The Pediatric Proton and Photon Therapy Comparison Cohort: Study Design for a Multicenter Retrospective Cohort to Investigate Subsequent Cancers After Pediatric Radiation Therapy.

Purpose: The physical properties of protons lower doses to surrounding normal tissues compared with photons, potentially reducing acute and long-term adverse effects, including subsequent cancers. The magnitude of benefit is uncertain, however, and currently based largely on modeling studies. Despite the paucity of directly comparative data, the number of proton centers and patients are expanding exponentially. Direct studies of the potential risks and benefits are needed in children, who have the highest risk of radiation-related subsequent cancers. The Pediatric Proton and Photon Therapy Comparison Cohort aims to meet this need. Methods and Materials: We are developing a record-linkage cohort of 10,000 proton and 10,000 photon therapy patients treated from 2007 to 2022 in the United States and Canada for pediatric central nervous system tumors, sarcomas, Hodgkin lymphoma, or neuroblastoma, the pediatric tumors most frequently treated with protons. Exposure assessment will be based on state-of-the-art dosimetry facilitated by collection of electronic radiation records for all eligible patients. Subsequent cancers and mortality will be ascertained by linkage to state and provincial cancer registries in the United States and Canada, respectively. The primary analysis will examine subsequent cancer risk after proton therapy compared with photon therapy, adjusting for potential confounders and accounting for competing risks. Results: For the primary aim comparing overall subsequent cancer rates between proton and photon therapy, we estimated that with 10,000 patients in each treatment group there would be 80% power to detect a relative risk of 0.8 assuming a cumulative incidence of subsequent cancers of 2.5% by 15 years after diagnosis. To date, 9 institutions have joined the cohort and initiated data collection; additional centers will be added in the coming year(s). Conclusions: Our findings will affect clinical practice for pediatric patients with cancer by providing the first large-scale systematic comparison of the risk of subsequent cancers from proton compared with photon therapy.

Normal Tissue Complication Probability Modeling of Severe Radiation-Induced Lymphopenia Using Blood Dose for Patients With Hepatocellular Carcinoma.

PURPOSE: This study aimed to develop a normal tissue complication probability (NTCP) model to estimate the risk of severe radiation-induced lymphopenia (SRIL; absolute lymphocyte count [ALC] < 500/µL) by using the blood dose of patients with hepatocellular carcinoma (HCC). METHODS AND MATERIALS: We retrospectively collected data from 75 patients with HCC who received radiation therapy (RT) between 2015 and 2018. The hematological dose framework calculated blood dose-volume histograms (DVHs) using a predefined blood flow model, organ DVHs, the number of treatment fractions, and beam delivery time. A Lyman-Kutcher-Burman model with a generalized equivalent dose was used to establish the NTCP model, reflecting the whole-blood DVHs. Optimization of the Lyman-Kutcher-Burman parameters was conducted by minimizing a negative log-likelihood function. RESULTS: There were 6, 4, 18, 33, and 14 patients in the groups with radiation-induced lymphopenia grades 0, 1, 2, 3, and 4, respectively. The median pre- and post-RT ALC values were 1410/µL (range, 520-3710/µL) and 470/µL (range, 60-1760/µL), respectively. There was a correlation between mean blood dose and ALC depletion (Pearson r = -0.664; P < .001). The average mean blood doses in each radiation-induced lymphopenia group were 2.90 Gy (95% CI, 1.96-3.85 Gy) for grade 0 to 1, 5.29 Gy (95% CI, 4.12-6.45 Gy) for grade 2, 8.81 Gy (95% CI, 7.55-10.07 Gy) for grade 3, and 11.69 Gy (95% CI, 9.82-17.57 Gy) for grade 4. When applying the developed NTCP model to predict SRIL, the area under the receiver operating characteristic curve and Brier score values were 0.89 and 0.12, respectively. CONCLUSIONS: We developed the first NTCP model based on whole-blood DVHs for estimating SRIL after abdominal RT in patients with HCC. Our results showed a strong correlation between blood dose and ALC depletion, suggesting the potential to predict the risk of SRIL occurrence using blood dose.

Monte Carlo simulation-based patient-specific QA using machine log files for line-scanning proton radiation therapy.

