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BACKGROUND: Two radiotherapy fractionation schedules are used to treat locally advanced bladder cancer: 64 Gy in 32 fractions over 6·5 weeks and a hypofractionated schedule of 55 Gy in 20 fractions over 4 weeks. Long-term outcomes of these schedules in several cohort studies and case series suggest that response, survival, and toxicity are similar, but no direct comparison has been published. The present study aimed to assess the non-inferiority of 55 Gy in 20 fractions to 64 Gy in 32 fractions in terms of invasive locoregional control and late toxicity in patients with locally advanced bladder cancer. METHODS: We did a meta-analysis of individual patient data from patients (age ≥18 years) with locally advanced bladder cancer (T1G3 [high-grade non-muscle invasive] or T2-T4, N0M0) enrolled in two multicentre, randomised, controlled, phase 3 trials done in the UK: BC2001 (NCT00024349; assessing addition of chemotherapy to radiotherapy) and BCON (NCT00033436; assessing hypoxia-modifying therapy combined with radiotherapy). In each trial, the fractionation schedule was chosen according to local standard practice. Co-primary endpoints were invasive locoregional control (non-inferiority margin hazard ratio [HR]=1·25); and late bladder or rectum toxicity, assessed with the Late Effects Normal Tissue Task Force-Subjective, Objective, Management, Analytic tool (non-inferiority margin for absolute risk difference [RD]=10%). If non-inferiority was met for invasive locoregional control, superiority could be considered if the 95% CI for the treatment effect excluded the null effect (HR=1). One-stage individual patient data meta-analysis models for the time-to-event and binary outcomes were used, accounting for trial differences, within-centre correlation, randomised treatment received, baseline variable imbalances, and potential confounding from relevant prognostic factors. FINDINGS: 782 patients with known fractionation schedules (456 from the BC2001 trial and 326 from the BCON trial; 376 (48%) received 64 Gy in 32 fractions and 406 (52%) received 55 Gy in 20 fractions) were included in our meta-analysis. Median follow-up was 120 months (IQR 99-159). Patients who received 55 Gy in 20 fractions had a lower risk of invasive locoregional recurrence than those who received 64 Gy in 32 fractions (adjusted HR 0·71 [95% CI 0·52-0·96]). Both schedules had similar toxicity profiles (adjusted RD -3·37% [95% CI -11·85 to 5·10]). INTERPRETATION: A hypofractionated schedule of 55 Gy in 20 fractions is non-inferior to 64 Gy in 32 fractions with regard to both invasive locoregional control and toxicity, and is superior with regard to invasive locoregional control. 55 Gy in 20 fractions should be adopted as a standard of care for bladder preservation in patients with locally advanced bladder cancer. FUNDING: Cancer Research UK.
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Fraccionamiento de la Dosis de Radiación , Recurrencia Local de Neoplasia/radioterapia , Hipofraccionamiento de la Dosis de Radiación/normas , Neoplasias de la Vejiga Urinaria/radioterapia , Supervivencia sin Enfermedad , Humanos , Recurrencia Local de Neoplasia/epidemiología , Recurrencia Local de Neoplasia/patología , Factores de Riesgo , Resultado del Tratamiento , Neoplasias de la Vejiga Urinaria/epidemiología , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
Developments in the genome organisation field has resulted in the recent methodology to infer spatial conformations of the genome directly from experimentally measured genome contacts (Hi-C data). This provides a detailed description of both intra- and inter-chromosomal arrangements. Chromosomal intermingling is an important driver for radiation-induced DNA mis-repair. Which is a key biological endpoint of relevance to the fields of cancer therapy (radiotherapy), public health (biodosimetry) and space travel. For the first time, we leverage these methods of inferring genome organisation and couple them to nano-dosimetric radiation track structure modelling to predict quantities and distribution of DNA damage within cell-type specific geometries. These nano-dosimetric simulations are highly dependent on geometry and are benefited from the inclusion of experimentally driven chromosome conformations. We show how the changes in Hi-C contract maps impact the inferred geometries resulting in significant differences in chromosomal intermingling. We demonstrate how these differences propagate through to significant changes in the distribution of DNA damage throughout the cell nucleus, suggesting implications for DNA repair fidelity and subsequent cell fate. We suggest that differences in the geometric clustering for the chromosomes between the cell-types are a plausible factor leading to changes in cellular radiosensitivity. Furthermore, we investigate changes in cell shape, such as flattening, and show that this greatly impacts the distribution of DNA damage. This should be considered when comparing in vitro results to in vivo systems. The effect may be especially important when attempting to translate radiosensitivity measurements at the experimental in vitro level to the patient or human level.
