Search

Background: Clinical data suggest that the relative biological effectiveness (RBE) in proton therapy (PT) varies with linear energy transfer (LET). However, LET calculations are neither standardized nor available in clinical routine. Here, the status of LET calculations among European PT institutions and their comparability are assessed. Materials and methods: Eight European PT institutions used suitable treatment planning systems with their center-specific beam model to create treatment plans in a water phantom covering different field arrangements and fulfilling commonly agreed dose objectives. They employed their locally established LET simulation environments and procedures to determine the corresponding LET distributions. Dose distributions D 1.1 and D RBE assuming constant and variable RBE, respectively, and LET were compared among the institutions. Inter-center variability was assessed based on dose- and LET-volume-histogram parameters. Results: Treatment plans from six institutions fulfilled all clinical goals and were eligible for common analysis. D 1.1 distributions in the target volume were comparable among PT institutions. However, corresponding LET values varied substantially between institutions for all field arrangements, primarily due to differences in LET averaging technique and considered secondary particle spectra. Consequently, D RBE using non-harmonized LET calculations increased inter-center dose variations substantially compared to D 1.1 and significantly in mean dose to the target volume of perpendicular and opposing field arrangements (p < 0.05). Harmonizing LET reporting (dose-averaging, all protons, LET to water or to unit density tissue) reduced the inter-center variability in LET to the order of 10–15% within and outside the target volume for all beam arrangements. Consequentially, inter-institutional variability in D RBE decreased to that observed for D 1.1. Conclusion: Harmonizing the reported LET among PT centers is feasible and allows for consistent multi-centric analysis and reporting of tumor control and toxicity in view of a variable RBE. It may serve as basis for harmonized variable RBE dose prescription in PT.

FLASH radiotherapy is a rapidly developing field which promises improved normal tissue protection compared to conventional irradiation and no compromise on tumour control. The transient hypoxic state induced by the depletion of oxygen at high dose rates provides one possible explanation. However, studies have mostly focused on uniform fields of dose and there is a lack of investigation into the spatial and temporal variation of dose from proton pencil-beam scanning (PBS). A model of oxygen reaction and diffusion in tissue has been extended to simulate proton PBS delivery and its impact on oxygen levels. This provides a tool to predict oxygen effects from various PBS treatments, and explore potential delivery strategies. Here we present a number of case applications to demonstrate the use of this tool for FLASH-related investigations. We show that levels of oxygen depletion could vary significantly across a large parameter space for PBS treatments, and highlight the need for in silico models such as this to aid in the development and optimisation of FLASH radiotherapy.

There is strong in vitro cell survival evidence that the relative biological effectiveness (RBE) of protons is variable, with dependence on factors such as linear energy transfer (LET) and dose. This is coupled with the growing in vivo evidence, from post-treatment image change analysis, of a variable RBE. Despite this, a constant RBE of 1.1 is still applied as a standard in proton therapy. However, there is a building clinical interest in incorporating a variable RBE. Recently, correlations summarising Monte Carlo-based mechanistic models of DNA damage and repair with absorbed dose and LET have been published as the Manchester mechanistic (MM) model. These correlations offer an alternative path to variable RBE compared to the more standard phenomenological models. In this proof of concept work, these correlations have been extended to acquire RBE-weighted dose distributions and calculated, along with other RBE models, on a treatment plan. The phenomenological and mechanistic models for RBE have been shown to produce comparable results with some differences in magnitude and relative distribution. The mechanistic model found a large RBE for misrepair, which phenomenological models are unable to do. The potential of the MM model to predict multiple endpoints presents a clear advantage over phenomenological models.