BACKGROUND: Quality assurance (QA) is a prerequisite for safe and accurate pencil-beam proton therapy. Conventional measurement-based patient-specific QA (pQA) can only verify limited aspects of patient treatment and is labor-intensive. Thus, a better method is needed to ensure the integrity of the treatment plan. PURPOSE: Line scanning, which involves continuous and rapid delivery of pencil beams, is a state-of-the-art proton therapy technique. Machine performance in delivering scanning protons is dependent on the complexity of the beam modulations. Moreover, it contributes to patient treatment accuracy. A Monte Carlo (MC) simulation-based QA method that reflects the uncertainty related to the machine during scanning beam delivery was developed and verified for clinical applications to pQA. METHODS: Herein, a tool for particle simulation (TOPAS) for nozzle modeling was used, and the code was commissioned against the measurements. To acquire the beam delivery uncertainty for each plan, patient plans were delivered. Furthermore, log files recorded every 60 µs by the monitors downstream of the nozzle were exported from the treatment control system. The spot positions and monitor unit (MU) counts in the log files were converted to dipole magnet strengths and number of particles, respectively, and entered into the TOPAS. For the 68 clinical cases, MC simulations were performed in a solid water phantom, and two-dimensional (2D) absolute dose distributions at 20-mm depth were measured using an ionization chamber array (Octavius 1500, PTW, Freiburg, Germany). Consequently, the MC-simulated 2D dose distributions were compared with the measured data, and the dose distributions in the pre-treatment QA plan created with RayStation (RaySearch Laboratories, Stockholm, Sweden). Absolute dose comparisons were made using gamma analysis with 3%/3 mm and 2%/2 mm criteria for 47 clinical cases without considering daily machine output variation in the MC simulation and 21 cases with daily output variation, respectively. All cases were analyzed with 90% or 95% of passing rate thresholds. RESULTS: For 47 clinical cases not considering daily output variations, the absolute gamma passing rates compared with the pre-treatment QA plan were 99.71% and 96.97%, and the standard deviations (SD) were 0.70% and 3.78% with the 3%/3 mm or 2%/2 mm criteria, respectively. Compared with the measurements, the passing rate of 2%/2 mm gamma criterion was 96.76% with 3.99% of SD. For the 21 clinical cases compared with pre-treatment QA plan data and measurements considering daily output variations, the 2%/2 mm absolute gamma analysis result was 98.52% with 1.43% of SD and 97.67% with 2.72% of SD, respectively. With a 95% passing rate threshold of 2%/2 mm criterion, the false-positive and false-negative were 21.8% and 8.3% for without and with considering output variation, respectively. With a 90% threshold, the false-positive and false-negative reduced to 11.4% and 0% for without and with considering output variation, respectively. CONCLUSIONS: A log-file-based MC simulation method for patient QA of line-scanning proton therapy was successfully developed. The proposed method exhibited clinically acceptable accuracy, thereby exhibiting a potential to replace the measurement-based dosimetry QA method with a 90% gamma passing rate threshold when applying the 2%/2 mm criterion.

NCIRF: an organ dose calculator for patients undergoing radiography and fluoroscopy.

Background. It is critical to monitor the radiation dose delivered to patients undergoing radiography and fluoroscopy to prevent both acute and potential long-term adverse health effects. Accurate estimation of organ doses is essential to ensuring that radiation dose is maintained As Low As Reasonably Achievable. We developed a graphical user interface-based organ dose calculation tool for pediatric and adult patients undergoing radiography and fluoroscopy examinations.Methods. Our dose calculator follows the four sequential steps. First, the calculator obtains input parameters related to patient age and gender, and x-ray source data. Second, the program creates an input file describing the anatomy and material composition of a phantom, x-ray source, and organ dose scorers for Monte Carlo radiation transport using the user input parameters. Third, a built-in Geant4 module was developed to import the input file and to calculate organ absorbed doses and skeletal fluences through Monte Carlo radiation transport. Lastly, active marrow and endosteum doses are derived from the skeletal fluences and effective dose is calculated from the organ and tissue doses. Following benchmarking with MCNP6, we conducted some benchmarking calculations calculated organ doses for an illustrative cardeiac interventional fluoroscopy and compared the results with those from an existing dose calculator, PCXMC.Results. The graphical user interface-based program was entitled National Cancer Institute dosimetry system for Radiography and Fluoroscopy (NCIRF). Organ doses calculated from NCIRF showed an excellent agreement with those from MCNP6 in the simulation of an illustrative fluoroscopy exam. In the cardiac interventional fluoroscopy exam of the adult male and female phantoms, the lungs received relatively greater doses than any other organs. PCXMC based on stylistic phantoms overall overestimated major organ doses calculated from NCIRF by up to 3.7-fold (active bone marrow).Conclusion. We developed an organ dose calculation tool for pediatric and adult patients undergoing radiography and fluoroscopy examinations. NCIRF could substantially increase the accuracy and efficiency of organ dose estimation in radiography and fluoroscopy exams.

Reduced radiation exposure to circulating blood cells in proton therapy compared with X-ray therapy in locally advanced lung cancer: Computational simulation based on circulating blood cells.