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Roturas del ADN de Doble Cadena , ADN/efectos de la radiación , Genoma , Neoplasias/tratamiento farmacológico , Cromosomas/efectos de la radiación , Análisis por Conglomerados , Simulación por Computador , Humanos , Tolerancia a RadiaciónRESUMEN
A new method to locate, with millimetre uncertainty, in 3D, a γ -ray source emitting multiple γ -rays in a cascade, employing conventional LaBr3(Ce) scintillation detectors, has been developed. Using 16 detectors in a symmetrical configuration the detector energy and time signals, resulting from the γ -ray interactions, are fed into a new source position reconstruction algorithm. The Monte-Carlo based Geant4 framework has been used to simulate the detector array and a 60Co source located at two positions within the spectrometer central volume. For a source located at (0,0,0) the algorithm reports X, Y, Z values of -0.3 ± 2.5, -0.4 ± 2.4, and -0.6 ± 2.5 mm, respectively. For a source located at (20,20,20) mm, with respect to the array centre, the algorithm reports X, Y, Z values of 20.2 ± 1.0, 20.2 ± 0.9, and 20.1 ± 1.2 mm. The resulting precision of the reconstruction means that this technique could find application in a number of areas including nuclear medicine, national security, radioactive waste assay and proton beam therapy.
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PURPOSE: For the 1.5 T Elekta MR-Linac it is essential that the optimisation of a treatment plan accounts for the electron return effect on the planned dose distribution. The ability of two algorithms for the first stage fluence optimisation, pencil beam (PB) and Monte Carlo (MC), to produce acceptable plan quality was investigated. Optimisation time for each algorithm was also compared. METHODS: Ten head and neck patients, ten lung patients and five prostate patients were selected from the clinical archive. These were retrospectively planned using a research version of Monaco with both the PB and MC algorithms for the fluence optimisation stage. After full optimisation DVH parameters, optimisation time and the number of Monitor Units (MU) as a measure of plan complexity were extracted. RESULTS: There were no clinically significant differences between any of the DVH parameters studied or the total number of MUs between using PB or MC for stage 1 optimisation across the three patient groups. However, planning time increased by a factor of ten using MC algorithms for stage 1. CONCLUSION: The use of MC calculations compared to PB, for stage 1 fluence optimisation, results in increased planning time without clinical improvement in plan quality or reduction in complexity and is therefore not necessary.
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Neoplasias de Cabeza y Cuello/radioterapia , Neoplasias Pulmonares/radioterapia , Aceleradores de Partículas/instrumentación , Neoplasias de la Próstata/radioterapia , Planificación de la Radioterapia Asistida por Computador/métodos , Radioterapia de Intensidad Modulada/normas , Humanos , Masculino , Método de Montecarlo , Dosificación Radioterapéutica , Radioterapia de Intensidad Modulada/métodos , Estudios RetrospectivosRESUMEN
Contouring structures in the head and neck is time-consuming, and automatic seg-mentation is an important part of an adaptive radiotherapy workflow. Geometric accuracy of automatic segmentation algorithms has been widely reported, but there is no consensus as to which metrics provide clinically meaningful results. This study investigated whether geometric accuracy (as quantified by several commonly used metrics) was associated with dosimetric differences for the parotid and larynx, comparing automatically generated contours against manually drawn ground truth contours. This enabled the suitability of different commonly used metrics to be assessed for measuring automatic segmentation accuracy of the parotid and larynx. Parotid and larynx structures for 10 head and neck patients were outlined by five clinicians to create ground truth structures. An automatic segmentation algorithm was used to create automatically generated normal structures, which were then used to create volumetric-modulated arc therapy plans. The mean doses to the automatically generated structures were compared with those of the corresponding ground truth structures, and the relative difference in mean dose was calculated for each structure. It was found that this difference did not correlate with the geometric accuracy provided by several metrics, notably the Dice similarity coefficient, which is a commonly used measure of spatial overlap. Surface-based metrics provided stronger correlation and are, therefore, more suitable for assessing automatic seg-mentation of the parotid and larynx.
