A Monte Carlo based radiation response modelling framework to assess variability of clinical RBE in proton therapy.

The clinical implementation of a variable relative biological effectiveness (RBE) in proton therapy is currently controversially discussed. Initial clinical evidence indicates a variable proton RBE, which needs to be verified. In this study, a radiation response modelling framework for assessing clinical RBE variability is established. It was applied to four selected glioma patients (grade III) treated with adjuvant radio(chemo)therapy and who developed late morphological image changes on T1-weighted contrast-enhanced (T1w-CE) magnetic resonance (MR) images within approximately two years of recurrence-free follow-up. The image changes were correlated voxelwise with dose and linear energy transfer (LET) values using univariable and multivariable logistic regression analysis. The regression models were evaluated by the area-under-the-curve (AUC) method performing a leave-one-out cross validation. The tolerance dose TD50 at which 50% of patient voxels experienced toxicity was interpolated from the models. A Monte Carlo (MC) model was developed to simulate dose and LET distributions, which includes variance reduction (VR) techniques to decrease computation time. Its reliability and accuracy were evaluated based on dose calculations of the clinical treatment planning system (TPS) as well as absolute dose measurements performed in the patient specific quality assurance. Morphological image changes were related to a combination of dose and LET. The multivariable models revealed cross-validated AUC values of up to 0.88. The interpolated TD50 curves decreased with increasing LET indicating an increase in biological effectiveness. The MC model reliably predicted average TPS dose within the clinical target volume as well as absolute water phantom dose measurements within 2% accuracy using dedicated VR settings. The observed correlation of dose and LET with late brain tissue damage suggests considering RBE variability for predicting chronic radiation-induced brain toxicities. The MC model simulates radiation fields in patients precisely and time-efficiently. Hence, this study encourages and enables in-depth patient evaluation to assess the variability of clinical proton RBE.

A Bayesian Approach for Measurements of Stray Neutrons at Proton Therapy Facilities: Quantifying Neutron Dose Uncertainty.

Bonner sphere measurements are typically analyzed using unfolding codes. It is well known that it is difficult to get reliable estimates of uncertainties for standard unfolding procedures. An alternative approach is to analyze the data using Bayesian parameter estimation. This method provides reliable estimates of the uncertainties of neutron spectra leading to rigorous estimates of uncertainties of the dose. We extend previous Bayesian approaches and apply the method to stray neutrons in proton therapy environments by introducing a new parameterized model which describes the main features of the expected neutron spectra. The parameterization is based on information that is available from measurements and detailed Monte Carlo simulations. The validity of this approach has been validated with results of an experiment using Bonner spheres carried out at the experimental hall of the OncoRay proton therapy facility in Dresden.

A light-weight compact proton gantry design with a novel dose delivery system for broad-energetic laser-accelerated beams.

Proton beams may provide superior dose-conformity in radiation therapy. However, the large sizes and costs limit the widespread use of proton therapy (PT). The recent progress in proton acceleration via high-power laser systems has made it a compelling alternative to conventional accelerators, as it could potentially reduce the overall size and cost of the PT facilities. However, the laser-accelerated beams exhibit different characteristics than conventionally accelerated beams, i.e. very intense proton bunches with large divergences and broad-energy spectra. For the application of laser-driven beams in PT, new solutions for beam transport, such as beam capture, integrated energy selection, beam shaping and delivery systems are required due to the specific beam parameters. The generation of these beams are limited by the low repetition rate of high-power lasers and this limitation would require alternative solutions for tumour irradiation which can efficiently utilize the available high proton fluence and broad-energy spectra per proton bunch to keep treatment times short. This demands new dose delivery system and irradiation field formation schemes. In this paper, we present a multi-functional light-weight and compact proton gantry design for laser-driven sources based on iron-less pulsed high-field magnets. This achromatic design includes improved beam capturing and energy selection systems, with a novel beam shaping and dose delivery system, so-called ELPIS. ELPIS system utilizes magnetic fields, instead of physical scatterers, for broadening the spot-size of broad-energetic beams while capable of simultaneously scanning them in lateral directions. To investigate the clinical feasibility of this gantry design, we conducted a treatment planning study with a 3D treatment planning system augmented for the pulsed beams with optimizable broad-energetic widths and selectable beam spot sizes. High quality treatment plans could be achieved with such unconventional beam parameters, deliverable via the presented gantry and ELPIS dose delivery system. The conventional PT gantries are huge and require large space for the gantry to rotate the beam around the patient, which could be reduced up to 4 times with the presented pulse powered gantry system. The further developments in the next generation petawatt laser systems and laser-targets are crucial to reach higher proton energies. However, if proton energies required for therapy applications are reached it could be possible in future to reduce the footprint of the PT facilities, without compromising on clinical standards.

