1:1 case-matched patient cohort (335 VMAT patients and 335 PBSPT patients including both the ORN and control groups) using the greedy nearest neighbor matching of propensity scores. Mandible dosimetric metrics were extracted from the case-matched patient cohort and statistically tested to evaluate the association with mandibular ORN to derive dose volume constraints (DVCs) for VMAT and PBSPT, respectively. We sought the equivalent constraint doses for VMAT so that the critical volumes of VMAT were equal to those of PBSPT at different physical doses. Empirical RBEs of PBSPT for ORN were obtained by calculating the ratio between the derived equivalent constraint doses and physical doses of PBSPT. Bootstrapping was further used to get the confidence intervals.ResultsClinical variables of age, gender, tumor stage, prescription dose, chemotherapy, hypertension or diabetes, dental extraction, smoking history, or current smoker were not statistically related to the incidence of ORN in the overall patient cohort. Smoking history was found to be significantly associated with the ORN incidence in PBSPT patients only. V40Gy[RBE], V50Gy[RBE], and V60Gy[RBE] were statistically different (p

The 2 Gy per fraction equivalent dose (EQD 2 ) is an important quantity used in determining equivalent prescription doses for different fractionation regimens and evaluating different fractionation regimens, but it does not match its definition when it is used for normal tissues. We propose to use the fractionation-specific biological equivalent dose to determine normal tissue dose constraints for different fractionation regimens. The concept of the biological equivalent dose is defined based on the linear-quadratic equation. The EQD 2 is derived based on the biological effective dose (BED), mimicking the prescription dose of a standard fractionation regimen with a fractional dose of 2 Gy and a fixed number of fractions. The FEQD(n) is also defined based on the BED as a function of the number of fractions, n, which is determined by the dose prescription. The FEQD(n) mimics any fractionation regimens with any fractional doses and numbers of fractionations. A given dose constraint can have different BED values and EQD 2 values for different fractionation regimens. The number of fractions for a given 2 Gy per fraction regimen derived from the EQD 2 for the target dose is different from that for the normal tissues. The value of the EQD2 derived for the target represents the total dose for the target for the 2 Gy fractional dose regimen, but the EQD 2 value derived for the normal tissues does not represent the total dose for the normal tissue for the same fractionation regimen. The fractionation-specific biological equivalent dose (FEQD(n)) for both target and normal tissues has the same number of fractions for any fractionation regimen, and represents the total dose for either the target or the normal tissue. Based on the clinical outcomes, the FEQD(n) curves for the brainstem, spinal cord, rectum, and lung were derived and can be directly used as dose constraints for various fractionation regimens in clinical practice. The EQD 2 does not match its definition and is not realistic when describing the biological equivalent dose for normal tissues. It is also not practical when used in determining tolerance doses or dose constraints. Instead, the FEQD(n) can be used to determine or convert the normal tissue dose constraints for any fractionation regimens in a realistic and practical manner. Using the FEQD(n), the dose constraints as a function of the number of fractions for the brainstem, spinal cord, rectum, and lung, which correspond to the given toxicity rates, were derived and can be directly used in clinical practice.

Objective. While the biological effective dose (BED) has been used to estimate the damage to tumor cells in radiotherapy, BED does not consider intrafractional interruption (IFI) occurring during irradiation. We aim to develop a framework to evaluate the decrease in BED [ΔBED] and to create a plan compensating for the decrease by IFI. Approach. ΔBEDwas calculated using a model based on the microdosimetric kinetic model (MKM) for four brain tumor cases treated using a volumetric-modulated arc therapy. Four biologically compensated plans (BCPs) were created in the treatment planning system by a single-time optimization using a base plan consideringΔBEDcreated in in-house software and optimization objectives for the original clinically delivered plan to achieve a homogeneous BED distribution within the planning target volume (PTV). The BED-volume histogram was evaluated for non-compensated plan and BCP with different timepoint of interruption, a percentage of gantry rotation angle (GRA) before interruption in planned GRA,ηand duration of interruptionτ. Characteristics of the dose accumulation were analyzed for different collimator angle sets, Plan A (10°, 85°) and Plan B (45° and 315°), for the first case. Main Results. Hot spots in theΔBEDdistribution forη= 25%, 50%, and 75% were observed at superior-and-interior ends, central region, and peripheral region in PTV, respectively. These behaviors could be understood by characteristics of the MKM-based model producing maximumΔBEDat 50% of the dose accumulation.ΔBED50%ranged 4.5%-6.6%, 5.0%-7.3%, and 5.3%-7.7% forτ= 60, 90, and 120 min, respectively. Plan A showed fast dose accumulation at superior and inferior edges while slow on peripheries in the lateral dose profile. Plan B showed more homogeneous PD distributions than Plan A during irradiation. Significance. The developed framework successfully evaluated and compensated for the decreased BED distribution., (© 2024 IOP Publishing Ltd. All rights, including for text and data mining, AI training, and similar technologies, are reserved.)