Background: We estimated the dose of circulating blood cells (CBCs) in patients with locally advanced non-small cell lung cancer for predicting severe radiation-induced lymphopenia (SRIL) and compared pencil-beam scanning proton therapy (PBSPT) and intensity-modulated (photon) radiotherapy (IMRT). Materials and methods: After reviewing 325 patients who received definitive chemoradiotherapy with PBSPT (n = 37) or IMRT (n = 164). SRIL was diagnosed when two or more events of an absolute lymphocyte count < 200 µL occurred during the treatment course. Dose information for the heart and lungs was utilized for the time-dependent computational dose calculation of CBCs. Results: The dose distribution of CBCs was significantly lesser in the PBSPT group than that in the IMRT group. Overall, 75 (37.3%) patients experienced SRIL during the treatment course; 72 and 3 patients were treated with IMRT and PBSPT, respectively. SRIL was associated with poor progression-free and overall survival outcomes. Upon incorporating the dose information of CBCs for predicting SRIL, CBC D90% > 2.6 GyE was associated with the development of SRIL with the baseline lymphocyte count and target volume. Furthermore, PBSPT significantly reduced the dose of CBC D90% (odds ratio = 0.11; p = 0.004) compared with IMRT. Conclusion: The results of this study demonstrate the significance of the dose distribution of CBCs in predicting SRIL. Furthermore, reducing the dose of CBCs after PBSPT minimized the risk of SRIL. Lymphocyte-sparing radiotherapy in PBSPT could improve outcomes, particularly in the setting of maintenance immunotherapy.

Predicting Severity of Radiation Induced Lymphopenia in Individual Proton Therapy Patients for Varying Dose Rate and Fractionation Using Dynamic 4-Dimensional Blood Flow Simulations.

PURPOSE: Radiation-induced lymphopenia has gained attention recently as the result of its correlation with survival in a range of indications, particularly when combining radiation therapy (RT) with immunotherapy. The purpose of this study is to use a dynamic blood circulation model combined with observed lymphocyte depletion in patients to derive the in vivo radiosensitivity of circulating lymphocytes and study the effect of RT delivery parameters. METHODS AND MATERIALS: We assembled a cohort of 17 patients with hepatocellular carcinoma treated with proton RT alone in 15 fractions (fx) using conventional dose rates (beam-on time [BOT], 120 seconds) for whom weekly absolute lymphocyte counts (ALCs) during RT and follow-up were available. We used HEDOS, a time-dependent, whole-body, blood flow computational framework, in combination with explicit liver blood flow modeling, to calculate the dose volume histograms for circulating lymphocytes for changing BOTs (1 second-300 seconds) and fractionations (5 fx, 15 fx). From this, we used the linear cell survival model and an exponential model to determine patient-specific lymphocyte radiation sensitivity, α, and recovery, σ, respectively. RESULTS: The in vivo-derived patient-specific α had a median of 0.65 Gy-1 (range, 0.30-1.38). Decreasing BOT to 1 second led to an increased average end-of-treatment ALC of 27.5%, increasing to 60.3% when combined with the 5-fx regimen. Decreasing to 5 fx at the conventional dose rate led to an increase of 17.0% on average. The benefit of both increasing dose rate and reducing the number of fractions was patient specificࣧpatients with highly sensitive lymphocytes benefited most from decreasing BOT, whereas patients with slow lymphocyte recovery benefited most from the shorter fractionation regimen. CONCLUSIONS: We observed that increasing dose rate at the same fractionation reduced ALC depletion more significantly than reducing the number of fractions. High-dose-rates led to an increased sparing of lymphocytes when shortening the fractionation regimen, particularly for patients with radiosensitive lymphocytes at elevated risk.

Proposing a Clinical Model for RBE Based on Proton Track-End Counts.

PURPOSE: In proton therapy, the clinical application of linear energy transfer (LET) optimization remains contentious, in part because of challenges associated with the definition and calculation of LET and its exact relationship with relative biological effectiveness (RBE) because of large variation in experimental in vitro data. This has raised interest in other metrics with favorable properties for biological optimization, such as the number of proton track ends in a voxel. In this work, we propose a novel model for clinical calculations of RBE, based on proton track end counts. METHODS AND MATERIALS: We developed an effective dose concept to translate between the total proton track-end count per unit mass in a voxel and a proton RBE value. Dose, track end, and dose-averaged LET (LETd) distributions were simulated using Monte Carlo models for a series of water phantoms, in vitro radiobiological studies, and patient treatment plans. We evaluated the correlation between track ends and regions of elevated biological effectiveness in comparison to LETd-based models of RBE. RESULTS: Track ends were found to correlate with biological effects in in vitro experiments with an accuracy comparable to LETd. In patient simulations, our track end model identified the same biological hotspots as predicted by LETd-based radiobiological models of proton RBE. CONCLUSIONS: These results suggest that, for clinical optimization and evaluation, an RBE model based on proton track end counts may match LETd-based models in terms of information provided while also offering superior statistical properties.

