RBE-based dose planning, and calculation of TCP and NTCP with gold nanoparticles for intermediate photon energy in pancreatic cancer.

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.

Modelling of RBE differences in selected points within similar spread-out Bragg-peaks (SOBP) placed at superficial and deep water phantom locations in passively scattered beams but not in scanned pencil beams: A hypothesis.

PURPOSE: To model relative biological effectiveness (RBE) differences found in two studies which used spread-out Bragg-peaks (SOBP) placed at (a) superficial depth and (b) at the maximum range depth. For pencil beam scanning (PBS), RBE at similar points within the SOBP did not change between the two extreme SOBP placement depths; in passively scattered beams (PSB), high RBE values (typically 1.2-1.3) were found within superficially- placed SOBP but reduced to lower values (1-1.07) at similar points within the extreme-depth positioned SOBP. The dose, LET (linear energy transfer) distributions along each SOBP were closely comparable regardless of placement depth, but significant changes in dose rate occurred with depth in the PSB beam. METHODS: The equations used allow α and ß changes with falling dose rate (the converse to FLASH studies) in PSB, resulting in reduced α/ß 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.

Quantifying the Dosimetric Impact of Proton Range Uncertainties on RBE-Weighted Dose Distributions in Intensity-Modulated Proton Therapy for Bilateral Head and Neck Cancer.

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. CONCLUSION: 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.

Evaluation of relative biological effectiveness for diseases of the circulatory system based on microdosimetry.

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.

Novel radiation quality metrics accounting for proton energy spectra for RBE proton models.

BACKGROUND: For proton therapy, a relative biological effectiveness (RBE) of 1.1 is widely applied clinically. However, due to abundant evidence of variable RBE in vitro, and as suggested in studies of patient outcomes, RBE might increase by the end of the proton tracks, as described by several proposed variable RBE models. Typically, the dose averaged linear energy transfer ( LET d $\text{LET}_d$ ) has been used as a radiation quality metric (RQM) for these models. However, the optimal choice of RQM has not been fully explored. PURPOSE: This study aims to propose novel RQMs that effectively weight protons of different energies, and assess their predictive power for variable RBE in proton therapy. The overall objective is to identify an RQM that better describes the contribution of individual particles to the RBE of proton beams. METHODS: High-throughput experimental set-ups of in vitro cell survival studies for proton RBE determination are simulated utilizing the SHIELD-HIT12A Monte Carlo particle transport code. For every data point, the proton energy spectra are simulated, allowing the calculation of novel RQMs by applying different power levels to the spectra of LET or effective Q $Q$ ( Q eff $Q_\mathrm{eff}$ ) values. A phenomenological linear-quadratic-based RBE model is then applied to the in vitro data, using various RQMs as input variables, and the model performance is evaluated by root-mean-square-error (RMSE) for the logarithm of cell surviving fractions of each data point. RESULTS: Increasing the power level, that is, putting an even higher weight on higher LET particles when constructing the RQM is generally associated with an increased model performance, with dose averaged LET 3 $\text{LET}^3$ (i.e., dose averaged cubed LET, cLET d $\mathrm{cLET}_d$ ) resulting in a RMSE value 0.31, compared to 0.45 for a model based on (linearly weighted) LET d $\text{LET}_d$ , with similar trends also observed for track averaged and Q eff $Q_\mathrm{eff}$ -based RQMs. CONCLUSIONS: The results indicate that improved proton variable RBE models can be constructed assuming a non-linear RBE(LET) relationship for individual protons. If similar trends hold also for an in vitro-environment, variable RBE effects are likely better described by cLET d $\mathrm{cLET}_d$ or tracked averaged cubed LET ( cLET t $\mathrm{cLET}_t$ ), or corresponding Q eff $Q_\mathrm{eff}$ -based RQM, rather than linearly weighted LET d $\text{LET}_d$ or LET t $\text{LET}_t$ which is conventionally applied today.

Research Trends in the Study of the Relative Biological Effectiveness: A Bibliometric Study.

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.

First in vitro measurement of VHEE relative biological effectiveness (RBE) in lung and prostate cancer cells using the ARES linac at DESY.