Thermal neutrons generated in the body during proton beam therapy (PBT) can be used to cause boron neutron capture reactions and have recently been proposed as neutron capture enhanced PBT (NCEPBT). However, the cell killing effect of NCEPBT remains underexplored. Here, we show an increase in the cell killing effect of NCEPBT. Using Monte Carlo simulations, we showed that neutrons generated by proton beam irradiation are uniformly spread on tissue culture plates. Human salivary gland tumor cell line (HSG), human osteosarcoma cell line (MG63), human tongue squamous cell carcinoma cell line (SAS), and human malignant melanoma cell line (G-361) were irradiated with X-rays, proton beams, and proton beams with 10 B-enriched boronophenylalanine (boron concentration of 20 and 80 ppm). The relative biological effectiveness (RBE) values of proton beams alone, proton beams with 20 ppm boron, and proton beams with 80 ppm boron for HSG, MG63, SAS, and G-361 were 1.02, 1.07, and 1.23; 1.01, 1.08, and 1.44; 1.05, 1.09, and 1.46; and 1.04, 1.13, and 1.63, respectively. NCEPBT with high boron concentration showed high RBE and a high sensitizing effect. Our results confirm an increase in the cell killing effect of NCEPBT, should aid in its clinical use, and warrant its further investigation., Competing Interests: Declarations Competing interests Boronophenylalanine used in this study was provided by Stella Pharma Corporation (Japan). Tatsuya Ohno received research funding from Hitachi. All other authors declare no conflict of interest., (© 2024. The Author(s).)

The method combining Monte Carlo (MC) simulation and mesh-type cell models provides a way to accurately assess the cellular dose induced by β -emitters. Although this approach allows for a specific evaluation of various nuclides and cell type combinations, the associated time cost for obtaining results is relatively high. In this work, we propose a Microdosimetric assessment method for Internal exposure of β -emitters based on Mesh-type Cell cluster models (abbreviated as MIMC- β ). This approach is applied to evaluate the dose in various types of cells (human bronchial epithelial cells, BEAS-2B; normal human liver cells, L-O2; and normal human small intestine epithelial cells, FHs74Int) exposed to β -emitters. Furthermore, microdosimetric quantity based on the cell cluster model are employed to estimate the relative biological effectiveness (RBE) of β -emitters. The results indicate that this method can accurately and rapidly predict cellular doses caused by different types of β -emitters, significantly mitigating the efficiency challenges associated with directly employing MC to estimate the overall dose of the mesh-type cell cluster model. In comparison with results obtained from direct simulations of uniform administration of β - sources using PHITS for validation, the cellular cluster overall S -values obtained through MIMC- β show discrepancies mostly below 5%, with the minimum deviation reaching 1.35%. Small sampling sizes within the cell nucleus led to larger average lineal energies. In comparison to C-14, the differences in cellular cluster average lineal energy for Cs-134, Cs-137, and I-131 are negligible, resulting in close numerical estimations of RBE based on lineal energy. The MIMC- β can be extended to diverse cell types and β -emitters. Additionally, the RBE assessment based on the cell cluster model offers valuable insights for predicting radiobiological damage resulting from internal exposure by β -emitters. This method is expected to find applicability in various realistic scenarios, including radiation protection and radioligand therapy., (© 2024 Institute of Physics and Engineering in Medicine. All rights, including for text and data mining, AI training, and similar technologies, are reserved.)