Requirements for a Compton camera for in vivo range verification of proton therapy.

To ensure the optimal outcome of proton therapy, in vivo range verification is highly desired. Prompt γ-ray imaging (PGI) is a possible approach for in vivo range monitoring. For PGI, dedicated detection systems, e.g. Compton cameras, are currently under investigation. The presented paper deals with substantial requirements regarding hardware and software that a Compton camera used in clinical routine has to meet. By means of GEANT4 simulations, we investigate the load on the detectors and the percentage of background expected in a realistic irradiation and we simulate γ-ray detections subsequently used as input data for the reconstruction. By reconstructing events from simulated sources of well-defined geometry, we show that large-area detectors are favourable. We investigate reconstruction results in dependence of the number of events. Finally, an end-to-end test for a realistic patient scenario is presented: starting with a treatment plan, the γ-ray emissions are calculated, the detector response is modelled, and the image reconstruction is performed. By this, the complexity of the system is shown, and requirements and limitations regarding precision and costs are determined.

Towards clinical application: prompt gamma imaging of passively scattered proton fields with a knife-edge slit camera.

Prompt γ-ray imaging with a knife-edge shaped slit camera provides the possibility of verifying proton beam range in tumor therapy. Dedicated experiments regarding the characterization of the camera system have been performed previously. Now, we aim at implementing the prototype into clinical application of monitoring patient treatments. Focused on this goal of translation into clinical operation, we systematically addressed remaining challenges and questions. We developed a robust energy calibration routine and corresponding quality assurance protocols. Furthermore, with dedicated experiments, we determined the positioning precision of the system to 1.1 mm (2σ). For the first time, we demonstrated the application of the slit camera, which was intentionally developed for pencil beam scanning, to double scattered proton beams. Systematic experiments with increasing complexity were performed. It was possible to visualize proton range shifts of 2-5 mm with the camera system in phantom experiments in passive scattered fields. Moreover, prompt γ-ray profiles for single iso-energy layers were acquired by synchronizing time resolved measurements to the rotation of the range modulator wheel of the treatment system. Thus, a mapping of the acquired profiles to different anatomical regions along the beam path is feasible and additional information on the source of potential range shifts can be obtained. With the work presented here, we show that an application of the slit camera in clinical treatments is possible and of potential benefit.

From prompt gamma distribution to dose: a novel approach combining an evolutionary algorithm and filtering based on Gaussian-powerlaw convolutions.

Range verification and dose monitoring in proton therapy is considered as highly desirable. Different methods have been developed worldwide, like particle therapy positron emission tomography (PT-PET) and prompt gamma imaging (PGI). In general, these methods allow for a verification of the proton range. However, quantification of the dose from these measurements remains challenging. For the first time, we present an approach for estimating the dose from prompt γ-ray emission profiles. It combines a filtering procedure based on Gaussian-powerlaw convolution with an evolutionary algorithm. By means of convolving depth dose profiles with an appropriate filter kernel, prompt γ-ray depth profiles are obtained. In order to reverse this step, the evolutionary algorithm is applied. The feasibility of this approach is demonstrated for a spread-out Bragg-peak in a water target.

Characterization of the microbunch time structure of proton pencil beams at a clinical treatment facility.