Home-dwelling older adults' experiences of living with both frailty and multimorbidity: A meta-ethnography.

OBJECTIVES: To systematically review qualitative studies about home-dwelling older adults' experiences of living with both frailty and multimorbidity. METHODS: This study adopted a meta-ethnography; the databases included PubMed, Embase, CINAHL, Web of Science, PsycINFO, SCOPUS, and Google Scholar. Qualitative peer-reviewed articles in English were searched up to December 31, 2021. Themes and concepts were extracted through constant comparison across the included studies by three reviewers. RESULTS: Of the 147 articles screened, nine qualitative articles, encompassing a total sample of 173 participants, were included. The four final synthesised themes were 'Being isolated in a closed life,' 'Being dependent on help from others,' 'Rebuilding to maximise quality of life,' and 'Struggling to live a meaningful life.' CONCLUSION: Home-dwelling older adults with both frailty and multimorbidity are more likely to be socially isolated due to their physical limitations and lack of integration between hospital-based care and community healthcare services.

MOQUI: an open-source GPU-based Monte Carlo code for proton dose calculation with efficient data structure.

Objective.Monte Carlo (MC) codes are increasingly used for accurate radiotherapy dose calculation. In proton therapy, the accuracy of the dose calculation algorithm is expected to have a more significant impact than in photon therapy due to the depth-dose characteristics of proton beams. However, MC simulations come at a considerable computational cost to achieve statistically sufficient accuracy. There have been efforts to improve computational efficiency while maintaining sufficient accuracy. Among those, parallelizing particle transportation using graphic processing units (GPU) achieved significant improvements. Contrary to the central processing unit, a GPU has limited memory capacity and is not expandable. It is therefore challenging to score quantities with large dimensions requiring extensive memory. The objective of this study is to develop an open-source GPU-based MC package capable of scoring those quantities.Approach.We employed a hash-table, one of the key-value pair data structures, to efficiently utilize the limited memory of the GPU and score the quantities requiring a large amount of memory. With the hash table, only voxels interacting with particles will occupy memory, and we can search the data efficiently to determine their address. The hash-table was integrated with a novel GPU-based MC code, moqui.Main results.The developed code was validated against an MC code widely used in proton therapy, TOPAS, with homogeneous and heterogeneous phantoms. We also compared the dose calculation results of clinical treatment plans. The developed code agreed with TOPAS within 2%, except for the fall-off and regions, and the gamma pass rates of the results were >99% for all cases with a 2 mm/2% criteria.Significance.We can score dose-influence matrix and dose-rate on a GPU for a 3-field H&N case with 10 GB of memory using moqui, which would require more than 100 GB of memory with the conventionally used array data structure.

A mesh-based model of liver vasculature: implications for improved radiation dosimetry to liver parenchyma for radiopharmaceuticals.

PURPOSE: To develop a model of the internal vasculature of the adult liver and demonstrate its application to the differentiation of radiopharmaceutical decay sites within liver parenchyma from those within organ blood. METHOD: Computer-generated models of hepatic arterial (HA), hepatic venous (HV), and hepatic portal venous (HPV) vascular trees were algorithmically created within individual lobes of the ICRP adult female and male livers (AFL/AML). For each iteration of the algorithm, pressure, blood flow, and vessel radii within each tree were updated as each new vessel was created and connected to a viable bifurcation site. The vascular networks created inside the AFL/AML were then tetrahedralized for coupling to the PHITS radiation transport code. Specific absorbed fractions (SAF) were computed for monoenergetic alpha particles, electrons, positrons, and photons. Dual-region liver models of the AFL/AML were proposed, and particle-specific SAF values were computed assuming radionuclide decays in blood within two locations: (1) sites within explicitly modeled hepatic vessels, and (2) sites within the hepatic blood pool residing outside these vessels to include the capillaries and blood sinuses. S values for 22 and 10 radionuclides commonly used in radiopharmaceutical therapy and imaging, respectively, were computed using the dual-region liver models and compared to those obtained in the existing single-region liver model. RESULTS: Liver models with virtual vasculatures of ~ 6000 non-intersecting straight cylinders representing the HA, HPV, and HV circulations were created for the ICRP reference. For alpha emitters and for beta and auger-electron emitters, S values using the single-region models were approximately 11% (AML) to 14% (AFL) and 11% (AML) to 13% (AFL) higher than the S values obtained using the dual-region models, respectively. CONCLUSIONS: The methodology employed in this study has shown improvements in organ parenchymal dosimetry through explicit consideration of blood self-dose for alpha particles (all energies) and for electrons at energies below ~ 100 keV.