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Algoritmos , Neoplasias de Cabeza y Cuello/diagnóstico por imagen , Laringe/diagnóstico por imagen , Glándula Parótida/diagnóstico por imagen , Reconocimiento de Normas Patrones Automatizadas/métodos , Planificación de la Radioterapia Asistida por Computador/métodos , Tomografía Computarizada por Rayos X/métodos , Neoplasias de Cabeza y Cuello/radioterapia , Humanos , Laringe/anatomía & histología , Glándula Parótida/anatomía & histología , Dosificación Radioterapéutica , Radioterapia de Intensidad ModuladaRESUMEN
Objectives: Proton therapy has a theoretical dosimetric advantage due to the Bragg peak, but the linear energy transfer (LET), and therefore the relative biological effectiveness (RBE), increase at the end of range. For patients with Hodgkin lymphoma, the distal edge of beam is often located within or close to the heart, where elevated RBE would be of potential concern. The purpose of this study was to investigate the impact of RBE and the choice of beam arrangement for adolescent patients with mediastinal Hodgkin lymphoma. Methods: For three previously treated adolescent patients, proton plans with 1-3 fields were created to a prescribed dose of 19.8 Gy (RBE) in 11 fractions (Varian Eclipse v13.7), assuming an RBE of 1.1. Plans were recalculated using Monte-Carlo (Geant4 v10.3.3/Gate v8.1) to calculate dose-averaged LET. Variable RBE-weighted dose was calculated using the McNamara model, assuming an α/ß ratio of 2 Gy for organs-at-risk. Results: Although the LET decreased as the number of fields increased, the difference in RBE-weighted dose (Δdose) to organs-at-risk did not consistently decrease. Δdose values varied by patient and organ and were mostly of the order of 0-3 Gy (RBE), with a worst-case of 4.75 Gy (RBE) in near-maximum dose to the left atrium for one plan. Conclusions: RBE-weighted doses to organs-at-risk are sensitive to the choice of RBE model, which is of particular concern for the heart. Advances in knowledge: There is a need to remain cautious when evaluating proton plans for Hodgkin lymphoma, especially when near-maximum doses to organs-at-risk are considered.
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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.
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Terapia de Protones , Protones , Humanos , Efectividad Biológica Relativa , Planificación de la Radioterapia Asistida por Computador/métodos , Terapia de Protones/métodos , Transferencia Lineal de Energía , Método de MontecarloRESUMEN
Immunofluorescent tagging of DNA double-strand break (DSB) markers, such as γ-H2AX and other DSB repair proteins, are powerful tools in understanding biological consequences following irradiation. However, whilst the technique is widespread, there are many uncertainties related to its ability to resolve and reliably deduce the number of foci when counting using microscopy. We present a new tool for simulating radiation-induced foci in order to evaluate microscope performance within in silico immunofluorescent images. Simulations of the DSB distributions were generated using Monte Carlo track-structure simulation. For each DSB distribution, a corresponding DNA repair process was modelled and the un-repaired DSBs were recorded at several time points. Corresponding microscopy images for both a DSB and (γ-H2AX) fluorescent marker were generated and compared for different microscopes, radiation types and doses. Statistically significant differences in miscounting were found across most of the tested scenarios. These inconsistencies were propagated through to repair kinetics where there was a perceived change between radiation-types. These changes did not reflect the underlying repair rate and were caused by inconsistencies in foci counting. We conclude that these underlying uncertainties must be considered when analysing images of DNA damage markers to ensure differences observed are real and are not caused by non-systematic miscounting.
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Reparación del ADNRESUMEN
OBJECTIVES: High-energy Proton Beam Therapy (PBT) commenced in England in 2018 and NHS England commissions PBT for 1.5% of patients receiving radical radiotherapy. We sought expert opinion on the level of provision. METHODS: Invitations were sent to 41 colleagues working in PBT, most at one UK centre, to contribute by completing a spreadsheet. 39 responded: 23 (59%) completed the spreadsheet; 16 (41%) declined, arguing that clinical outcome data are lacking, but joined six additional site-specialist oncologists for two consensus meetings. The spreadsheet was pre-populated with incidence data from Cancer Research UK and radiotherapy use data from the National Cancer Registration and Analysis Service. 'Mechanisms of Benefit' of reduced growth impairment, reduced toxicity, dose escalation and reduced second cancer risk were examined. RESULTS: The most reliable figure for percentage of radical radiotherapy patients likely to benefit from PBT was that agreed by 95% of the 23 respondents at 4.3%, slightly larger than current provision. The median was 15% (range 4-92%) and consensus median 13%. The biggest estimated potential benefit was from reducing toxicity, median benefit to 15% (range 4-92%), followed by dose escalation median 3% (range 0 to 47%); consensus values were 12 and 3%. Reduced growth impairment and reduced second cancer risk were calculated to benefit 0.5% and 0.1%. CONCLUSIONS: The most secure estimate of percentage benefit was 4.3% but insufficient clinical outcome data exist for confident estimates. The study supports the NHS approach of using the evidence base and developing it through randomised trials, non-randomised studies and outcomes tracking. ADVANCES IN KNOWLEDGE: Less is known about the percentage of patients who may benefit from PBT than is generally acknowledged. Expert opinion varies widely. Insufficient clinical outcome data exist to provide robust estimates. Considerable further work is needed to address this, including international collaboration; much is already underway but will take time to provide mature data.
