OBJECTIVE: Carbon-ion radiotherapy (CiRT) has been used for the treatment of locally advanced pancreatic cancer (LAPC) with uniform dose plan. The aim of the present study is to investigate the effectiveness of a simultaneous integrated boost (SIB) technique with scanned CiRT against LAPC.
METHODS: Data of 21 patients with LAPC were used to compare two treatment planning approaches: a conventional uniform dose approach and a SIB approach. A relative biological effectiveness (RBE)-weighted dose (DRBE) of 55.2 Gy (RBE) in 12 fractions was prescribed to the planning target volume (PTV) in the conventional approach. In the SIB approach, DRBE of 67.2 Gy (RBE) and 43.2 Gy (RBE) in 12 fractions were prescribed to a high-risk PTV (HR-PTV) and low-risk PTV (LR-PTV), respectively. The DRBE and dose-averaged linear energy transfer (LETd) of targets and gastrointestinal tracts as organs at risk (OARs) were evaluated.
RESULTS: The HR-PTV D90% and LR-PTV D90% were 64.4±0.6 and 42.5±0.1 Gy (RBE) in SIB approach compared to the PTV D90% of 54.1±0.4 Gy (RBE) in the conventional approach. All SIB plans achieved the D2cc lower than 46 Gy (RBE) and V30 lower than 4 cm3 within OARs. The SIB approach increased the minimum LETd within the GTV to 44 keV/μm or higher for 20 out of 21 patients as compared to 16 out of 21 patients in the conventional approach.
CONCLUSIONS: The SIB approach effectively increased the RBE-weighted dose and LETd within the HR-PTV and GTV by accumulating the high-LET stopping carbon-ions into the HR-PTV in addition to the decreased RBE-weighted dose to OARs.

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 (MSRS), 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. .

Objective.This study simulated the potential of gold nanoparticles (GNPs) to improve the effectiveness of radiation therapy in pancreatic cancer cases. The purpose of this study was to assess the impact of GNPs on tumor control probability (TCP) and normal tissue complication probability (NTCP) in pancreatic cancer cases undergoing radiation therapy. The work aimed to compare treatment plans generated with a novel 2.5 MV beam using GNPs to conventional 6 MV plans and evaluate the dose-volume histogram (DVH), TCP, and NTCP.Approach.Treatment planning for five pancreatic computed tomography (CT) images was performed using the open-source MATLAB-based treatment planning program matRad. MATLAB codes were developed to calculate the relative biological effectiveness (RBE) of GNPs and apply the corresponding dose and RBE values to each voxel. TCP and NTCP were calculated based on the applied RBE values.Main results.Adding GNPs to the 2.5 MV treatment plan resulted in a significant increase in TCP, from around 59% to 93.5%, indicating that the inclusion of GNPs improved the effectiveness of the radiation treatment. The range in NTCP without GNPs was relatively larger compared to that with GNPs.Significance.The results indicated that the addition of GNPs to a 2.5 MV plan can increase TCP while maintaining a relatively low NTCP value (<1%). The use of GNPs may also reduce NTCP values by decreasing the dose to normal tissues while maintaining the same prescribed dose to the tumor. Hence, the addition of GNPs can improve the balance between TCP and NTCP.

OBJECTIVE: To model relative biological effectiveness (RBE) differences found in two studies which used spread-out Bragg-peaks (SOBP) placed at (a) superficial depth and (b) at the maximum range depth. For pencil beam scanning (PBS), RBE at similar points within the SOBP did not change between the two extreme SOBP placement depths; in passively scattered beams (PSB), high RBE values (typically 1.2-1.3) were found within superficially- placed SOBP but reduced to lower values (1-1.07) at similar points within the extreme-depth positioned SOBP. The dose, LET (linear energy transfer) distributions along each SOBP were closely comparable regardless of placement depth, but significant changes in dose rate occurred with depth in the PSB beam.
METHODS: The equations used allow α and β changes with falling dose rate (the converse to FLASH studies) in PSB, resulting in reduced α/β ratios, compatible with a reduction in micro-volumetric energy transfer (the product of Fluence and LET), with commensurate reductions in RBE. The experimental depth-distances, positions within SOBP, observed dose-rates and radiosensitivity ratios were used to estimate the changes in RBE.
RESULTS: RBE values within a 5 % tolerance limit of the experimental results for PSB were found at the deepest SOBP placement. No RBE changes were predicted for PBS beams, as in the published results.
CONCLUSIONS: Enhanced proton therapy toxicity might occur with PBS when compared with PSB for deeply positioned SOBP due to the maintenance of higher RBE. Scanned pencil beam users need to be vigilant about RBE and further research is indicated.