Very high energy electrons (VHEE) are a potential candidate for radiotherapy applications. This includes tumours in inhomogeneous regions such as lung and prostate cancers, due to the insensitivity of VHEE to inhomogeneities. This study explores how electrons in the VHEE range can be used to perform successful in vitro radiobiological studies. The ARES (accelerator research experiment at SINBAD) facility at DESY, Hamburg, Germany was used to deliver 154 MeV electrons to both prostate (PC3) and lung (A549) cancer cells in suspension. Dose was delivered to samples with repeatability and uniformity, quantified with Gafchromic film. Cell survival in response to VHEE was measured using the clonogenic assay to determine the biological effectiveness of VHEE in cancer cells for the first time using this method. Equivalent experiments were performed using 300 kVp X-rays, to enable VHEE irradiated cells to be compared with conventional photons. VHEE irradiated cancer cell survival was fitted to the linear quadratic (LQ) model (R2 = 0.96-0.97). The damage from VHEE and X-ray irradiated cells at doses between 1.41 and 6.33 Gy are comparable, suggesting similar relative biological effectiveness (RBE) between the two modalities. This suggests VHEE is as damaging as photon radiotherapy and therefore could be used to successfully damage cancer cells during radiotherapy. The RBE of VHEE was quantified as the relative doses required for 50% (D0.5) and 10% (D0.1) cell survival. Using these values, VHEE RBE was measured as 0.93 (D0.5) and 0.99 (D0.1) for A549 and 0.74 (D0.5) and 0.93 (D0.1) for PC3 cell lines respectively. For the first time, this study has shown that 154 MeV electrons can be used to effectively kill lung and prostate cancer cells, suggesting that VHEE would be a viable radiotherapy modality. Several studies have shown that VHEE has characteristics that would offer significant improvements over conventional photon radiotherapy for example, electrons are relatively easy to steer and can be used to deliver dose rapidly and with high efficiency. Studies have shown improved dose distribution with VHEE in treatment plans, in comparison to VMAT, indicating that VHEE can offer improved and safer treatment plans with reduced side effects. The biological response of cancer cells to VHEE has not been sufficiently studied as of yet, however this initial study provides some initial insights into cell damage. VHEE offers significant benefits over photon radiotherapy and therefore more studies are required to fully understand the biological effectiveness of VHEE.

DNA-damage RBE assessment for combined boron and gadolinium neutron capture therapy.

PURPOSE: Neutron capture therapy (NCT) by 10B and 157Gd agents is a unique irradiation-based method which can be used to treat brain tumors. Current study aims to quantitatively evaluate the relative biological effectiveness (RBE) and dose distributions during the combined BNCT and GdNCT modalities through a hybrid Monte Carlo (MC) simulation approach. METHODS: Snyder head phantom as well as a cubic hypothetical tumor was at first modeled by Geant4 MC Code. Then, the energy spectra and dose distribution relevant to the released secondary particles during the combined Gd/BNCT were scored for different concentrations of 157Gd and 10B inside tumor volume. Finally, the scored energy spectra were imported to the MCDS code to estimate both RBESSB and RBEDSB values for different 157Gd concentrations. RESULTS: The results showed that combined Gd/BNCT increases the fluence-averaged RBESSB values by about 1.7 times when 157Gd concentration increments from 0 to 2000 µg/g for both considered cell oxygen levels (pO2 = 10% and 100%). Besides, a reduction of about 26% was found for fluence-averaged RBEDSB values with an increment of 157Gd concentration in tumor volume. CONCLUSION: From the results, it can be concluded that combined Gd/BNCT technique can improve tumor coverage with higher dose levels but in the expense of RBEDSB reduction which can affect the clinical efficacy of the NCT technique.

Dose and DNA damage modelling of diffusing alpha-emitters radiation therapy using Geant4.

PURPOSE: Diffusing alpha-emitters radiation therapy (DaRT) is a brachytherapy technique using α-particles to treat solid tumours. The high linear energy transfer (LET) and short range of α-particles make them good candidates for the targeted treatment of cancer. Treatment planning of DaRT requires a good understanding of the dose from α-particles and the other particles released in the 224Ra decay chain. METHODS: The Geant4 Monte Carlo toolkit has been used to simulate a DaRT seed to better understand the dose contribution from all particles and simulate the DNA damage due to this treatment. RESULTS: Close to the seed α-particles deliver the majority of dose, however at radial distances greater than 4 mm, the contribution of ß-particles is greater. The RBE has been estimated as a function of number of double strand breaks (DSBs) and complex DSBs. A maximum seed spacing of 5.5 mm and 6.5 mm was found to deliver at least 20 Gy RBE weighted dose between the seeds for RBEDSB and RBEcDSB respectively. CONCLUSIONS: The DNA damage changes with radial distance from the seed and has been found to become less complex with distance, which is potentially easier for the cell to repair. Close to the seed α-particles contribute the majority of dose, however the contribution from other particles cannot be neglected and may influence the choice of seed spacing.