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Neoplasias Primarias Secundarias , Terapia de Protones , Terapia por Rayos X , Humanos , Neoplasias Primarias Secundarias/radioterapiaRESUMEN
Objective: The Covid-19 pandemic placed unprecedented strain on medical education and led to a vast increase in online learning. Subsequently, the Christie International Proton School moved from face-to-face to online. Delegate feedback and current literature were studied to determine benefits, challenges, and potential solutions, for online proton therapy education. Methods: The course was converted to a 6-week online course with twice weekly 2-h sessions. Feedback was studied pre-, during-, and post-course regarding demographics, learning objectives, proton therapy knowledge, ease of engagement, technical difficulties, and course format. Statistical analyses were performed for proton therapy knowledge pre- and post-course. Results: An increase in delegate attendance was seen with increased international and multidisciplinary diversity. Learner objectives included treatment planning, clinical applications, physics, and centre development. Average learner reported scores of confidence in proton therapy knowledge improved significantly from 3, some knowledge, to 4, adequate knowledge after the course (p<0.0001). There were minimal reported difficulties using the online platform, good reported learner engagement, and shorter twice weekly sessions were reported conducive for learning. Recordings for asynchronous learning addressed time zone difficulties. Conclusion: The obligatory switch to online platforms has catalysed a paradigm shift towards online learning with delegates reporting educational benefit. We propose solutions to challenges of international online education, and a pedagogical model for online proton therapy education. Advances in knowledge: Online education is an effective method to teach proton therapy to international audiences. The future of proton education includes a hybrid of online and practical face-to-face learning depending on the level of cognitive skill required.
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Learning health systems and rapid-learning are well developed at the conceptual level. The promise of rapidly generating and applying evidence where conventional clinical trials would not usually be practical is attractive in principle. The connectivity of modern digital healthcare information systems and the increasing volumes of data accrued through patients' care pathways offer an ideal platform for the concepts. This is particularly true in radiotherapy where modern treatment planning and image guidance offers a precise digital record of the treatment planned and delivered. The vision is of real-world data, accrued by patients during their routine care, being used to drive programmes of continuous clinical improvement as part of standard practice. This vision, however, is not yet a reality in radiotherapy departments. In this article we review the literature to explore why this is not the case, identify barriers to its implementation, and suggest how wider clinical application might be achieved.
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Aprendizaje del Sistema de Salud , Oncología por Radiación , Humanos , AprendizajeRESUMEN
The strongin vitroevidence that proton Relative Biological Effectiveness (RBE) varies with Linear Energy Transfer (LET) has led to an interest in applying LET within treatment planning. However, there is a lack of consensus on LET definition, Monte Carlo (MC) parameters or clinical methodology. This work aims to investigate how common variations of LET definition may affect potential clinical applications. MC simulations (GATE/GEANT4) were used to calculate absorbed dose and different types of LET for a simple Spread Out Bragg Peak (SOBP) and for four clinical PBT plans covering a range of tumour sites. Variations in the following LET calculation methods were considered: (i) averaging (dose-averaged LET (LETd) & track-averaged LET); (ii) scoring (LETdto water, to medium and to mass density); (iii) particle inclusion (LETdto all protons, to primary protons and to particles); (iv) MC settings (hit type and Maximum Step Size (MSS)). LET distributions were compared using: qualitative comparison, LET Volume Histograms (LVHs), single value criteria (maximum and mean values) and optimised LET-weighted dose models. Substantial differences were found between LET values in averaging, scoring and particle type. These differences depended on the methodology, but for one patient a difference of â¼100% was observed between the maximum LETdfor all particles and maximum LETdfor all protons within the brainstem in the high isodose region (4 keVµm-1and 8 keVµm-1respectively). An RBE model using LETdincluding heavier ions was found to predict substantially different LET-weighted dose compared to those using other LET definitions. In conclusion, the selection of LET definition may affect the results of clinical metrics considered in treatment planning and the results of an RBE model. The authors' advocate for the scoring of dose-averaged LET to water for primary and secondary protons using a random hit type and automated MSS.