Proton therapy is an advantageous treatment modality compared to conventional radiotherapy. In contrast to photons, charged particles have a finite range and can thus spare organs at risk. Additionally, the increased ionization density in the so-called Bragg peak close to the particle range can be utilized for maximum dose deposition in the tumour volume. Unfortunately, the accuracy of the therapy can be affected by range uncertainties, which have to be covered by additional safety margins around the treatment volume. A real-time range and dose verification is therefore highly desired and would be key to exploit the major advantages of proton therapy. Prompt gamma rays, produced in nuclear reactions between projectile and target nuclei, can be used to measure the proton's range. The prompt gamma-ray timing (PGT) method aims at obtaining this information by determining the gamma-ray emission time along the proton path using a conventional time-of-flight detector setup. First tests at a clinical accelerator have shown the feasibility to observe range shifts of about 5 mm at clinically relevant doses. However, PGT spectra are smeared out by the bunch time spread. Additionally, accelerator related proton bunch drifts against the radio frequency have been detected, preventing a potential range verification. At OncoRay, first experiments using a proton bunch monitor (PBM) at a clinical pencil beam have been conducted. Elastic proton scattering at a hydrogen-containing foil could be utilized to create a coincident proton-proton signal in two identical PBMs. The selection of coincident events helped to suppress uncorrelated background. The PBM setup was used as time reference for a PGT detector to correct for potential bunch drifts. Furthermore, the corrected PGT data were used to image an inhomogeneous phantom. In a further systematic measurement campaign, the bunch time spread and the proton transmission rate were measured for several beam energies between 69 and 225 MeV as well as for variable momentum limiting slit openings. We conclude that the usage of a PBM increases the robustness of the PGT method in clinical conditions and that the obtained data will help to create reliable range verification procedures in clinical routine.

Experimental investigation of irregular motion impact on 4D PET-based particle therapy monitoring.

Particle therapy positron emission tomography (PT-PET) is an in vivo and non-invasive imaging technique to monitor treatment delivery in particle therapy. The inevitable patient respiratory motion during irradiation causes artefacts and inaccurate activity distribution in PET images. Four-dimensional (4D) maximum likelihood expectation maximisation (4D MLEM) allows for a compensation of these effects, but has up to now been restricted to regular motion for PT-PET investigations. However, intra-fractional motion during treatment might differ from that during acquisition of the 4D-planning CT (e.g. amplitude variation, baseline drift) and therefore might induce inaccurate 4D PET reconstruction results. This study investigates the impact of different irregular analytical one-dimensional (1D) motion patterns on PT-PET imaging by means of experiments with a radioactive source and irradiated moving phantoms. Three sorting methods, namely phase sorting, equal amplitude sorting and event-based amplitude sorting, were applied to manage the PET list-mode data. The influence of these sorting methods on the motion compensating algorithm has been analysed. The event-based amplitude sorting showed a superior performance and it is applicable for irregular motions with ⩽ 4 mm amplitude elongation and drift. For motion with 10 mm baseline drift, the normalised root mean square error was as high as 10.5% and a 10 mm range deviation was observed.

Simulation and experimental verification of prompt gamma-ray emissions during proton irradiation.

Irradiation with protons and light ions offers new possibilities for tumor therapy but has a strong need for novel imaging modalities for treatment verification. The development of new detector systems, which can provide an in vivo range assessment or dosimetry, requires an accurate knowledge of the secondary radiation field and reliable Monte Carlo simulations. This paper presents multiple measurements to characterize the prompt γ-ray emissions during proton irradiation and benchmarks the latest Geant4 code against the experimental findings. Within the scope of this work, the total photon yield for different target materials, the energy spectra as well as the γ-ray depth profile were assessed. Experiments were performed at the superconducting AGOR cyclotron at KVI-CART, University of Groningen. Properties of the γ-ray emissions were experimentally determined. The prompt γ-ray emissions were measured utilizing a conventional HPGe detector system (Clover) and quantitatively compared to simulations. With the selected physics list QGSP_BIC_HP, Geant4 strongly overestimates the photon yield in most cases, sometimes up to 50%. The shape of the spectrum and qualitative occurrence of discrete γ lines is reproduced accurately. A sliced phantom was designed to determine the depth profile of the photons. The position of the distal fall-off in the simulations agrees with the measurements, albeit the peak height is also overestimated. Hence, Geant4 simulations of prompt γ-ray emissions from irradiation with protons are currently far less reliable as compared to simulations of the electromagnetic processes. Deviations from experimental findings were observed and quantified. Although there has been a constant improvement of Geant4 in the hadronic sector, there is still a gap to close.