Assessment of fluence- and dose-averaged linear energy transfer with passive luminescence detectors in clinical proton beams.

Objective.This work investigates the use of passive luminescence detectors to determine different types of averaged linear energy transfer (LET-) for the energies relevant to proton therapy. The experimental results are compared to reference values obtained from Monte Carlo simulations.Approach.Optically stimulated luminescence detectors (OSLDs), fluorescent nuclear track detectors (FNTDs), and two different groups of thermoluminescence detectors (TLDs) were irradiated at four different radiation qualities. For each irradiation, the fluence- (LET-f) and dose-averaged LET (LET-d) were determined. For both quantities, two sub-types of averages were calculated, either considering the contributions from primary and secondary protons or from all protons and heavier, charged particles. Both simulated and experimental data were used in combination with a phenomenological model to estimate the relative biological effectiveness (RBE).Main results.All types ofLET-could be assessed with the luminescence detectors. The experimental determination ofLET-fis in agreement with reference data obtained from simulations across all measurement techniques and types of averaging. On the other hand,LET-dcan present challenges as a radiation quality metric to describe the detector response in mixed particle fields. However, excluding secondaries heavier than protons from theLET-dcalculation, as their contribution to the luminescence is suppressed by ionization quenching, leads to equal accuracy betweenLET-fandLET-d. Assessment of RBE through the experimentally determinedLET-dvalues agrees with independently acquired reference values, indicating that the investigated detectors can determineLET-with sufficient accuracy for proton therapy.Significance.OSLDs, TLDs, and FNTDs can be used to determineLET-and RBE in proton therapy. With the capability to determine dose through ionization quenching corrections derived fromLET-, OSLDs and TLDs can simultaneously ascertain dose,LET-, and RBE. This makes passive detectors appealing for measurements in phantoms to facilitate validation of clinical treatment plans or experiments related to proton therapy.

Dose averaged linear energy transfer optimization for large sacral chordomas in carbon ion therapy.