Gold nanoparticles (GNPs) have been shown to sensitize cancer cells to x-ray radiation, particularly at kV energies where photoelectric interactions dominate and the high atomic number of gold makes a large difference to x-ray absorption. Protons have a high cross-section for gold at a large range of relevant clinical energies, and so potentially could be used with GNPs for increased therapeutic effect.Here, we investigate the contribution of secondary electron emission to cancer cell radiosensitization and investigate how this parameter is affected by proton energy and a free radical scavenger. We simulate the emission from a realistic cell phantom containing GNPs after traversal by protons and x-rays with different energies. We find that with a range of proton energies (1-250 MeV) there is a small increase in secondaries compared to a much larger increase with x-rays. Secondary electrons are known to produce toxic free radicals. Using a cancer cell line in vitro we find that a free radical scavenger has no protective effect on cells containing GNPs irradiated with 3 MeV protons, while it does protect against cells irradiated with x-rays. We conclude that GNP generated free radicals are a major cause of radiosensitization and that there is likely to be much less dose enhancement effect with clinical proton beams compared to x-rays.

As a part of a systematic study on mechanisms involved in physical cancer therapies, this work investigated response of mammalian cells to ultra-low-dose ion beam irradiation. The ion beam irradiation was performed using the recently completed nanobeam facility at the Surrey Ion Beam Centre. A scanning focused vertical ion nano-beam was applied to irradiate Chinese hamster V79 cells. The V79 cells were irradiated in two different beam modes, namely, focused single ion beam and defocused scanning broad ion beam of 3.8-MeV protons. The single ion beam was capable of irradiating a single cell with a precisely controlled number of the ions to extremely low doses. After irradiation and cell incubation, the number of surviving colonies as a function of the number of the irradiating ions was measured for the cell survival fraction curve. A lower survival for the single ion beam irradiation than that of the broad beam case implied the hypersensitivity and bystander effect. The ion-beam-induced cell survival curves were compared with that from 300-kV X-ray irradiation. Theoretical studies indicated that the cell death in single ion irradiation mainly occurred in the cell cycle phases of cell division and intervals between the cell division and the DNA replication. The success in the experiment demonstrated the Surrey vertical nanobeam successfully completed.

Purpose In proton therapy precise knowledge of the beam range is essential to guarantee the treatment’s efficacy and to avoid unnecessary toxicities. Over a fractionated course of treatment anatomical changes can severely impact the delivered dose distribution from that planned; evaluation of these changes on a fraction-by-fraction basis is essential. We report the first results of a new method to determine proton beam range in three dimensions, for pencil-beam scanning systems, with an uncertainty below 3 mm. Methods The range is determined through the reconstruction of the origin of prompt gamma (PG) rays emitted from nuclear de-excitations following proton bombardment. PG emission is almost instantaneous and is characterised by a high-production rate. The prototype system is comprised of 16 symmetrically-spaced LaBr3(Ce) detectors, in a spherical design. Initially the position reconstruction capability of the detector system was examined using Geant4 simulations. To determine the PG-rays emission positions in 3D, the information recorded by each detector is fed into a reconstruction algorithm, developed in the MATLAB environment. The development, testing and laboratory validation of the algorithm has been conducted using a sealed 60 Co source. Furthermore the algorithm has been employed to investigate, by means of Geant4 simulations, how the system performs with a proton pencil beam at different clinical energies. In the simulations a water phantom with 2-cm thick body materials slabs embedded inside has been modelled. Results Preliminary simulation results show that for an ideal detector system the reconstruction algorithm is capable of determining the source position to within 1 mm in the 3D space. The algorithm is also able of discriminating between multiple sources with a relative separation of 0.15 mm. A good agreement has been observed between the dose and the prompt-gamma distribution from a proton pencil beam impinging the different phantoms at all the employed clinical energies. Conclusions Proof-of-principle for the reconstruction algorithm with a sealed 60 Co source has been obtained. The response of the system with a clinical proton beam has been evaluated, by means on Monte Carlo simulations. The next stage is to test the system with a proton beam experimentally.