Experimental verification of a 4D MLEM reconstruction algorithm used for in-beam PET measurements in particle therapy.

In-beam positron emission tomography (PET) has been proven to be a reliable technique in ion beam radiotherapy for the in situ and non-invasive evaluation of the correct dose deposition in static tumour entities. In the presence of intra-fractional target motion an appropriate time-resolved (four-dimensional, 4D) reconstruction algorithm has to be used to avoid reconstructed activity distributions suffering from motion-related blurring artefacts and to allow for a dedicated dose monitoring. Four-dimensional reconstruction algorithms from diagnostic PET imaging that can properly handle the typically low counting statistics of in-beam PET data have been adapted and optimized for the characteristics of the double-head PET scanner BASTEI installed at GSI Helmholtzzentrum Darmstadt, Germany (GSI). Systematic investigations with moving radioactive sources demonstrate the more effective reduction of motion artefacts by applying a 4D maximum likelihood expectation maximization (MLEM) algorithm instead of the retrospective co-registration of phasewise reconstructed quasi-static activity distributions. Further 4D MLEM results are presented from in-beam PET measurements of irradiated moving phantoms which verify the accessibility of relevant parameters for the dose monitoring of intra-fractionally moving targets. From in-beam PET listmode data sets acquired together with a motion surrogate signal, valuable images can be generated by the 4D MLEM reconstruction for different motion patterns and motion-compensated beam delivery techniques.

4D particle therapy PET simulation for moving targets irradiated with scanned ion beams.

Particle therapy positron emission tomography (PT-PET) allows for an in vivo and in situ verification of applied dose distributions in ion beam therapy. Since the dose distribution cannot be extracted directly from the ß(+)-activity distribution gained from the PET scan the validation is done by means of a comparison between the reconstructed ß(+)-activity distributions from a PT-PET measurement and from a PT-PET simulation. Thus, the simulation software for generating PET data predicted from the treatment planning is an essential part of the dose verification routine. For the dose monitoring of intra-fractionally moving target volumes the PET data simulation needs to be upgraded by using time resolved (4D) algorithms to account correctly for the motion dependent displacement of the positron emitters. Moreover, it has to consider the time dependent relative movement between target volume and scanned beam to simulate the accurate positron emitter distribution generated during irradiation. Such a simulation program is presented which properly proceeds with motion compensated dose delivery by scanned ion beams to intra-fractionally moving targets. By means of a preclinical phantom study it is demonstrated that even the sophisticated motion-mitigated beam delivery technique of range compensated target tracking can be handled correctly by this simulation code. The new program is widely based on the 3D PT-PET simulation program which had been developed at the Helmholtz-Zentrum Dresden-Rossendorf, Germany (HZDR) for application within a pilot project to simulate in-beam PET data for about 440 patients with static tumor entities irradiated at the former treatment facility of the GSI Helmholtzzentrum für Schwerionenforschung, Darmstadt, Germany (GSI). A simulation example for a phantom geometry irradiated with a tracked (12)C-ion beam is presented for demonstrating the proper functionality of the program.

On the feasibility of automatic detection of range deviations from in-beam PET data.

In-beam PET is a clinically proven method for monitoring ion beam cancer treatment. The objective is predominantly the verification of the range of the primary particles. Due to different processes leading to dose and activity, evaluation is done by comparing measured data to simulated. Up to now, the comparison is performed by well-trained observers (clinicians, physicists). This process is very time consuming and low in reproducibility. However, an automatic method is desirable. A one-dimensional algorithm for range comparison has been enhanced and extended to three dimensions. System-inherent uncertainties are handled by means of a statistical approach. To test the method, a set of data was prepared. Distributions of ß(+)-activity calculated from treatment plans were compared to measurements performed in the framework of the German Heavy Ion Tumor Therapy Project at GSI Helmholtz Centre for Heavy Ion Research, Darmstadt, Germany. Artificial range deviations in the simulations served as test objects for the algorithm. Range modifications of different depth (4, 6 and 10 mm water equivalent path length) can be detected. Even though the sensitivity and specificity of a visual evaluation are higher, the method is feasible as the basis for the selection of patients from the data pool for retrospective evaluation of treatment and treatment plans and correlation with follow-up data. Furthermore, it can be used for the development of an assistance tool for a clinical application.