A dynamic blood flow model to compute absorbed dose to circulating blood and lymphocytes in liver external beam radiotherapy.

We have developed a novel 4D dynamic liver blood flow model, capable of accurate dose estimation to circulating blood cells during liver-directed external beam radiotherapy, accounting for blood recirculation and radiation delivery time structure. Adult male and adult female liver computational phantoms with detailed vascular trees were developed to include the hepatic arterial, hepatic portal venous, and hepatic venous trees. A discrete time Markov Chain approach was applied to determine the spatiotemporal distribution of 105blood particles (BP) in the human body based on reference values for cardiac output and organ blood volumes. For BPs entering the liver, an explicit Monte Carlo simulation was implemented to track their propagation along ∼2000 distinct vascular pathways through the liver. The model tracks accumulated absorbed dose from time-dependent radiation fields with a 0.1 s time resolution. The computational model was then evaluated for 3 male and 3 female patients receiving photon (VMAT and IMRT) and proton (passive SOBP and active PBS) treatments. The dosimetric impact of treatment modality, delivery time, and fractionation on circulating blood cells was investigated and quantified using the mean dose (µdose,b),V>0Gy,V>0.125Gy,andD2%. Average reductions inµdose,b,V>0Gy,V>0.125GyandD2%of 45%, 6%, 53%, 19% respectively, were observed for proton treatments as compared to photon treatments. Our simulation also showed thatV>0Gy,V>0.125Gy, andD2%were highly sensitive to the beam-on time. BothV>0GyandV>0.125Gyincreased with beam-on time, whereasD2%decreased with increasing beam-on time, demonstrating the tradeoff between low dose to a large fraction of blood cells and high dose to a small fraction of blood cells. Consequently, proton treatments are not necessarily advantageous in terms of dose to the blood simply based on integral dose considerations. Instead, both integral dose and beam-on time can substantially impact relevant dosimetric indices.

Dosimetric Modeling of Lymphopenia in Patients With Metastatic Cancer Receiving Palliative Radiation and PD-1 Immune Checkpoint Inhibitors.

PURPOSE: Radiation therapy (RT)-associated lymphopenia may adversely affect treatment outcomes, particularly in the era of immunotherapy. We sought to determine dosimetric factors correlated with lymphopenia after palliative RT in a cohort of patients with advanced cancer treated with anti-PD-1 immune checkpoint inhibitors. METHODS AND MATERIALS: We included patients with metastatic lung cancer, melanoma, or renal cell carcinoma who were treated with either pembrolizumab or nivolumab and received palliative RT to an extracranial site. Baseline and nadir absolute lymphocyte counts (ALCs) within 6 weeks of RT were recorded. Dosimetric factors were extracted from the corresponding dose-volume histograms and also used to model the dose to circulating lymphocytes via a whole-body blood flow model that simulates the spatiotemporal distribution of blood particles in major organs during RT. RESULTS: We analyzed 55 patients who underwent 80 total courses of palliative RT; most (94%) were treated with 3-dimensional conformal RT. Doses to the whole body, bone, and large blood vessels (LBVs) were negatively correlated with the ALC nadir, with the strongest correlations seen at V15 (rs, -0.38, -0.43, and -0.37, and P = .0004, .0001, and .0008, respectively). Doses to other organs were not significantly correlated with the ALC nadir. The modeled dose to circulating lymphocytes was also negatively correlated with the ALC nadir and percent ALC change (for D2%, rs, -0.31 and -0.44, and P = .005 and .0001, respectively). Grade ≥3 lymphopenia was associated with LBV V15 (odds ratio [OR], 1.16; 95% CI, 1.07-1.26; P < .001), bone V15 (OR, 1.04; 95% CI, 1.01-1.08; P = .03), body V15 (OR, 1.003; 95% CI, 1.001-1.006; P = .008), and modeled lymphocyte dose (OR, 1.45; 95% CI, 1.16-1.82; P < .001). CONCLUSIONS: The RT dose to the whole body, bone, and LBVs and the modeled dose to circulating lymphocytes were correlated with lymphopenia in patients treated with palliative RT and anti-PD-1 immune checkpoint inhibitors. These findings may inform future radiation planning in this setting.

HEDOS-a computational tool to assess radiation dose to circulating blood cells during external beam radiotherapy based on whole-body blood flow simulations.

