[Planning target volume : Management of uncertainties, immobilization, image guided and adaptive radiation therapy]. / Planungszielvolumen : Management von Ungenauigkeiten, Immobilisierung, bildgeführte und adaptive Strahlentherapie.

CLINICAL/METHODICAL ISSUE: As a standard, today's radiation therapy is based on CT images which are used for therapy planning. These images are obtained once before therapy starts and serve as a basis to obtain the position and shape of the target volume. As the patient has to be positioned anew for each fraction, deviations of the tumor position relative to the radiation field but also internal motion of the tumor may occur. These deviations lead to uncertainties, which are taken into account by adding a safety margin around the clinical target volume (CTV) to create the planning target volume (PTV). STANDARD RADIOLOGICAL METHODS: As a standard today, CT-based treatment planning is used, where images are obtained once prior to therapy. The information on tumor position and shape, which is obtained from these images, is used throughout the whole cycle of radiation therapy without any change. This cycle may last several weeks. METHODICAL INNOVATIONS: By repeated imaging of the patient in the treatment position prior to each fraction, the position of the tumor can be assessed and corrected for each fraction. PERFORMANCE: A reduction of positioning uncertainty may be used to reduce the safety margin. This leads to a decreased volume of irradiated normal tissue. ACHIEVEMENTS: A reduced volume of irradiated normal tissue leads to reduced side effects and provides the opportunity of increased tumor control by dose escalation. PRACTICAL RECOMMENDATIONS: Before the PTV is reduced, a detailed analysis of the uncertainties for the specific imaging method and radiation technique must be performed.

Monte Carlo simulation for proton dosimetry in magnetic fields: Fano test and magnetic field correction factorskBfor Farmer-type ionization chambers.

Objective. In this contribution we present a special Fano test for charged particles in presence of magnetic fields in the MC code TOol for PArticle Simulation (TOPAS), as well as the determination of magnetic field correction factorskBfor Farmer-type ionization chambers using proton beams.Approach. Customized C++ extensions for TOPAS were implemented to model the special Fano tests in presence of magnetic fields for electrons and protons. The Geant4-specific transport parameters,DRoverRandfinalRange,were investigated to optimize passing rate and computation time. ThekBwas determined for the Farmer-type PTW 30013 ionization chamber, and 5 custom built ionization chambers with same geometry but varying inner radius, testing magnetic flux density ranging from 0 to 1.0 T and two proton beam energies of 157.43 and 221.05 MeV.Main results. Using the investigated parameters, TOPAS passed the Fano test within 0.39 ± 0.15% and 0.82 ± 0.42%, respectively for electrons and protons. The chamber response (kB,M,Q) gives a maximum at different magnetic flux densities depending of the chamber size, 1.0043 at 1.0 T for the smallest chamber and 1.0051 at 0.2 T for the largest chamber. The local dose differencecBremained ≤ 0.1% for both tested energies. The magnetic field correction factorkB, for the chamber PTW 30013, varied from 0.9946 to 1.0036 for both tested energies.Significance. The developed extension for the special Fano test in TOPAS MC code with the adjusted transport parameters, can accurately transport electron and proton particles in magnetic field. This makes TOPAS a valuable tool for the determination ofkB. The ionization chambers we tested showed thatkBremains small (≤0.72%). To the best of our knowledge, this is the first calculations ofkBfor proton beams. This work represents a significant step forward in the development of MRgPT and protocols for proton dosimetry in presence of magnetic field.

Experimental helium-beam radiography with a high-energy beam: Water-equivalent thickness calibration and first image-quality results.