Proton beam writing (PBW) is a direct write technique that employs a focused MeV proton beam which is scanned in a pre-determined pattern over a target material which is subsequently electrochemically etched or chemically developed. By changing the energy of the protons the range of the protons can be changed. The ultimate depth of the structure is determined by the range of the protons in the material and this allows structures to be formed to different depths. PBW has been successfully employed on etchable glasses, polymers and semiconductor materials such as silicon (Si) and gallium arsenide (GaAs). This study reports on PBW in p–type GaAs and compares experimental results with computer simulations using the Atlas© semiconductor device package from SILVACO. It has already been proven that hole transport is required for the electrochemical etching of GaAs using Tiron (4,5-dihydroxy-m-benzenedisulfonic acid, di-sodium salt). PBW in GaAs results in carrier removal in the irradiated regions and consequently minimal hole transport (in these regions) during electrochemical etching. As a result the irradiated regions are significantly more etch resistant than the non-irradiated regions. This allows high aspect ratio structures to be formed.

In proton beam therapy precise knowledge of the proton beam range is essential to guarantee the treatment’s efficacy and to avoid unnecessary toxicities. Unlike photon beams, protons stop inside the patient’s body, therefore a direct detection of the distal fall-off is impossible. One technique to determine the beam range is to detect the prompt gamma (PG) rays emitted from the nuclei de-exciting following proton bombardment [1] . PG emission is almost instantaneous and has a high-production rate. The aim of this project is to develop a new method, based on an optimized PG detector system, which can achieve 3D range determination with an uncertainty of no more than 2 mm. The presented method is based on the detection of discrete gamma-rays. As a first step, the position reconstruction capability of the PG detector system was examined by means of Geant4 simulations. The prototype system is comprised of 12 LaBr 3 (Ce) detectors. The information recorded by each individual detector is fed into a reconstruction algorithm to determine the gamma-ray emission point in 3 dimensions. The development of the algorithm, proof-of-principle and simulation validation, have all been conducted using a sealed 60 Co source. Our simulations demonstrate that an ideal detector system with the current reconstruction algorithm is capable of determining the source position with sub-millimetre accuracy. Having obtained proof-of-principle for the reconstruction algorithm the next stage is to investigate how implementing a realistic detector system affects the reconstruction performance. In addition, the ability of the detector system to discriminate between multiple sources in different positions is under evaluation.

Gold nanoparticles (GNPs) have shown a potential as a radiosensitizer in radiotherapy. The radiosensitization effect is thought to be linked to the increased dose deposition around the GNP. Monte Carlo simulations have been implemented for the calculation of the dose distributions around the GNPs and have been used for the calculation of the dose enhancement. They have also been imported to radiobiological models to predict biological endpoints. This work assessed the implications of different physical interaction models on the dose distribution and dose enhancement of GNPs surrounded by water under proton irradiation. The Penelope and Livermore physical interaction model implementation of the Geant4 simulation toolkit were compared considering the following parameters: (i) GNP size, (ii) proton energy, and (iii) alternative physics model parameters in the gold or water medium. We found that neither the dose distribution nor the dose enhancement is sensitive to the model selection after the first 100 nm from the GNP surface. Within the first 100 nm the Livermore models calculated a higher dose, attributed to a higher production of low energy secondary electrons inside the GNP.

The potential that laser based particle accelerators offer to solve sizing and cost issues arising with conventional proton therapy has generated great interest in the understanding and development of laser ion acceleration, and in investigating the radiobiological effects induced by laser accelerated ions. Laser-driven ions are produced in bursts of ultra-short duration resulting in ultra-high dose rates, and an investigation at Queen's University Belfast was carried out to investigate this virtually unexplored regime of cell rdaiobiology. This employed the TARANIS terawatt laser producing protons in the MeV range for proton irradiation, with dose rates exceeding 109 Gys-1 on a single exposure. A clonogenic assay was implemented to analyse the biological effect of proton irradiation on V79 cells, which, when compared to data obtained with the same cell line irradiated with conventionally accelerated protons, was found to show no significant difference. A Relative Biological effectiveness of 1.4±0.2 at 10 % Survival Fraction was estimated from a comparison with a 225 kVp X-ray source. © 2013 SPIE.