We have developed a time-dependent computational framework, hematological dose (HEDOS), to estimate dose to circulating blood cells from radiation therapy treatment fields for any treatment site. Two independent dynamic models were implemented in HEDOS: one describing the spatiotemporal distribution of blood particles (BPs) in organs and the second describing the time-dependent radiation field delivery. A whole-body blood flow network based on blood volumes and flow rates from ICRP Publication 89 was simulated to produce the spatiotemporal distribution of BPs in organs across the entire body using a discrete-time Markov process. Constant or time-varying transition probabilities were applied and their impact on transition time was investigated. The impact of treatment time and anatomical site were investigated using imaging data and dose distributions from a liver cancer and a brain cancer patient. The simulations revealed different dose levels to the circulating blood for brain irradiation compared to liver irradiation even for similar field sizes due to the different blood flow properties of the two organs. The volume of blood receiving any dose (V>0 Gy) after a single radiation fraction increases from 1.2% for a 1 s delivery time to 20.9% for 120 s delivery time for the brain cancer treatment, and from 10% (1 s) to 48.7% (120 s) for a liver cancer treatment. Other measures of the low-dose bath to the circulating blood such as the dose to small volumes of blood (D2%) decreases with longer delivery time. Furthermore, we demonstrate that the blood dose-volume histogram is highly sensitive to changes in the treatment time, indicating that dynamic modeling of blood flow and radiation fields is necessary to evaluate dose to circulating blood cells for the assessment of radiation-induced lymphopenia. HEDOS is publicly available and allows for the estimation of patient-specific dose to circulating blood cells based on organ DVHs, thus enabling the study of the impact of different treatment plans, dose rates, and fractionation schemes.

The impact of variable relative biological effectiveness in proton therapy for left-sided breast cancer when estimating normal tissue complications in the heart and lung.

The aim of this study was to evaluate the clinical impact of relative biological effectiveness (RBE) variations in proton beam scanning treatment (PBS) for left-sided breast cancer versus the assumption of a fixed RBE of 1.1, particularly in the context of comparisons with photon-based three-dimensional conformal radiotherapy (3DCRT) and volumetric modulated arc therapy (VMAT). Ten patients receiving radiation treatment to the whole breast/chest wall and regional lymph nodes were selected for each modality. For PBS, the dose distributions were re-calculated with both a fixed RBE and a variable RBE using an empirical RBE model. Dosimetric indices based on dose-volume histogram analysis were calculated for the entire heart wall, left anterior descending artery (LAD) and left lung. Furthermore, normal tissue toxicity probabilities for different endpoints were evaluated. The results show that applying a variable RBE significantly increases the RBE-weighted dose and consequently the calculated dosimetric indices increases for all organs compared to a fixed RBE. The mean dose to the heart and the maximum dose to the LAD and the left lung are significantly lower for PBS assuming a fixed RBE compared to 3DCRT. However, no statistically significant difference is seen when a variable RBE is applied. For a fixed RBE, lung toxicities are significantly lower compared to 3DCRT but when applying a variable RBE, no statistically significant differences are noted. A disadvantage is seen for VMAT over both PBS and 3DCRT. One-to-one plan comparison on 8 patients between PBS and 3DCRT shows similar results. We conclude that dosimetric analysis for all organs and toxicity estimation for the left lung might be underestimated when applying a fixed RBE for protons. Potential RBE variations should therefore be considered as uncertainty bands in outcome analysis.

DICOM-RT Ion interface to utilize MC simulations in routine clinical workflow for proton pencil beam radiotherapy.

To adopt Monte Carlo (MC) simulations as an independent dose calculation method for proton pencil beam radiotherapy, an interface that converts the plan information in DICOM format into MC components such as geometries and beam source is a crucial element. For this purpose, a DICOM-RT Ion interface (https://github.com/topasmc/dicom-interface) has been developed and integrated into the TOPAS MC code to perform such conversions on-the-fly. DICOM-RT objects utilized in this interface include Ion Plan (RTIP), Ion Beams Treatment Record (RTIBTR), CT image, and Dose. Beamline geometries, gantry and patient coordinate systems, and fluence maps are determined from RTIP and/or RTIBTR. In this interface, DICOM information is processed and delivered to a MC engine in two steps. A MC model, which consists of beamline geometries and beam source, to represent a treatment machine is created by a DICOM parser of the interface. The complexities from different DICOM types, various beamline configurations and source models are handled in this step. Next, geometry information and beam source are transferred to TOPAS on-the-fly via the developed TOPAS extensions. This interface with two treatment machines was successfully deployed into our automated MC workflow which provides simulated dose and LET distributions in a patient or a water phantom automatically when a new plan is identified. The developed interface provides novel features such as handling multiple treatment systems based on different DICOM types, DICOM conversions on-the-fly, and flexible sampling methods that significantly reduce the burden of handling DICOM based plan or treatment record information for MC simulations.