BACKGROUND: In current clinical practice, intensity-modulated proton therapy (IMPT) head and neck cancer (HNC) plans are generated using a constant relative biological effectiveness (cRBE) of 1.1. The primary goal of this study was to explore the dosimetric impact of proton range uncertainties on RBE-weighted dose (RWD) distributions using a variable RBE (vRBE) model in the context of bilateral HNC IMPT plans.
METHODS: The current study included the computed tomography (CT) datasets of ten bilateral HNC patients who had undergone photon therapy. Each patient\'s plan was generated using three IMPT beams to deliver doses to the CTV_High and CTV_Low for doses of 70 Gy(RBE) and 54 Gy(RBE), respectively, in 35 fractions through a simultaneous integrated boost (SIB) technique. Each nominal plan calculated with a cRBE of 1.1 was subjected to the range uncertainties of ±3%. The McNamara vRBE model was used for RWD calculations. For each patient, the differences in dosimetric metrices between the RWD and nominal dose distributions were compared.
RESULTS: The constrictor muscles, oral cavity, parotids, larynx, thyroid, and esophagus showed average differences in mean dose (Dmean) values up to 6.91 Gy(RBE), indicating the impact of proton range uncertainties on RWD distributions. Similarly, the brachial plexus, brain, brainstem, spinal cord, and mandible showed varying degrees of the average differences in maximum dose (Dmax) values (2.78-10.75 Gy(RBE)). The Dmean and Dmax to the CTV from RWD distributions were within ±2% of the dosimetric results in nominal plans.
CONCLUSIONS: The consistent trend of higher mean and maximum doses to the OARs with the McNamara vRBE model compared to cRBE model highlighted the need for consideration of proton range uncertainties while evaluating OAR doses in bilateral HNC IMPT plans.

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.

Objective.This study explores the use of neural networks (NNs) as surrogate models for Monte-Carlo (MC) simulations in predicting the dose-averaged linear energy transfer (LETd) of protons in proton-beam therapy based on the planned dose distribution and patient anatomy in the form of computed tomography (CT) images. As LETdis associated with variability in the relative biological effectiveness (RBE) of protons, we also evaluate the implications of using NN predictions for normal tissue complication probability (NTCP) models within a variable-RBE context.Approach.The predictive performance of three-dimensional NN architectures was evaluated using five-fold cross-validation on a cohort of brain tumor patients (n= 151). The best-performing model was identified and externally validated on patients from a different center (n= 107). LETdpredictions were compared to MC-simulated results in clinically relevant regions of interest. We assessed the impact on NTCP models by leveraging LETdpredictions to derive RBE-weighted doses, using the Wedenberg RBE model.Main results.We found NNs based solely on the planned dose distribution, i.e. without additional usage of CT images, can approximate MC-based LETddistributions. Root mean squared errors (RMSE) for the median LETdwithin the brain, brainstem, CTV, chiasm, lacrimal glands (ipsilateral/contralateral) and optic nerves (ipsilateral/contralateral) were 0.36, 0.87, 0.31, 0.73, 0.68, 1.04, 0.69 and 1.24 keV µm-1, respectively. Although model predictions showed statistically significant differences from MC outputs, these did not result in substantial changes in NTCP predictions, with RMSEs of at most 3.2 percentage points.Significance.The ability of NNs to predict LETdbased solely on planned dose distributions suggests a viable alternative to compute-intensive MC simulations in a variable-RBE setting. This is particularly useful in scenarios where MC simulation data are unavailable, facilitating resource-constrained proton therapy treatment planning, retrospective patient data analysis and further investigations on the variability of proton RBE.

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

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

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