PURPOSE: A clinical implementation of ion-beam radiography (iRad) is envisaged to provide a method for on-couch verification of ion-beam treatment plans. The aim of this work is to introduce and evaluate a method for quantitative water-equivalent thickness (WET) measurements for a specific helium-ion imaging system for WETs that are relevant for imaging thicker body parts in the future. METHODS: Helium-beam radiographs (αRads) are measured at the Heidelberg Ion-beam Therapy Center with an initial beam energy of 239.5 MeV/u. An imaging system based on three pairs of thin silicon pixel detectors is used for ion path reconstruction and measuring the energy deposition (dE) of each particle behind the object to be imaged. The dE behind homogeneous plastic blocks is related to their well-known WETs between 280.6 and 312.6 mm with a calibration curve that is created by a fit to measured data points. The quality of the quantitative WET measurements is determined by the uncertainty of the measured WET of a single ion (single-ion WET precision) and the deviation of a measured WET value to the well-known WET (WET accuracy). Subsequently, the fitted calibration curve is applied to an energy deposition radiograph of a phantom with a complex geometry. The spatial resolution (modulation transfer function at 10 % -MTF10% ) and WET accuracy (mean absolute percentage difference-MAPD) of the WET map are determined. RESULTS: In the optimal imaging WET-range from ∼280 to 300 mm, the fitted calibration curve reached a mean single-ion WET precision of 1.55 ± $\,{\pm}\,$ 0.00%. Applying the calibration to an ion radiograph (iRad) of a more complex WET distribution, the spatial resolution was determined to be MTF10% = 0.49 ± $\,{\pm}\,$ 0.03 lp/mm and the WET accuracy was assessed as MAPD to 0.21 %. CONCLUSIONS: Using a beam energy of 239.5 MeV/u and the proposed calibration procedure, quantitative αRads of WETs between ∼280 and 300 mm can be measured and show high potential for clinical use. The proposed approach with the resulting image qualities encourages further investigation toward the clinical application of helium-beam radiography.

Efficient uncertainty quantification for Monte Carlo dose calculations using importance (re-)weighting.

Objective. To present an efficient uncertainty quantification method for range and set-up errors in Monte Carlo (MC) dose calculations. Further, we show that uncertainty induced by interplay and other dynamic influences may be approximated using suitable error correlation models.Approach. We introduce an importance (re-)weighting method in MC history scoring to concurrently construct estimates for error scenarios, the expected dose and its variance from a single set of MC simulated particle histories. The approach relies on a multivariate Gaussian input and uncertainty model, which assigns probabilities to the initial phase space sample, enabling the use of different correlation models. Through modification of the phase space parameterization, accuracy can be traded between that of the uncertainty or the nominal dose estimate.Main results. The method was implemented using the MC code TOPAS and validated for proton intensity-modulated particle therapy (IMPT) with reference scenario estimates. We achieve accurate results for set-up uncertainties (γ2 mm/2%≥ 99.01% (E[d]),γ2 mm/2%≥ 98.04% (σ(d))) and expectedly lower but still sufficient agreement for range uncertainties, which are approximated with uncertainty over the energy distribution. Here pass rates of 99.39% (E[d])/ 93.70% (σ(d)) (range errors) and 99.86% (E[d])/ 96.64% (σ(d)) (range and set-up errors) can be achieved. Initial evaluations on a water phantom, a prostate and a liver case from the public CORT dataset show that the CPU time decreases by more than an order of magnitude.Significance. The high precision and conformity of IMPT comes at the cost of susceptibility to treatment uncertainties in particle range and patient set-up. Yet, dose uncertainty quantification and mitigation, which is usually based on sampled error scenarios, becomes challenging when computing the dose with computationally expensive but accurate MC simulations. As the results indicate, the proposed method could reduce computational effort while also facilitating the use of high-dimensional uncertainty models.

Three-voltage linear method to determine ion recombination in proton and light-ion beams.

A new practical method to determine the ion recombination correction factor (k s ) for plane-parallel and Farmer-type cylindrical chambers in particle beams is investigated. Experimental data were acquired in passively scattered and scanned particle beams and compared with theoretical models developed by Boag and/or Jaffé. The new method, named the three-voltage linear method (3VL-method), is simple and consists of determining the saturation current using the current measured at three voltages in a linear region and dividing it by the current at the operating voltage (V) (even if it is not in the linear region) to obtain k s . For plane-parallel chambers, comparing k s -values obtained by model fits to values obtained using the 3VL-method, an excellent agreement is found. For cylindrical chambers, recombination is due to volume recombination only. At low voltages, volume recombination is too large and Boag's models are not applicable. However, for Farmer-type chambers (NE2571), using a smaller voltage range, limited down to 100 V, we observe a linear variation of k s with 1/V 2 or 1/V for continuous or pulsed beams, respectively. This linearity trend allows applying the 3VL-method to determine k s at any polarizing voltage. For the particle beams used, the 3VL-method gives an accurate determination of k s at any polarizing voltage. The choice of the three voltages must to be done with care to ensure to be in a linear region. For Roos-type or Markus-type chambers (i.e. chambers with an electrode spacing of 2 mm) and NE2571 chambers, the use of the 3VL-method with 300 V, 200 V and 150 V is adequate. A difference with the 2V-method and some 3V-methods in the literature is that in the 3VL-method the operational voltage does not have to be one of the three voltages. An advantage over a 2V-method is that the 3VL-method can inherently verify if the linearity condition is fulfilled.