End-of-Range Radiobiological Effect on Rib Fractures in Patients Receiving Proton Therapy for Breast Cancer.

PURPOSE: A prospective trial of proton therapy for breast cancer revealed an increased rib fracture rate of 7%, which is higher than the expected rate based on the literature on photon therapies. We aim to evaluate the hypothesis that the increased relative biological effectiveness (RBE) at the distal edge of proton beams is the cause. METHODS AND MATERIALS: We combined the cohort from the prospective clinical trial and a retrospective cohort from a database. Monte Carlo simulations were performed to recalculate the physical dose and dose-averaged linear energy transfer (LETd). The first 10 ribs and fracture areas in patients with fractures were contoured and deformably registered. The LETd-weighted dose was used as a surrogate for biological effectiveness and compared with the conventional fixed RBE of 1.1. Dose to 0.5 cm3 of the ribs (D0.5) was selected to analyze the dose-response relationship using logistic regression. We chose an alpha/beta ratio of 3 to calculate the biological effective dose in Gy3(RBE). RESULTS: Thirteen of 203 patients in the cohorts exhibited a total of 25 fractures. The LETd in fractured areas is increased (6.1 ± 2.0 keV/µm, mean ± standard deviation), suggesting possible end-of-range radiobiological effects with increased RBE. The D0.5 of the fractured ribs is 80.3 ± 9.4 Gy3(RBE) with a generic factor of 1.1 and is relatively low compared with historical photon results. On the other hand, the D0.5 of the fractured ribs is 100.0 ± 12.5 Gy3(RBE) using the LETd-based model with a dose-response curve that is more consistent with historical photon data. CONCLUSIONS: The increased rib fracture rate seen in our trial is probably associated with the increased LETd and RBE at the distal edge of proton beams. This phenomenon warrants further investigation and possible integration of LETd into treatment planning and optimization in proton therapy.

The TOPAS tool for particle simulation, a Monte Carlo simulation tool for physics, biology and clinical research.

PURPOSE: This paper covers recent developments and applications of the TOPAS TOol for PArticle Simulation and presents the approaches used to disseminate TOPAS. MATERIALS AND METHODS: Fundamental understanding of radiotherapy and imaging is greatly facilitated through accurate and detailed simulation of the passage of ionizing radiation through apparatus and into a patient using Monte Carlo (MC). TOPAS brings Geant4, a reliable, experimentally validated MC tool mainly developed for high energy physics, within easy reach of medical physicists, radiobiologists and clinicians. Requiring no programming knowledge, TOPAS provides all of the flexibility of Geant4. RESULTS: After 5 years of development followed by its initial release, TOPAS was subsequently expanded from its focus on proton therapy physics to incorporate radiobiology modeling. Next, in 2018, the developers expanded their user support and code maintenance as well as the scope of TOPAS towards supporting X-ray and electron therapy and medical imaging. Improvements have been achieved in user enhancement through software engineering and a graphical user interface, calculational efficiency, validation through experimental benchmarks and QA measurements, and either newly available or recently published applications. A large and rapidly increasing user base demonstrates success in our approach to dissemination of this uniquely accessible and flexible MC research tool. CONCLUSIONS: The TOPAS developers continue to make strides in addressing the needs of the medical community in applications of ionizing radiation to medicine, creating the only fully integrated platform for four-dimensional simulation of all forms of radiotherapy and imaging with ionizing radiation, with a design that promotes inter-institutional collaboration.

A Monte Carlo model for organ dose reconstruction of patients in pencil beam scanning (PBS) proton therapy for epidemiologic studies of late effects.