The ultra short duration of laser-driven multi-MeV ion bursts offers the possibility of radiobiological studies at extremely high dose rates. Employing the TARANIS Terawatt laser at Queen's University, the effect of proton irradiation at MeV-range energies on live cells has been investigated at dose rates exceeding 10 Gy/s as a single exposure. A clonogenic assay showed consistent lethal effects on V-79 live, cells, which, even at these dose rates, appear to be in line with previously published results employing conventional sources. A Relative Biological Effectiveness (RBE) of 1.4±0.2 at 10% survival is estimated from a comparison with a 225 kVp X-ray source. © 2013 AIP Publishing LLC.

The ultrashort duration of laser-driven multi-MeV ion bursts offers the possibility of radiobiological studies at extremely high dose rates. Employing the TARANIS Terawatt laser at Queen's University, the effect of proton irradiation at MeV-range energies on live cells has been investigated at dose rates exceeding 109Gy/s as a single exposure. A clonogenic assay showed consistent lethal effects on V-79 live cells, which, even at these dose rates, appear to be in line with previously published results employing conventional sources. A Relative Biological Effectiveness (RBE) of 1.4±0.2 at 10% survival is estimated from a comparison with a 225 kVp X-ray source.

Laser-driven proton and ion acceleration is an area of increasing research interest given the recent development of short pulse-high intensity lasers. Several groups have reported experiments to understand whether a laser-driven beam can be applied for radiobiological purposes and in each of these, the method to obtain dose and spectral analysis was slightly different. The difficulty with these studies is that the very large instantaneous dose rate is a challenge for commonly used dosimetry techniques, so that other more sophisticated procedures need to be explored. This paper aims to explain a method for obtaining the energetic spectrum and the dose of a laser-driven proton beam irradiating a cell dish used for radiobiology studies. The procedure includes the use of a magnet to have charge and energy separation of the laser-driven beam, Gafchromic films to have information on dose and partially on energy, and a Monte Carlo code to expand the measured data in order to obtain specific details of the proton spectrum on the cells. Two specific correction factors have to be calculated: one to take into account the variation of the dose response of the films as a function of the proton energy and the other to obtain the dose to the cell layer starting from the dose measured on the films. This method, particularly suited to irradiation delivered in a single laser shot, can be applied in any other radiobiological experiment performed with laser-driven proton beams, with the only condition that the initial proton spectrum has to be at least roughly known. The method was tested in an experiment conducted at Queen's University of Belfast using the TARANIS laser, where the mean energy of the protons crossing the cells was between 0.9 and 5 MeV, the instantaneous dose rate was estimated to be close to 10(9) Gy s(-1) and doses between 0.8 and 5 Gy were delivered to the cells in a single laser shot. The combination of the applied corrections modified the initial estimate of dose by up to 40%.

Next generation intense, short-pulse laser facilities require new high repetition rate diagnostics for the detection of ionizing radiation. We have designed a new scintillator-based ion beam profiler capable of measuring the ion beam transverse profile for a number of discrete energy ranges. The optical response and emission characteristics of four common plastic scintillators has been investigated for a range of proton energies and fluxes. The scintillator light output (for 1 MeV > Ep < 28 MeV) was found to have a non-linear scaling with proton energy but a linear response to incident flux. Initial measurements with a prototype diagnostic have been successful, although further calibration work is required to characterize the total system response and limitations under the high flux, short pulse duration conditions of a typical high intensity laser-plasma interaction.

Relative Biological Effectiveness (RBE), the ratio of doses between radiation modalities to produce the same biological endpoint, is a controversial and important topic in proton therapy. A number of phenomenological models incorporate variable RBE as a function of Linear Energy Transfer (LET), though a lack of mechanistic description limits their applicability. In this work we take a different approach, using a track structure model employing fundamental physics and chemistry to make predictions of proton and photon induced DNA damage, the first step in the mechanism of radiation-induced cell death. We apply this model to a proton therapy clinical case showing, for the first time, predictions of DNA damage on a patient treatment plan. Our model predictions are for an idealised cell and are applied to an ependymoma case, at this stage without any cell specific parameters. By comparing to similar predictions for photons, we present a voxel-wise RBE of DNA damage complexity. This RBE of damage complexity shows similar trends to the expected RBE for cell kill, implying that damage complexity is an important factor in DNA repair and therefore biological effect.