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Transferencia Lineal de Energía , Terapia de Protones , Humanos , Método de Montecarlo , Terapia de Protones/métodos , Protones , Efectividad Biológica RelativaRESUMEN
PURPOSE: Experimental assessment of inter-centre variation and absolute accuracy of stopping-power-ratio (SPR) prediction within 17 particle therapy centres of the European Particle Therapy Network. MATERIAL AND METHODS: A head and body phantom with seventeen tissue-equivalent materials were scanned consecutively at the participating centres using their individual clinical CT scan protocol and translated into SPR with their in-house CT-number-to-SPR conversion. Inter-centre variation and absolute accuracy in SPR prediction were quantified for three tissue groups: lung, soft tissues and bones. The integral effect on range prediction for typical clinical beams traversing different tissues was determined for representative beam paths for the treatment of primary brain tumours as well as lung and prostate cancer. RESULTS: An inter-centre variation in SPR prediction (2σ) of 8.7%, 6.3% and 1.5% relative to water was determined for bone, lung and soft-tissue surrogates in the head setup, respectively. Slightly smaller variations were observed in the body phantom (6.2%, 3.1%, 1.3%). This translated into inter-centre variation of integral range prediction (2σ) of 2.9%, 2.6% and 1.3% for typical beam paths of prostate-, lung- and primary brain-tumour treatments, respectively. The absolute error in range exceeded 2% in every fourth participating centre. The consideration of beam hardening and the execution of an independent HLUT validation had a positive effect, on average. CONCLUSION: The large inter-centre variations in SPR and range prediction justify the currently clinically used margins accounting for range uncertainty, which are of the same magnitude as the inter-centre variation. This study underlines the necessity of higher standardisation in CT-number-to-SPR conversion.
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Terapia de Protones , Humanos , Masculino , Fantasmas de Imagen , Planificación de la Radioterapia Asistida por Computador , Tomografía Computarizada por Rayos X , IncertidumbreRESUMEN
In the UK, one in two people will develop cancer during their lifetimes and radiotherapy (RT) plays a key role in effective treatment. High energy proton beam therapy commenced in the UK National Health Service in 2018. Heavier charged particles have potential advantages over protons by delivering more dose in the Bragg peak, with a sharper penumbra, lower oxygen dependence and increased biological effectiveness. However, they also require more costly equipment including larger gantries to deliver the treatment. There are significant uncertainties in the modelling of relative biological effectiveness and the effects of the fragmentation tail which can deliver dose beyond the Bragg peak. These effects need to be carefully considered especially in relation to long-term outcomes.In 2019, a group of clinicians, clinical scientists, engineers, physical and life scientists from academia and industry, together with funding agency stakeholders, met to consider how the UK should address new technologies for RT, especially the use of heavier charged particles such as helium and carbon and new modes of delivery such as FLASH and spatially fractionated radiotherapy (SFRT).There was unanimous agreement that the UK should develop a facility for heavier charged particle therapy, perhaps constituting a new National Ion Research Centre to enable research using protons and heavier charged particles. Discussion followed on the scale and features, including which ions should be included, from protons through helium, boron, and lithium to carbon, and even oxygen. The consensus view was that any facility intended to treat patients must be located in a hospital setting while providing dedicated research space for physics, preclinical biology and clinical research with beam lines designed for both in vitro and in vivo research. The facility should to be able to investigate and deliver both ultra-high dose rate FLASH RT and SFRT (GRID, minibeams etc.). Discussion included a number of accelerator design options and whether gantries were required. Other potential collaborations might be exploited, including with space agencies, electronics and global communications industries and the nuclear industry.In preparation for clinical delivery, there may be opportunities to send patients overseas (for 12C or 4He ion therapy) using the model of the National Health Service (NHS) Proton Overseas Programme and to look at potential national clinical trials which include heavier ions, FLASH or SFRT. This could be accomplished under the auspices of NCRI CTRad (National Cancer Research Institute, Clinical and Translational Radiotherapy Research Working Group).The initiative should be a community approach, involving all interested parties with a vision that combines discovery science, a translational research capability and a clinical treatment facility. Barriers to the project and ways to overcome them were discussed. Finally, a set of different scenarios of features with different costs and timelines was constructed, with consideration given to the funding environment (prer-Covid-19) and need for cross-funder collaboration.