Methodology paper: a novel phantom setup for commissioning of scanned ion beam delivery and TPS.

BACKGROUND: Commissioning of treatment planning systems (TPS) and beam delivery for scanned light ion beams is an important quality assurance task. This requires measurement of large sets of high quality dosimetric data in anthropomorphic phantoms to benchmark the TPS and dose delivery under realistic conditions. METHOD: A novel measurement setup is described, which allows for an efficient collection of a large set of accurate dose data in complex phantom geometries. This setup allows dose measurements based on a set of 24 small volume ionization chambers calibrated in dose to water and mounted in a holder, which can be freely positioned in a water phantom with various phantoms mounted in front of the water tank. The phantoms can be scanned in a CT and a CT-based treatment planning can be performed for a direct benchmark of the dose calculation algorithm in various situations. RESULTS: The system has been used for acceptance testing in scanned light ion beam therapy at Heidelberg Ion Beam Therapy Center for scanned proton and carbon ion beams. It demonstrated to be useful to collect large amounts of high quality data for comparison with the TPS calculation using various phantom geometries. CONCLUSION: The setup is an efficient tool for commissioning and verification of treatment planning systems. It is especially suited for dynamic beam delivery, as many data points can be obtained during a single plan delivery, but can be adapted also for other dynamic therapies, like rotational IMRT.

Investigation of single carbon ion fragmentation in water and PMMA for hadron therapy.

Carbon ion radiotherapy is an attractive alternative to conventional radiotherapy, especially in case of deep-seated and radio-resistant tumors. As a consequence of inelastic nuclear reactions between primary particles and patient's tissues, the primary carbon ions may undergo nuclear fragmentation. The resulting decrease of primary ions and production of secondary fragments have to be carefully considered for accurate dose calculations in the treatment planning systems. The experimental data currently available provide only general information on carbon ion fragmentation and are not sufficient to cover the entire range of beam energies, target configurations and compositions relevant for radiotherapy. Therefore, new investigations were carried out to analyse the outcomes of the inelastic nuclear reaction processes on a single-ion-based approach. Measurements were performed at HIT, using 430 MeV/u carbon ion beams crossing water and PMMA targets. Unique in this method is the possibility of measuring number and type of fragments produced from each single carbon ion, provided that they are within the acceptance of the experimental apparatus. Concerning the amount of residual carbon ions behind water and PMMA targets with the same water equivalent thickness (WET), no significant differences were found. The experimental attenuation curve was well reproduced by the simulations. However, in the experiments, differences were observed regarding the amount of secondary fragments produced in water and in PMMA targets with the same WET. Differences were also found between experiments and simulations. These findings should be considered when dosimetric measurements are performed with PMMA instead of water phantoms. The found differences between experiments and simulations may contribute to improve the nuclear interaction and fragmentation models in Monte Carlo codes.

The antiproton depth-dose curve in water.

We have measured the depth-dose curve of 126 MeV antiprotons in a water phantom using ionization chambers. Since the antiproton beam provided by CERN has a pulsed structure and possibly carries a high-LET component from the antiproton annihilation, it is necessary to correct the acquired charge for ion recombination effects. The results are compared with Monte Carlo calculations and were found to be in good agreement. Based on this agreement we calculate the antiproton depth-dose curve for antiprotons and compare it with that for protons and find a doubling of the physical dose in the peak region for antiprotons.

Helium ion beam imaging for image guided ion radiotherapy.