BACKGROUND: Carbon ion beams are well accepted as densely ionizing radiation with a high linear energy transfer (LET). However, the current clinical practice does not fully exploit the highest possible dose-averaged LET (LETd) and, consequently, the biological potential in the target. This aspect becomes worse in larger tumors for which inferior clinical outcomes and corresponding lower LETd was reported. PURPOSE: The vicinity to critical organs in general and the inferior overall survival reported for larger sacral chordomas treated with carbon ion radiotherapy (CIRT), makes the treatment of such tumors challenging. In this work it was aimed to increase the LETd in large volume tumors while maintaining the relative biological effectiveness (RBE)-weighted dose, utilizing the LETd optimization functions of a commercial treatment planning system (TPS). METHODS: Ten reference sequential boost carbon ion treatment plans, designed to mimic clinical plans for large sacral chordoma tumors, were generated. High dose clinical target volumes (CTV-HD) larger than 250 cm 3 $250 \,{\rm cm}^{3}$ were considered as large targets. The total RBE-weighted median dose prescription with the local effect model (LEM) was D RBE , 50 % = 73.6 Gy $\textrm {D}_{\rm RBE, 50\%}=73.6 \,{\rm Gy}$ in 16 fractions (nine to low dose and seven to high dose planning target volume). No LETd optimization was performed in the reference plans, while LETd optimized plans used the minimum LETd (Lmin) optimization function in RayStation 2023B. Three different Lmin values were investigated and specified for the seven boost fractions: L min = 60 keV / µ m $\textrm {L}_{\rm min}=60 \,{\rm keV}/{\umu }{\rm m}$ , L min = 80 keV / µ m $\textrm {L}_{\rm min}=80 \,{\rm keV}/{\umu }{\rm m}$ and L min = 100 keV / µ m $\textrm {L}_{\rm min}=100 \,{\rm keV}/{\umu }{\rm m}$ . To compare the LETd optimized against reference plans, LETd and RBE-weighted dose based goals similar to and less strict than clinical ones were specified for the target. The goals for the organs at risk (OAR) remained unchanged. Robustness evaluation was studied for eight scenarios ( ± 3.5 % $\pm 3.5\%$ range uncertainty and ± 3 mm $\pm 3 \,{\rm mm}$ setup uncertainty along the main three axes). RESULTS: The optimization method with L min = 60 keV / µ m $\textrm {L}_{\rm min}=60 \,{\rm keV}/{\umu }{\rm m}$ resulted in an optimal LETd distribution with an average increase of LET d , 98 % ${\rm {LET}}_{{\rm {d,}}98\%}$ (and LET d , 50 % ${\rm {LET}}_{{\rm {d,}}50\%}$ ) in the CTV-HD by 8.9 ± 1.5 keV / µ m $8.9\pm 1.5 \,{\rm keV}/{\umu }{\rm m}$ ( 27 % $27\%$ ) (and 6.9 ± 1.3 keV / µ m $6.9\pm 1.3 \,{\rm keV}/{\umu }{\rm m}$ ( 17 % $17\%$ )), without significant difference in the RBE-weighted dose. By allowing ± 5 % $\pm 5\%$ over- and under-dosage in the target, the LET d , 98 % ${\rm {LET}}_{{\rm {d,}}98\%}$ (and LET d , 50 % ${\rm {LET}}_{{\rm {d,}}50\%}$ ) can be increased by 11.3 ± 1.2 keV / µ m $11.3\pm 1.2 \,{\rm keV}/{\umu }{\rm m}$ ( 34 % $34\%$ ) (and 11.7 ± 3.4 keV / µ m $11.7\pm 3.4 \,{\rm keV}/{\umu }{\rm m}$ ( 29 % $29\%$ )), using the optimization parameters L min = 80 keV / µ m $\textrm {L}_{\rm min}=80 \,{\rm keV}/{\umu }{\rm m}$ . The pass rate for the OAR goals in the LETd optimized plans was in the same level as the reference plans. LETd optimization lead to less robust plans compared to reference plans. CONCLUSIONS: Compared to conventionally optimized treatment plans, the LETd in the target was increased while maintaining the RBE-weighted dose using TPS LETd optimization functionalities. Regularly assessing RBE-weighted dose robustness and acquiring more in-room images remain crucial and inevitable aspects during treatment.

A method to predict space radiation biological effectiveness for non-cancer effects following intense Solar Particle Events.

In addition to the continuous exposure to cosmic rays, astronauts in space are occasionally exposed to Solar Particle Events (SPE), which involve less energetic particles but can deliver much higher doses. The latter can exceed several Gy in a few hours for the most intense SPEs, for which non-stochastic effects are thus a major concern. To identify adequate shielding conditions that would allow respecting the dose limits established by the various space agencies, the absorbed dose in the considered organ/tissue must be multiplied by the corresponding Relative Biological Effectiveness (RBE), which is a complex quantity depending on several factors including particle type and energy, considered biological effect, level of effect (and thus absorbed dose), etc. While in several studies only the particle-type dependence of RBE is taken into account, in this work we developed and applied a new approach where, thanks to an interface between the FLUKA Monte Carlo transport code and the BIANCA biophysical model, the RBE dependence on particle energy and absorbed dose was also considered. Furthermore, we included in the considered SPE spectra primary particles heavier than protons, which in many studies are neglected. This approach was then applied to the October 2003 SPE (the most intense SPE of solar cycle 23, also known as "Halloween event") and the January 2005 event, which was characterized by a lower fluence but a harder spectrum, i.e., with higher-energy particles. The calculation outcomes were then discussed and compared with the current dose limits established for skin and blood forming organs in case of 30-days missions. This work showed that the BIANCA model, if interfaced to a radiation transport code, can be used to calculate the RBE values associated to Solar Particle Events. More generally, this work emphasizes the importance of taking into account the RBE dependence on particle energy and dose when calculating equivalent doses.

Evaluation of specific RBE in different cells of hippocampus under high-dose proton irradiation in rats.