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Fraccionamiento de la Dosis de Radiación , Radioterapia de Iones Pesados/métodos , Neoplasias/radioterapia , Humanos , Reino UnidoRESUMEN
PURPOSE: Due to differences in attenuation and the electron return effect (ERE), the presence of gas can increase the risk of toxicity in organs at risk (OAR) during magnetic resonance-guided radiotherapy (MRgRT). Current adaptive MRgRT workflows using density overrides negate gas from the dose calculation, meaning that the effects of ERE around gas are not taken into account. In order to achieve an accurate adaptive MRgRT treatment, we should be able to quickly evaluate whether gas present during treatment causes dose constraint violation during an MRgRT fraction. We propose an analytic method for predicting dose perturbations caused by air cavities in OARs during MRgRT. METHOD: Ten virtual water phantoms were created: nine containing a centrally located spherical air cavity and a reference phantom without an air cavity. Monte Carlo dose calculations were produced to irradiate the phantoms with a single 7 MV photon beam under the influence of a 1.5 T transverse magnetic field (Monaco 5.19.02 Treatment Panning System (TPS) (Elekta AB, Stockholm, Sweden)). Dose distributions of the phantoms with and without air cavities were compared. We used a spherical coordinate system originating in the center of the cavity to sample the dose distributions and calculate the dose perturbation as a result of the presence of each air cavity, ∆D%(θ,Φ)calc . . Dose effects due to ERE and differences in attenuation due to density changes were considered separately. Least squared analysis was used to fit the calculated dose perturbations to mathematical functions. Effects due to ERE were fit to a modulated sinusoidal function and those due to attenuation differences were fit to a 2D Gaussian function. We used the fits to derive a single equation describing dose perturbations around spherical air cavities as a function of angles, θ, Φ, distance from cavity surface, d, and cavity radius, r. We measured the fitting error by calculating the residual error (RE); the difference between the calculated and fitted dose perturbation. RESULTS: Both ERE and differences in attenuation contribute toward the total dose effects of air cavities in MRgRT. Whereas ERE dominates close to the surface of the cavities, attenuation effects dominate at distances >0.5 cm from the cavities. We showed that dose effects around a spherical air cavity (≤1 cm from the surface) due to ERE fit a modulated sinusoidal function with mean (RE) ≤-1.4E-5% and root mean square error (rms) (RE) ≤4.1%. Effects due to attenuation differences fit a Gaussian function with mean (RE) ≤0.7% and rms (RE) ≤1.8%. Our general equation, which we verified using multiple sizes of spherical and cylindrical air cavity, fits Monte Carlo simulated data with mean (RE) ≤±0.9% and rms (RE) ≤6.9%. CONCLUSION: We show that local dose perturbations around unplanned spherical air cavities during MRgRT can be well characterized analytically. We present an equation that can be incorporated into the clinical workflow to allow for fast evaluation of dose effects of unplanned gas. We also envision this method contributing to the clinical implementation of real time adaptive radiotherapy (ART) for MRgRT using MRI planning.
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Planificación de la Radioterapia Asistida por Computador , Radioterapia Guiada por Imagen , Espectroscopía de Resonancia Magnética , Método de Montecarlo , Fantasmas de Imagen , Dosificación Radioterapéutica , SueciaRESUMEN
OBJECTIVE: Monte Carlo (MC) simulations substantially improve the accuracy of predicted doses. This study aims to determine and quantify the uncertainties of setting up such a MC system. METHODS: Doses simulated with two Geant4-based MC calculation codes, but independently tuned to the same beam data, have been compared. Different methods of MC modelling of a pre-absorber have been employed, either modifying the beam source parameters (descriptive) or adding the pre-absorber as a physical component (physical). RESULTS: After the independent beam modelling of both systems in water (resulting in excellent range agreement) range differences of up to 3.6/4.8 mm (1.5% of total range) in bone/brain-like tissues were found, which resulted from the use of different mean water ionisation potentials during the energy tuning process. When repeating using a common definition of water, ranges in bone/brain agreed within 0.1 mm and gamma-analysis (global 1%,1mm) showed excellent agreement (>93%) for all patient fields. However, due to a lack of modelling of proton fluence loss in the descriptive pre-absorber, differences of 7% in absolute dose between the pre-absorber definitions were found. CONCLUSION: This study quantifies the influence of using different water ionisation potentials during the MC beam modelling process. Furthermore, when using a descriptive pre-absorber model, additional Faraday cup or ionisation chamber measurements with pre-absorber are necessary. ADVANCES IN KNOWLEDGE: This is the first study quantifying the uncertainties caused by the MC beam modelling process for proton pencil beam scanning, and a more detailed beam modelling process for MC simulations is proposed to minimise the influence of critical parameters.