Significant efforts such as the Pediatric Proton/Photon Consortium Registry (PPCR) involving multiple proton therapy centers have been made to conduct collaborative studies evaluating outcomes following proton therapy. As a groundwork dosimetry effort for the late effect investigation, we developed a Monte Carlo (MC) model of proton pencil beam scanning (PBS) to estimate organ/tissue doses of pediatric patients at the Maryland Proton Treatment Center (MPTC), one of the proton centers involved in the PPCR. The MC beam modeling was performed using the TOPAS (TOol for PArticle Simulation) MC code and commissioned to match measurement data within 1% for range, and 0.3 mm for spot sizes. The established MC model was then tested by calculating organ/tissue doses for sample intracranial and craniospinal irradiations on whole-body pediatric computational human phantoms. The simulated dose distributions were compared with the treatment planning system dose distributions, showing the 3 mm/3% gamma index passing rates of 94%-99%, validating our simulations with the MC model. The calculated organ/tissue doses per prescribed doses for the craniospinal irradiations (1 mGy Gy-1 to 1 Gy Gy-1) were generally much higher than those for the intracranial irradiations (2.1 µGy Gy-1 to 0.1 Gy Gy-1), which is due to the larger field coverage of the craniospinal irradiations. The largest difference was observed at the adrenal dose, i.e. ∼3000 times. In addition, the calculated organ/tissue doses were compared with those calculated with a simplified MC model, showing that the beam properties (i.e. spot size, spot divergence, mean energy, and energy spread) do not significantly influence dose calculations despite the limited irradiation cases. This implies that the use of the MC model commissioned to the MPTC measurement data might be dosimetrically acceptable for patient dose reconstructions at other proton centers particularly when their measurement data are unavailable. The developed MC model will be used to reconstruct organ/tissue doses for MPTC pediatric patients collected in the PPCR.

Development of a chest digital tomosynthesis R/F system and implementation of low-dose GPU-accelerated compressed sensing (CS) image reconstruction.

PURPOSE: This work describes the hardware and software developments of a prototype chest digital tomosynthesis (CDT) R/F system. The purpose of this study was to validate the developed system for its possible clinical application on low-dose chest tomosynthesis imaging. METHODS: The prototype CDT R/F system was operated by carefully controlling the electromechanical subsystems through a synchronized interface. Once a command signal was delivered by the user, a tomosynthesis sweep started to acquire 81 projection views (PVs) in a limited angular range of ±20°. Among the full projection dataset of 81 images, several sets of 21 (quarter view) and 41 (half view) images with equally spaced angle steps were selected to represent a sparse view condition. GPU-accelerated and total-variation (TV) regularization strategy-based compressed sensing (CS) image reconstruction was implemented. The imaged objects were a flat-field using a copper filter to measure the noise power spectrum (NPS), a Catphan® CTP682 quality assurance (QA) phantom to measure a task-based modulation transfer function (MTFTask ) of three different cylinders' edge, and an anthropomorphic chest phantom with inserted lung nodules. The authors also verified the accelerated computing power over CPU programming by checking the elapsed time required for the CS method. The resultant absorbed and effective doses that were delivered to the chest phantom from two-view digital radiographic projections, helical computed tomography (CT), and the prototype CDT system were compared. RESULTS: The prototype CDT system was successfully operated, showing little geometric error with fast rise and fall times of R/F x-ray pulse less than 2 and 10 ms, respectively. The in-plane NPS presented essential symmetric patterns as predicted by the central slice theorem. The NPS images from 21 PVs were provided quite different pattern against 41 and 81 PVs due to aliased noise. The voxel variance values which summed all NPS intensities were inversely proportional to the number of PVs, and the CS method gave much lower voxel variance by the factors of 3.97-6.43 and 2.28-3.36 compared to filtered backprojection (FBP) and 20 iterations of simultaneous algebraic reconstruction technique (SART). The spatial frequencies of the f50 at which the MTFTask reduced to 50% were 1.50, 1.55, and 1.67 cycles/mm for FBP, SART, and CS methods, respectively, in the case of Bone 20% cylinder using 41 views. A variety of ranges of TV reconstruction parameters were implemented during the CS method and we could observe that the NPS and MTFTask preserved best when the regularization and TV smoothing parameters α and τ were in a range of 0.001-0.1. For the chest phantom data, the signal difference to noise ratios (SDNRs) were higher in the proposed CS scheme images than in the FBP and SART, showing the enhanced rate of 1.05-1.43 for half view imaging. The total averaged reconstruction time during 20 iterations of the CS scheme was 124.68 s, which could match-up a clinically feasible time (<3 min). This computing time represented an enhanced speed 386 times greater than CPU programming. The total amounts of estimated effective doses were 0.12, 0.53 (half view), and 2.56 mSv for two-view radiographs, the prototype CDT system, and helical CT, respectively, showing 4.49 times higher than conventional radiography and 4.83 times lower than a CT exam, respectively. CONCLUSIONS: The current work describes the development and performance assessment of both hardware and software for tomosynthesis applications. The authors observed reasonable outcomes by showing a potential for low-dose application in CDT imaging using GPU acceleration.

Correction: Dependence of gold nanoparticle radiosensitization on cell geometry.

Correction for 'Dependence of gold nanoparticle radiosensitization on cell geometry' by Wonmo Sung, et al., Nanoscale, 2017, 9, 5843-5853.