BACKGROUND: Ion beam radiotherapy provides potential for increased dose conformation to the target volume. To translate it into a clinical advantage, it is necessary to guarantee a precise alignment of the actual internal patient geometry with the treatment beam. This is in particular challenging for inter- and intrafractional variations, including movement. Ion beams have the potential for a high sensitivity imaging of the patient geometry. However, the research on suitable imaging methods is not conclusive yet. Here we summarize the research activities within the "Clinical research group heavy ion therapy" funded by the DFG (KFO214). Our aim was to develop a method for the visualization of a 1 mm thickness difference with a spatial resolution of about 1 mm at clinically applicable doses. METHODS: We designed and built a dedicated system prototype for ion radiography using exclusively the pixelated semiconductor technology Timepix developed at CERN. Helium ions were chosen as imaging radiation due to their decreased scattering in comparison to protons, and lower damaging potential compared to carbon ions. The data acquisition procedure and a dedicated information processing algorithm were established. The performance of the method was evaluated at the ion beam therapy facility HIT in Germany with geometrical phantoms. The quality of the images was quantified by contrast-to-noise ratio (CNR) and spatial resolution (SR) considering the imaging dose. RESULTS: Using the unique method for single ion identification, degradation of the images due to the inherent contamination of the outgoing beam with light secondary fragments (hydrogen) was avoided. We demonstrated experimentally that the developed data processing increases the CNR by 350%. Consideration of the measured ion track directions improved the SR by 150%. Compared to proton radiographs at the same dose, helium radiographs exhibited 50% higher SR (0.56 ± 0.04lp/mm vs. 0.37 ± 0.02lp/mm) at a comparable CNR in the middle of the phantom. The clear visualization of the aimed inhomogeneity at a diagnostic dose level demonstrates a resolution of 0.1 g/cm2 or 0.6% in terms of water-equivalent thickness. CONCLUSIONS: We developed a dedicated method for helium ion radiography, based exclusively on pixelated semiconductor detectors. The achievement of a clinically desired image quality in simple phantoms at diagnostic dose levels was demonstrated experimentally.

Direct determination of k Q for Farmer-type ionization chambers in a clinical scanned carbon ion beam using water calorimetry.

Until now, the dosimetry of carbon ions with ionization chambers has not reached the same level of accuracy as that of high-energy photons. This is mainly caused by the approximately threefold larger uncertainty of the k Q factor of ionization chambers, which, due to the lack of experimental data, is still derived by calculations. Measurements of absorbed dose to water, D w, by means of water calorimetry have now been performed in the entrance channel of a scanned 6 cm × 6 cm radiation field of 429 MeV/u carbon ions, allowing the direct calibration of ionization chambers and thus the experimental determination of k Q. Within this work, values for k Q have been determined for the Farmer-type ionization chambers FC65-G and TM30013. A detailed investigation of the radiation field enabled the accurate determination of correction factors needed for both calorimetric and ionometric measurements. Finally, a relative standard measurement uncertainty of 0.8% (k = 1) could be achieved for the experimental k Q values. For both chambers, the experimental k Q factors were found to be about 1% larger than those tabulated in the German DIN 6801-1 protocol, whereas compared to the theoretical values stated in the TRS-398 protocol, the experimental k Q value agrees within 0.4% for the TM30013 chamber but is about 1% lower in the case of the FC65-G chamber.

Application of fluorescent nuclear track detectors for cellular dosimetry.

Ion beams radiotherapy with charged particles show greater relative biological effectiveness (RBE) compared to conventional photon therapy. This enhanced RBE is due to a localized energy deposition pattern, which is subject to large fluctuations on cellular scales. Fluorescent nuclear track detectors (FNTDs) based on Al2O3:C,Mg crystals coated with cells (Cell-Fit-HD) can provide information on individual cellular energy deposition. In this study we provide a theoretical framework to obtain the distribution of microscopic energy deposition and ionization density in cells exposed to ion beams and identifies contributions of five different sources of variations to the overall energy fluctuation at different depths of a biologically optimized spread-out Bragg peak. We show that fluctuation in the individual energy loss of the particles is the major source of variability while the fluctuation in particle hits plays a minor role. With the Cell-Fit-HD system the uncertainty arising from four of these sources, namely the nucleus area, the number of nuclear hits, the particle linear energy transfer and the chord length can be reduced and only energy loss straggling remains fundamentally unknown. The ability to quantify these factors results in a reduction of the uncertainty in cellular energy deposition from 24-55% down to only 7-12%. We have also shown current experimental results with FNTDs which show promising results, but need further improvements to reach the ideals predicted in this study.

STED microscopy visualizes energy deposition of single ions in a solid-state detector beyond diffraction limit.