Combined proton-neutron therapy can be the best opportunity for neutron radiation therapy due to highly conformal proton irradiation and high relative biological effectiveness of neutrons. The study compares 4 schemes of sequential in vitro exposure of Chinese hamster fibrosarcoma cells B14-150 to 14.5 MeV neutrons and a scanning beam of protons. Treatment efficiency increased with increasing the contribution of the neutron component to the total dose from 30 to 40% and the delivery of the neutron dose as the first fraction in the two-fraction proton-neutron exposure., (© 2024. Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: The radio-surgical literature increasingly uses biological effective dose (BED) as a replacement for absorbed dose to analyze outcome of stereotactic radiosurgery (SRS). There are as yet no studies which specifically investigate the association of BED to local tumor control in para-sellar meningioma., Methods: we did a retrospective analysis of patients underwent stereotactic radiosurgery (SRS) for para-sellar meningioma during the period of 1995-2022. Demographic, clinical, SRS parameters, and outcome data were collected. The target margin BED with and without a model for sub-lethal repair was calculated, as well as a ratio of BED at the target margin to the absorbed dose at the target margin. Factors related to local control were further analyzed., Results: The study was comprised of 91 patients, 20 (22.0%) and 71 (78.0%) of whom were male and female, respectively. The median age was 55.0 (interquartile range Q1, Q3:47.5,65.5years). 34 (37%) patients had a resection of their meningioma prior to SRS. The median interval from SRS to last clinical follow up or progression was 89 months. 13 (14.3%) patients were found to have progression. 3-, 5- and 10-years local tumor control were 98%, 92% and 77%, respectively. In cox univariate analysis, the following factors were significant: Number of prior surgical resections (Hazard Ratio [HR] = 1.82, 95% CI = 1.08-3.05, p = 0.024), BED (HR = 0.96, 95% CI = 0.92-1.00, p = 0.03), and BED/margin (HR = 0.44, 95% CI = 0.21-0.92, p = 0.028). A BED threshold above 68 Gy was associated significantly with tumor control (P = 0.04)., Conclusion: BED and BED /margin absorbed dose ratio can be predictors of local control after SRS in parasellar meningioma. Optimizing the BED above 68Gy 2.47 may afford better long-term tumor control., (© 2024. The Author(s).)

Objective . We propose a criterion of biological effectiveness of nonuniform hypoxia-targeted dose distributions in heterogeneous hypoxic tumors based on equivalent uniform aerobic dose (EUAD). We demonstrate the utility of this criterion by applying it to the model problems in radiotherapy for tumors with different levels of oxygen enhancement ratio (OER) and different degrees of dose nonuniformity. Approach . The EUAD is defined as the uniform dose that, under well-oxygenated conditions, produces equal integrated survival of clonogenic cells in radiotherapy for heterogeneous hypoxic tumors with a non-uniform dose distribution. We define the dose nonuniformity effectiveness (DNE) in heterogeneous tumors as the ratio of the EUAD( D N ) for a non-uniform distribution D N and the reference EUAD( D U ) for the uniform dose distribution D U with equal integral tumor dose. The DNE concept is illustrated in a radiotherapy model problem for non-small cell lung cancer treated with hypoxia targeted dose escalation. A two-level cell population tumor model was used to consider the hypoxic and oxygenated tumor cells. Results . Theoretical analysis of the DNE shows that the entire region of the OER can be separated in two regions by a threshold OER th : (1) OER > OER th where DNE > 1 indicating higher effectiveness of nonuniform dose distributions and (2) OER < OER th where DNE < 1 indicating higher effectiveness of uniform dose distributions. Our simulations show that the value of the threshold OER th in radiotherapy with conventional fractionation is significant in the range of about 1.2-1.6 depending on selected radiotherapy parameters. In general, the OER th increases with reoxygenation rate, relative hypoxic volume and dose escalation factor. The threshold value of OER th is smaller of about 1.1 for hypofractionated radiotherapy. Significance . The analysis of dose distributions using the DNE shows that the uniform dose distributions may improve biological cell killing effect in heterogeneous tumors with intermediate oxygen levels compared to targeted nonuniform dose distribution., (© 2024 IOP Publishing Ltd. All rights, including for text and data mining, AI training, and similar technologies, are reserved.)

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).)