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Método de Montecarlo , Terapia de Protones/métodos , Incertidumbre , Absorción de Radiación , Aire , Huesos/efectos de la radiación , Encéfalo/efectos de la radiación , Humanos , Hipofraccionamiento de la Dosis de Radiación , Dosificación Radioterapéutica , Reproducibilidad de los Resultados , AguaRESUMEN
OBJECTIVES: Software re-calculation of proton pencil beam scanning plans provides a method of verifying treatment planning system (TPS) dose calculations prior to patient treatment. This study describes the implementation of AutoMC, a Geant4 v10.3.3/Gate v8.1 (Gate-RTion v1.0)-based Monte-Carlo (MC) system for automated plan re-calculation, and presents verification results for 153 patients (730 fields) planned within year one of the proton service at The Christie NHS Foundation Trust. METHODS: A MC beam model for a Varian ProBeam delivery system with four range-shifter options (none, 2 cm, 3 cm, 5 cm) was derived from beam commissioning data and implemented in AutoMC. MC and TPS (Varian Eclipse v13.7) calculations of 730 fields in solid-water were compared to physical plan-specific quality assurance (PSQA) measurements acquired using a PTW Octavius 1500XDR array and PTW 31021 Semiflex 3D ion chamber. RESULTS: TPS and MC showed good agreement with array measurements, evaluated using γ analyses at 3%, 3 mm with a 10% lower dose threshold:>94% of fields calculated by the TPS and >99% of fields calculated by MC had γ ≤ 1 for>95% of measurement points within the plane. TPS and MC also showed good agreement with chamber measurements of absolute dose, with systematic differences of <1.5% for all range-shifter options. CONCLUSIONS: Reliable independent verification of the TPS dose calculation is a valuable complement to physical PSQA and may facilitate reduction of the physical PSQA workload alongside a thorough delivery system quality assurance programme. ADVANCES IN KNOWLEDGE: A Gate/Geant4-based MC system is thoroughly validated against an extensive physical PSQA dataset for 730 clinical fields, showing that clinical implementation of MC for PSQA is feasible.
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Terapia de Protones/métodos , Garantía de la Calidad de Atención de Salud , Planificación de la Radioterapia Asistida por Computador , Algoritmos , Calibración , Inglaterra , Humanos , Método de Montecarlo , Dosificación Radioterapéutica , Reproducibilidad de los ResultadosRESUMEN
After radiation exposure, one of the critical processes for cellular survival is the repair of DNA double strand breaks. The pathways involved in this response are complex in nature and involve many individual steps that act across different time scales, all of which combine to produce an overall behaviour. It is therefore experimentally challenging to unambiguously determine the mechanisms involved and how they interact whilst maintaining strict control of all confounding variables. In silico methods can provide further insight into results produced by focused experimental investigations through testing of the hypotheses generated. Such computational testing can asses competing hypotheses by investigating their effects across all time scales concurrently, highlighting areas where further experimental work can have the most significance. We describe the construction of a mechanistic model by combination of several hypothesised mechanisms reported in the literature and supported by experiment. Compatibility of these mechanisms was tested by fitting simulation to results reported in the literature. To avoid over-fitting, we used an approach of sequentially testing individual mechanisms within this pathway. We demonstrate that using this approach the model is capable of reproducing published protein kinetics and overall repair trends. This provides evidence supporting the feasibility of the proposed mechanisms and revealed how they interact to produce an overall behaviour. Furthermore, we show that the assumed motion of individual double strand break ends plays a crucial role in determining overall system behaviour.
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Biología Computacional/métodos , Roturas del ADN de Doble Cadena , Reparación del ADN por Unión de Extremidades , Animales , Simulación por Computador , ADN/efectos de la radiación , Estudios de Factibilidad , Humanos , Modelos GenéticosRESUMEN
The UK has an important role in the evaluation of proton beam therapy (PBT) and takes its place on the world stage with the opening of the first National Health Service (NHS) PBT centre in Manchester in 2018, and the second in London coming in 2020. Systematic evaluation of the role of PBT is a key objective. By September 2019, 108 patients had started treatment, 60 paediatric, 19 teenagers and young adults and 29 adults. Obtaining robust outcome data is vital, if we are to understand the strengths and weaknesses of current treatment approaches. This is important in demonstrating when PBT will provide an advantage and when it will not, and in quantifying the magnitude of benefit.The UK also has an important part to play in translational PBT research, and building a research capability has always been the vision. We are perfectly placed to perform translational pre-clinical biological and physical experiments in the dedicated research room in Manchester. The nature of DNA damage from proton irradiation is considerably different from X-rays and this needs to be more fully explored. A better understanding is needed of the relative biological effectiveness (RBE) of protons, especially at the end of the Bragg peak, and of the effects on tumour and normal tissue of PBT combined with conventional chemotherapy, targeted drugs and immunomodulatory agents. These experiments can be enhanced by deterministic mathematical models of the molecular and cellular processes of DNA damage response. The fashion of ultra-high dose rate FLASH irradiation also needs to be explored.