Fluorescent nuclear track detectors (FNTDs) allow for visualization of single-particle traversal in clinical ion beams. The point spread function of the confocal readout has so far hindered a more detailed characterization of the track spots-the ion's characteristic signature left in the FNTD. Here we report on the readout of the FNTD by optical nanoscopy, namely stimulated emission depletion microscopy. It was firstly possible to visualize the track spots of carbon ions and protons beyond the diffraction limit of conventional light microscopy with a resolving power of approximately 80 nm (confocal: 320 nm). A clear discrimination of the spatial width, defined by the full width half maximum of track spots from particles (proton and carbon ions), with a linear energy transfer (LET) ranging from approximately 2-1016 keV µm-1 was possible. Results suggest that the width depends on LET but not on particle charge within the uncertainties. A discrimination of particle type by width thus does not seem possible (as well as with confocal microscopy). The increased resolution, however, could allow for refined determination of the cross-sectional area facing substantial energy deposition. This work could pave the way towards development of optical nanoscopy-based analysis of radiation-induced cellular response using cell-fluorescent ion track hybrid detectors.

Investigation of mixed ion fields in the forward direction for 220.5 MeV/u helium ion beams: comparison between water and PMMA targets.

Currently there is a rising interest in helium ion beams for radiotherapy. For benchmarking of the physical beam models used in treatment planning, there is a need for experimental data on the composition and spatial distribution of mixed ion fields. Of particular interest are the attenuation of the primary helium ion fluence and the build-up of secondary hydrogen ions due to nuclear interactions. The aim of this work was to provide such data with an enhanced precision. Moreover, the validity and limits of the mixed ion field equivalence between water and PMMA targets were investigated. Experiments with a 220.5 MeV/u helium ion pencil beam were performed at the Heidelberg Ion-Beam Therapy Center in Germany. The compact detection system used for ion tracking and identification was solely based on Timepix position-sensitive semiconductor detectors. In comparison to standard techniques, this system is two orders of magnitude smaller, and provides higher precision and flexibility. The numbers of outgoing helium and hydrogen ions per primary helium ion as well as the lateral particle distributions were quantitatively investigated in the forward direction behind water and PMMA targets with 5.2-18 cm water equivalent thickness (WET). Comparing water and PMMA targets with the same WET, we found that significant differences in the amount of outgoing helium and hydrogen ions and in the lateral particle distributions arise for target thicknesses above 10 cm WET. The experimental results concerning hydrogen ions emerging from the targets were reproduced reasonably well by Monte Carlo simulations using the FLUKA code. Concerning the amount of outgoing helium ions, significant differences of 3-15% were found between experiments and simulations. We conclude that if PMMA is used in place of water in dosimetry, differences in the dose distributions could arise close to the edges of the field, in particular for deep seated targets.

Visualization of air and metal inhomogeneities in phantoms irradiated by carbon ion beams using prompt secondary ions.

PURPOSE: Non-invasive methods for monitoring of the therapeutic ion beam extension in the patient are desired in order to handle deteriorations of the dose distribution related to changes of the patient geometry. In carbon ion radiotherapy, secondary light ions represent one of potential sources of information about the dose distribution in the irradiated target. The capability to detect range-changing inhomogeneities inside of an otherwise homogeneous phantom, based on single track measurements, is addressed in this paper. METHODS: Air and stainless steel inhomogeneities, with PMMA equivalent thickness of 10mm and 4.8mm respectively, were inserted into a PMMA-phantom at different positions in depth. Irradiations of the phantom with therapeutic carbon ion pencil beams were performed at the Heidelberg Ion Beam Therapy Center. Tracks of single secondary ions escaping the phantom under irradiation were detected with a pixelized semiconductor detector Timepix. The statistical relevance of the found differences between the track distributions with and without inhomogeneities was evaluated. RESULTS: Measured shifts of the distal edge and changes in the fragmentation probability make the presence of inhomogeneities inserted into the traversed medium detectable for both, 10mm air cavities and 1mm thick stainless steel. Moreover, the method was shown to be sensitive also on their position in the observed body, even when localized behind the Bragg-peak. CONCLUSIONS: The presented results demonstrate experimentally, that the method using distributions of single secondary ion tracks is sensitive to the changes of homogeneity of the traversed material for the studied geometries of the target.

Ion recombination correction factor in scanned light-ion beams for absolute dose measurement using plane-parallel ionisation chambers.