The relative biological effectiveness (RBE) of densely ionizing radiation can depend on the biological context. From a radiological perspective, age is an important factor affecting health risks of radiation exposure, but little is known about the modifying impact of age on the effects of densely ionizing radiation. Herein, we addressed the influence of age on leukemogenesis induced by accelerator-generated fast neutrons (mean energy, ∼2 MeV). Male C3H/HeNrs mice were exposed to 137Cs γ rays (0.2-3.0 Gy) or neutrons (0.0485-0.97 Gy, γ ray contamination 0.0105-0.21 Gy) at 1, 3, 8, or 35 weeks of age and observed over their lifetimes under specific pathogen-free conditions. Leukemia and lymphoma were diagnosed pathologically. Hazard ratio (HR) and RBE for myeloid leukemia mortality as well as the age dependence of these two parameters were modeled and analyzed using Cox regression. Neutron exposure increased HR concordant with a linear dose response. The increase of HR per dose depended on age at exposure, with no significant dose dependence at age 1 or 3 weeks but a significant increase in HR of 5.5 per Gy (γ rays) and 16 per Gy (neutrons) at 8 weeks and 5.8 per Gy (γ rays) and 9 per Gy (neutrons) at 35 weeks. The RBE of neutrons was 2.1 (95% confidence interval, 1.1-3.7), with no dependence on age. The development of lymphoid neoplasms was not related to radiation exposure. The observed increasing trend of radiation-associated mortality of myeloid leukemia with age at exposure supports previous epidemiological and experimental findings. The results also suggest that exposure at the susceptible age of 8 or 35 weeks does not significantly influence the RBE value for neutrons for induction of leukemia, unlike what has been documented for breast and brain tumors., (© 2024 by Radiation Research Society. All rights of reproduction in any form reserved.)

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.)

Background: Recent studies suggest strong correlations between Biologically Effective Doses (BED) and single fraction stereotactic radiosurgery treatment outcomes, as demonstrated for vestibular schwannomas (VS), arterio-venous malformations and pituitary adenomas. The BEDs calculated in these studies consider an uniform dose delivery where the spatio-temporal aspects of dose delivery were neglected., Purpose: The aim of the study is to quantify the discrepancies between the BED values calculated with a simplified model of uniform dose delivery against the more complex model that incorporates the temporo-spatial incrementation of dose delivery and the bi-exponential effect of the sub-lethal damage repair., Methods: A software tool that computes the BED distributions based on individual isocenter dose matrices extracted from the GammaPlan (Elekta) treatment planning was developed. Two cohorts 5 VS and 5 jugular foramen schwannoma cases of various tumor volumes and isocenter number were utilized to benchmark the method. Their BEDs covering 98% of tumor volumes were compared against those determined with the uniform delivery model., Results: The BEDs covering 98% of the tumor volumes as calculated with both models show an approximately linear dependency with the treatment time. For all studied cases, the uniform delivery model overestimates the BEDs calculated with the full spatio-temporal delivery model. This discrepancy seems to accentuate with the tumor volume and treatment complexity., Conclusions: Despite their resemblance, the BED distributions provide a plethora of BED measures more suitable to characterize clinical outcomes than the unique peripheral BED value calculated with the simplified model of uniform dose delivery., 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.)

Objective. The energy deposition of photons and protons differs. It depends on the position in the proton Bragg peak (BP) and the linear energy transfer (LET) leading to a variable relative biological effectiveness (RBE). Here, we investigate LET dependent alterations on metabolic viability and proliferation of sarcoma and endothelium cell lines following proton irradiation in comparison to photon exposure. Approach. Using a multi-step range shifter, each column of a 96-well plate was positioned in a different depth along four BP curves with increasing intensities. The high-throughput experimental setup covers dose, LET, and RBE changes seen in a treatment field. Photon irradiation was performed to calculate the RBE along the BP curve. Two biological information out of one experiment were extracted allowing a correlation between metabolic viability and proliferation of the cells. Main results. The metabolic viability and cellular proliferation were column-wise altered showing a depth-dose profile. Endothelium cell viability recovers within 96 h post BP irradiation while sarcoma cell viability remains reduced. Highest RBE values were observed at the BP distal fall-off regarding proliferation of the sarcoma and endothelial cells. Significance. The high-throughput experimental setup introduced here (I) covers dose, LET, and RBE changes seen in a treatment field, (II) measures short-term effects within 48 h to 96 h post irradiation, and (III) can additionally be transferred to various cell types without time consuming experimental adaptations. Traditionally, RBE values are calculated from clonogenic cell survival. Measured RBE profiles strongly depend on physical characteristics such as dose and LET and biological characteristics for example cell type and time point. Metabolic viability and proliferation proofed to be in a similar effect range compared to clonogenic survival results. Based on limited data of combined irradiation with doxorubicin, future experiments will test combined treatment with systemic therapies applied in clinics e.g. cyclin-dependent inhibitors., (Creative Commons Attribution license.)

This study introduces the MKM&#95;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&#95;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&#95;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.)