Efficient laser-ion acceleration from closely stacked ultrathin foils.

A new scheme to efficiently accelerate protons by a single linear polarized high-intensity ultrashort laser pulse using multiple ultrathin foils is proposed. The foils are stacked at a spacing comparable to their thickness and subsequently irradiated by the same laser pulse. The foil thicknesses are chosen such that the laser light pressure can displace all electrons out of the foil. The authors present a simple, yet precise dynamical model of the acceleration process from which both optimum foil thickness and spacing can be derived. Extensive two-dimensional (2D) particle-in-cell simulations verify the model predictions and suggest an enhancement of the maximum proton kinetic energy by 30% for the two-foil case compared to a single foil.

Tumour bed irradiation of human tumour xenografts in a nude rat model using a common X-ray tube.

Studies that investigate the radiation of human tumour xenografts require an appropriate radiation source and highly standardized conditions during radiation. This work reports on the design of a standardized irradiation device using a commercially available X-ray tube with a custom constructed lead collimator with two circular apertures and an animal bed plate, permitting synchronous irradiation of two animals. Dosimetry and the corresponding methodology for radiotherapy of human non-small cell lung cancer xenograft tumours transplanted to and growing subcutaneously on the right lower limb in a nude rat model were investigated. Procedures and results described herein prove the feasibility of use of the device, which is applicable for any investigation involving irradiation of non-tumorous and tumorous lesions in small animals.

Establishment of technical prerequisites for cell irradiation experiments with laser-accelerated electrons.

PURPOSE: In recent years, laser-based acceleration of charged particles has rapidly progressed and medical applications, e.g., in radiotherapy, might become feasible in the coming decade. Requirements are monoenergetic particle beams with long-term stable and reproducible properties as well as sufficient particle intensities and a controlled delivery of prescribed doses at the treatment site. Although conventional and laser-based particle accelerators will administer the same dose to the patient, their different time structures could result in different radiobiological properties. Therefore, the biological response to the ultrashort pulse durations and the resulting high peak dose rates of these particle beams have to be investigated. The technical prerequisites, i.e., a suitable cell irradiation setup and the precise dosimetric characterization of a laser-based particle accelerator, have to be realized in order to prepare systematic cell irradiation experiments. METHODS: The Jena titanium:sapphire laser system (JETI) was customized in preparation for cell irradiation experiments with laser-accelerated electrons. The delivered electron beam was optimized with regard to its spectrum, diameter, dose rate, and dose homogeneity. A custom-designed beam and dose monitoring system, consisting of a Roos ionization chamber, a Faraday cup, and EBT-1 dosimetry films, enables real-time monitoring of irradiation experiments and precise determination of the dose delivered to the cells. Finally, as proof-of-principle experiment cell samples were irradiated using this setup. RESULTS: Laser-accelerated electron beams, appropriate for in vitro radiobiological experiments, were generated with a laser shot frequency of 2.5 Hz and a pulse length of 80 fs. After laser acceleration in the helium gas jet, the electrons were filtered by a magnet, released from the vacuum target chamber, and propagated in air for a distance of 220 mm. Within this distance a lead collimator (aperture of 35 mm) was introduced, leading, along with the optimized setup, to a beam diameter of 35 mm, sufficient for the irradiation of common cell culture vessels. The corresponding maximum dose inhomogeneity over the beam spot was less than 10% for all irradiated samples. At cell position, the electrons posses a mean kinetic energy of 13.6 MeV, a bunch length of about 5 ps (FWHM), and a mean pulse dose of 1.6 mGy/bunch. Cross correlations show clear linear dependencies for the online recorded accumulated bunch charges, pulse doses, and pulse numbers on absolute doses determined with EBT-1 films. Hence, the established monitoring system is suitable for beam control and a dedicated dose delivery. Additionally, reasonable day-to-day stable and reproducible properties of the electron beam were achieved. CONCLUSIONS: Basic technical prerequisites for future cell irradiation experiments with ultrashort pulsed laser-accelerated electrons were established at the JETI laser system. The implemented online control system is suitable to compensate beam intensity fluctuations and the achieved accuracy of dose delivery to the cells is sufficient for radiobiological cell experiments. Hence, systematic in vitro cell irradiation experiments can be performed, being the first step toward clinical application of laser-accelerated particles. Further steps, including the transfer of the established methods to experiments on higher biological systems or to other laser-based particle accelerators, will be prepared.