Asunto(s)
Instituciones Oncológicas/estadística & datos numéricos , Terapia de Protones/estadística & datos numéricos , Medicina Estatal/estadística & datos numéricos , Adolescente , Adulto , Instituciones Oncológicas/provisión & distribución , Creación de Capacidad , Niño , Ensayos Clínicos como Asunto , Terapia Combinada/métodos , Daño del ADN , Inglaterra , Humanos , Modelos Teóricos , Neoplasias/radioterapia , Órganos en Riesgo/efectos de la radiación , Evaluación de Programas y Proyectos de Salud , Terapia de Protones/efectos adversos , Oncología por Radiación/educación , Planificación de la Radioterapia Asistida por Computador , Efectividad Biológica Relativa , Investigación , Investigación Biomédica Traslacional , Resultado del Tratamiento , Incertidumbre , Adulto JovenRESUMEN
PURPOSE: Geant4 is a multi-purpose Monte Carlo simulation tool for modeling particle transport in matter. It provides a wide range of settings, which the user may optimize for their specific application. This study investigates GATE/Geant4 parameter settings for proton pencil beam scanning therapy. METHODS: GATE8.1/Geant4.10.3.p03 (matching the versions used in GATE-RTion1.0) simulations were performed with a set of prebuilt Geant4 physics lists (QGSP_BIC, QGSP_BIC_EMY, QGSP_BIC_EMZ, QGSP_BIC_HP_EMZ), using 0.1mm-10mm as production cuts on secondary particles (electrons, photons, positrons) and varying the maximum step size of protons (0.1mm, 1mm, none). The results of the simulations were compared to measurement data taken during clinical patient specific quality assurance at The Christie NHS Foundation Trust pencil beam scanning proton therapy facility. Additionally, the influence of simulation settings was quantified in a realistic patient anatomy based on computer tomography (CT) scans. RESULTS: When comparing the different physics lists, only the results (ranges in water) obtained with QGSP_BIC (G4EMStandardPhysics_Option0) depend on the maximum step size. There is clinically negligible difference in the target region when using High Precision neutron models (HP) for dose calculations. The EMZ electromagnetic constructor provides a closer agreement (within 0.35 mm) to measured beam sizes in air, but yields up to 20% longer execution times compared to the EMY electromagnetic constructor (maximum beam size difference 0.79 mm). The impact of this on patient-specific quality assurance simulations is clinically negligible, with a 97% average 2%/2 mm gamma pass rate for both physics lists. However, when considering the CT-based patient model, dose deviations up to 2.4% are observed. Production cuts do not substantially influence dosimetric results in solid water, but lead to dose differences of up to 4.1% in the patient CT. Small (compared to voxel size) production cuts increase execution times by factors of 5 (solid water) and 2 (patient CT). CONCLUSIONS: Taking both efficiency and dose accuracy into account and considering voxel sizes with 2 mm linear size, the authors recommend the following Geant4 settings to simulate patient specific quality assurance measurements: No step limiter on proton tracks; production cuts of 1 mm for electrons, photons and positrons (in the phantom and range-shifter) and 10 mm (world); best agreement to measurement data was found for QGSP_BIC_EMZ reference physics list at the cost of 20% increased execution times compared to QGSP_BIC_EMY. For simulations considering the patient CT model, the following settings are recommended: No step limiter on proton tracks; production cuts of 1 mm for electrons, photons and positrons (phantom/range-shifter) and 10 mm (world) if the goal is to achieve sufficient dosimetric accuracy to ensure that a plan is clinically safe; or 0.1 mm (phantom/range-shifter) and 1 mm (world) if higher dosimetric accuracy is needed (increasing execution times by a factor of 2); most accurate results expected for QGSP_BIC_EMZ reference physics list, at the cost of 10-20% increased execution times compared to QGSP_BIC_EMY.