The study aimed to determine the specific relative biological effectiveness (RBE) of various cells in the hippocampus following proton irradiation. Sixty Sprague-Dawley rats were randomly allocated to 5 groups receiving 20 or 30 Gy of proton or photon irradiation. Pathomorphological neuronal damage in the hippocampus was assessed using Hematoxylin-eosin (HE) staining. The expression level of NeuN, Nestin, Caspase-3, Olig2, CD68 and CD45 were determined by immunohistochemistry (IHC). The RBE range established by comparing the effects of proton and photon irradiation at equivalent biological outcomes. Proton20Gy induced more severe damage to neurons than photon20Gy, but showed no difference compared to photon30Gy. The RBE of neuron was determined to be 1.65. Similarly, both proton20Gy and proton30Gy resulted in more inhibition of oligodendrocytes and activation of microglia in the hippocampal regions than photon20Gy and photon30Gy. However, the expression of Olig2 was higher and CD68 was lower in the proton20Gy group than in the photon30Gy group. The RBE of oligodendrocyte and microglia was estimated to be between 1.1 to 1.65. For neural stem cells (NSCs) and immune cells, there were no significant difference in the expression of Nestin and CD45 between proton and photon irradiation (both 20 and 30 Gy). Therefore, the RBE for NSCs and immune cell was determined to be 1.1. These findings highlight the varying RBE values of different cells in the hippocampus in vivo. Moreover, the actual RBE of the hippocampus may be higher than 1.1, suggesting that using as RBE value of 1.1 in clinical practice may underestimate the toxicities induced by proton radiation.

Estimation of the relative biological effectiveness for double strand break induction of clinical kilovoltage beams using Monte Carlo simulations.

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

Biological dose optimization incorporating intra-tumoural cellular radiosensitivity heterogeneity in ion-beam therapy treatment planning.

Objective.Treatment plans of ion-beam therapy have been made under an assumption that all cancer cells within a tumour equally respond to a given radiation dose. However, an intra-tumoural cellular radiosensitivity heterogeneity clearly exists, and it may lead to an overestimation of therapeutic effects of the radiation. The purpose of this study is to develop a biological model that can incorporate the radiosensitivity heterogeneity into biological optimization for ion-beam therapy treatment planning.Approach.The radiosensitivity heterogeneity was modeled as the variability of a cell-line specific parameter in the microdosimetric kinetic model following the gamma distribution. To validate the developed intra-tumoural-radiosensitivity-heterogeneity-incorporated microdosimetric kinetic (HMK) model, a treatment plan with H-ion beams was made for a chordoma case, assuming a radiosensitivity heterogeneous region within the tumour. To investigate the effects of the radiosensitivity heterogeneity on the biological effectiveness of H-, He-, C-, O-, and Ne-ion beams, the relative biological effectiveness (RBE)-weighted dose distributions were planned for a cuboid target with the stated ion beams without considering the heterogeneity. The planned dose distributions were then recalculated by taking the heterogeneity into account.Main results. The cell survival fraction and corresponding RBE-weighted dose were formulated based on the HMK model. The first derivative of the RBE-weighted dose distribution was also derived, which is needed for fast biological optimization. For the patient plan, the biological optimization increased the dose to the radiosensitivity heterogeneous region to compensate for the heterogeneity-induced reduction in biological effectiveness of the H-ion beams. The reduction in biological effectiveness due to the heterogeneity was pronounced for low linear energy transfer (LET) beams but moderate for high-LET beams. The RBE-weighted dose in the cuboid target decreased by 7.6% for the H-ion beam, while it decreased by just 1.4% for the Ne-ion beam.Significance.Optimal treatment plans that consider intra-tumoural cellular radiosensitivity heterogeneity can be devised using the HMK model.

Early Experience With Biologically Effective Dose-Comparable Short-Course Whole Brain Radiation Therapy for Metastatic Intracranial Disease.