In-beam PET monitoring of mono-energetic (16)O and (12)C beams: experiments and FLUKA simulations for homogeneous targets.

(16)O and (12)C ion beams will be used-besides lighter ions-for cancer treatment at the Heidelberg Ion Therapy Center (HIT), Germany. It is planned to monitor the treatment by means of in-beam positron emission tomography (PET) as it is done for therapy with (12)C beams at the experimental facility at the Gesellschaft für Schwerionenforschung (GSI), Darmstadt, Germany. To enable PET also for (16)O beams, experimental data of the beta(+)-activity created by these beams are needed. Therefore, in-beam PET measurements of the activity created by (16)O beams of various energies on targets of PMMA, water and graphite were performed at GSI for the first time. Additionally reference measurements of (12)C beams on the same target materials were done. The results of the measurements are presented. The deduction of clinically relevant results from in-beam PET data requires reliable simulations of the beta(+)-activity production, which is done presently by a dedicated code limited to (12)C beams. Because this code is not extendable to other ions in an easy way, a new code, capable of simulating the production of the beta(+)-activity by all ions of interest, is needed. Our choice is the general purpose Monte Carlo code FLUKA which was used to simulate the ion transport, the beta(+)-active isotope production, the decay, the positron annihilation and the transport of the annihilation photons. The detector response was simulated with an established software that gives the output in the same list-mode data format as in the experiment. This allows us to use the same software to reconstruct measured and simulated data, which makes comparisons easier and more reliable. The calculated activity distribution shows general good agreement with the measurements.

Comparison of two dedicated 'in beam' PET systems via simultaneous imaging of (12)C-induced beta(+)-activity.

The selective energy deposition of hadrontherapy has led to a growing interest in quality assurance techniques such as 'in-beam' PET. Due to the current lack of commercial solutions, dedicated detectors need to be developed. In this paper, we compare the performances of two different 'in-beam' PET systems which were simultaneously operated during and after low energy carbon ion irradiation of PMMA phantoms at GSI Darmstadt. The results highlight advantages and drawbacks of a novel in-beam PET prototype against a long-term clinically operated tomograph for ion therapy monitoring.

In-beam PET measurement of 7Li3+ irradiation induced beta+-activity.

At present positron emission tomography (PET) is the only feasible method of an in situ and non-invasive monitoring of patient irradiation with ions. At the experimental carbon ion treatment facility of the Gesellschaft für Schwerionenforschung (GSI) Darmstadt an in-beam PET scanner has been integrated into the treatment site and lead to a considerable quality improvement of the therapy. Since ions other than carbon are expected to come into operation in future patient treatment facilities, it is highly desirable to extend in-beam PET also to other therapeutic relevant ions, e.g. (7)Li. Therefore, by means of the in-beam PET scanner at GSI the beta(+)-activity induced by (7)Li(3+) ions has been investigated for the first time. Targets of PMMA, water, graphite and polyethylene were irradiated with monoenergetic, pencil-like beams of (7)Li(3+) with energies between 129.1 A MeV and 205.3 A MeV and intensities ranging from 3.0 x 10(7) to 1.9 x 10(8) ions s(-1). This paper presents the measured beta(+)-activity profiles as well as depth dependent thick target yields which have been deduced from the experimental data. The beta(+)-activity induced by (7)Li ions was found to be a factor of 1.76 higher than the one induced by (12)C ions at the same physical dose and particle range.

First in-beam PET measurement of beta+ radioactivity induced by hard photon beams.

In this note, we present the first experimental results of in-beam PET measurements during high energy photon phantom irradiation. An inhomogeneous phantom was irradiated with pulsed 34 MV bremsstrahlung. The measurements have been conducted with a dedicated double head positron camera. A high material contrast could be achieved and furthermore production rates of (11)C and (15)O were derived from the time-dependent activity.