OBJECTIVES: For inpatients with metastatic intracranial disease burden exceeding established guidelines for stereotactic radiosurgery (SRS), the standard of care involves whole brain radiation therapy (WBRT), typically administered as a 2-week course of treatment with biologically effective dose (BED) of 60 Gy. However, shorter course WBRT provides theoretical advantages in quality of life and decreasing systemic therapy delay. This retrospective study evaluates our early experience with BED-comparable short-course WBRT (23 Gy in 5 fractions; BED=58.3 Gy) for metastatic intracranial disease. METHODS: Over a recent 2-month timeframe, 3 inpatients with intracranial disease burden exceeding SRS guidelines were administered BED-comparable short-course WBRT. Due to the high intracranial disease burden, 23 Gy was chosen over 20 Gy for 5-fraction WBRT due to the desire to optimally mimic the durability of the classic 30 Gy in 10 fraction treatment regimen. RESULTS: The mean age at treatment was 65.7 years, the mean Karnofsky Performance Status (KPS) was 60, and the mean number of intracranial metastases was 20.3. The mean duration between inpatient Radiation Oncology consultation and the start of WBRT (following CT radiation therapy simulation) was 6.7 days. All patients completed WBRT no later than 2 weeks from the initial inpatient consultation. CONCLUSIONS: For inpatients with intracranial metastatic disease burden exceeding established SRS guidelines, BED-comparable short-course WBRT administered to 23 Gy in 5 fractions (4.6 Gy/fraction) is safe and efficacious. Given previous literature indicating that nearly half of the patients prescribed traditional 2-week WBRT die without completing treatment, BED-comparable WBRT represents an attractive and promising WBRT alternative in this patient population.

Benchmarking proton RBE models.

Objective.To biologically optimise proton therapy, models which can accurately predict variations in proton relative biological effectiveness (RBE) are essential. Current phenomenological models show large disagreements in RBE predictions, due to different model assumptions and differences in the data to which they were fit. In this work, thirteen RBE models were benchmarked against a comprehensive proton RBE dataset to evaluate predictions when all models are fit using the same data and fitting techniques, and to assess the statistical robustness of the models.Approach.Model performance was initially evaluated by fitting to the full dataset, and then a cross-validation approach was applied to assess model generalisability and robustness. The impact of weighting the fit and the choice of biological endpoint (either single or multiple survival levels) was also evaluated.Main results.Fitting the models to a common dataset reduced differences between their predictions, however significant disagreements remained due to different underlying assumptions. All models performed poorly under cross-validation in the weighted fits, suggesting that some uncertainties on the experimental data were significantly underestimated, resulting in over-fitting and poor performance on unseen data. The simplest model, which depends linearly on the LET but has no tissue or dose dependence, performed best for a single survival level. However, when fitting to multiple survival levels simultaneously, more complex models with tissue dependence performed better. All models had significant residual uncertainty in their predictions compared to experimental data.Significance.This analysis highlights that poor quality of error estimation on the dose response parameters introduces substantial uncertainty in model fitting. The significant residual error present in all approaches illustrates the challenges inherent in fitting to large, heterogeneous datasets and the importance of robust statistical validation of RBE models.

Dose and dose rate dependence of the tissue sparing effect at ultra-high dose rate studied for proton and electron beams using the zebrafish embryo model.

PURPOSE: A better characterization of the dependence of the tissue sparing effect at ultra-high dose rate (UHDR) on physical beam parameters (dose, dose rate, radiation quality) would be helpful towards a mechanistic understanding of the FLASH effect and for its broader clinical translation. To address this, a comprehensive study on the normal tissue sparing at UHDR using the zebrafish embryo (ZFE) model was conducted. METHODS: One-day-old ZFE were irradiated over a wide dose range (15-95 Gy) in three different beams (proton entrance channel, proton spread out Bragg peak and 30 MeV electrons) at UHDR and reference dose rate. After irradiation the ZFE were incubated for 4 days and then analyzed for four different biological endpoints (pericardial edema, curved spine, embryo length and eye diameter). RESULTS: Dose-effect curves were obtained and a sparing effect at UHDR was observed for all three beams. It was demonstrated that proton relative biological effectiveness and UHDR sparing are both relevant to predict the resulting dose response. Dose dependent FLASH modifying factors (FMF) for ZFE were found to be compatible with rodent data from the literature. It was found that the UHDR sparing effect saturates at doses above âˆ¼ 50 Gy with an FMF of âˆ¼ 0.7-0.8. A strong dose rate dependence of the tissue sparing effect in ZFE was observed. The magnitude of the maximum sparing effect was comparable for all studied biological endpoints. CONCLUSION: The ZFE model was shown to be a suitable pre-clinical high-throughput model for radiobiological studies on FLASH radiotherapy, providing results comparable to rodent models. This underlines the relevance of ZFE studies for FLASH radiotherapy research.

An updated variable RBE model for proton therapy.

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

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

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