Based on international reference dosimetry protocols for light-ion beams, a correction factor (k s) has to be applied to the response of a plane-parallel ionisation chamber, to account for recombination of negative and positive charges in its air cavity before these charges can be collected on the electrodes. In this work, k s for IBA PPC40 Roos-type chambers is investigated in four scanned light-ion beams (proton, helium, carbon and oxygen). To take into account the high dose-rates used with scanned beams and LET-values, experimental results are compared to a model combining two theories. One theory, developed by Jaffé, describes the variation of k s with the ionization density within the ion track (initial recombination) and the other theory, developed by Boag, describes the variation of k s with the dose rate (volume recombination). Excellent agreement is found between experimental and theoretical k s-values. All results confirm that k s cannot be neglected. The solution to minimise k s is to use the ionisation chamber at high voltage. However, one must be aware that charge multiplication may complicate the interpretation of the measurement. For the chamber tested, it was found that a voltage of 300 V can be used without further complication. As the initial recombination has a logarithmic variation as a function of 1/V, the two-voltage method is not applicable to these scanned beams.

A phenomenological relative biological effectiveness approach for proton therapy based on an improved description of the mixed radiation field.

Proton therapy treatment planning systems (TPSs) are based on the assumption of a constant relative biological effectiveness (RBE) of 1.1 without taking into account the found in vitro experimental variations of the RBE as a function of tissue type, linear energy transfer (LET) and dose. The phenomenological RBE models available in literature are based on the dose-averaged LET (LET D ) as an indicator of the physical properties of the proton radiation field. The LET D values are typically calculated taking into account primary and secondary protons, neglecting the biological effect of heavier secondaries. In this work, we have introduced a phenomenological RBE approach which considers the biological effect of primary protons, and of secondary protons, deuterons, tritons (Z = 1) and He fragments (3He and 4He, Z = 2). The calculation framework, coupled with a Monte Carlo (MC) code, has been successfully benchmarked against clonogenic in vitro data measured in this work for two cell lines and then applied to determine biological quantities for spread-out Bragg peaks and a prostate and a head case. The introduced RBE formalism, which depends on the mixed radiation field, the dose and the ratio of the linear-quadratic model parameters for the reference radiation [Formula: see text], predicts, when integrated in an MC code, higher RBE values in comparison to LET D -based parameterizations. This effect is particular enhanced in the entrance channel of the proton field and for low [Formula: see text] tissues. For the prostate and the head case, we found higher RBE-weighted dose values up to about 5% in the entrance channel when including or neglecting the Z = 2 secondaries in the RBE calculation. TPSs able to proper account for the mixed radiation field in proton therapy are thus recommended for an accurate determination of the RBE in the whole treatment field.

Calculation of stopping power ratios for carbon ion dosimetry.

Water-to-air stopping power ratio calculations for the ionization chamber dosimetry of clinical carbon ion beams with initial energies from 50 to 450 MeV/u have been performed using the Monte Carlo technique. To simulate the transport of a particle in water the computer code SHIELD-HIT v2 was used, which is a newly developed version where substantial modifications were implemented on its predecessor SHIELD-HIT v1 (Gudowska et al 2004 Phys. Med. Biol. 49 1933-58). The code was completely rewritten replacing formerly used single precision variables with double precision variables. The lowest particle transport specific energy was decreased from 1 MeV/u down to 10 keV/u by modifying the Bethe-Bloch formula, thus widening its range for medical dosimetry applications. In addition, the code includes optionally MSTAR and ICRU-73 stopping power data. The fragmentation model was verified and its parameters were also adjusted. The present code version shows excellent agreement with experimental data. It has been used to compute the physical quantities needed for the calculation of stopping power ratios, s(water,air), of carbon beams. Compared with the recommended constant value given in the IAEA Code of Practice, the differences found in the present investigations varied between 0.5% and 1% at the plateau region, respectively for 400 MeV/u and 50 MeV/u beams, and up to 2.3% in the vicinity of the Bragg peak for 50 MeV/u.

Fluence-based dosimetry of proton and heavier ion beams using single track detectors.

Due to their superior spatial resolution, small and biocompatible fluorescent nuclear track detectors (FNTDs) open up the possibility of characterizing swift heavy charged particle fields on a single track level. Permanently stored spectroscopic information such as energy deposition and particle field composition is of particular importance in heavy ion radiotherapy, since radiation quality is one of the decisive predictors for clinical outcome. Findings presented within this paper aim towards single track reconstruction and fluence-based dosimetry of proton and heavier ion fields. Three-dimensional information on individual ion trajectories through the detector volume is obtained using fully automated image processing software. Angular distributions of multidirectional fields can be measured accurately within ±2° uncertainty. This translates into less than 5% overall fluence deviation from the chosen irradiation reference. The combination of single ion tracking with an improved energy loss calibration curve based on 90 FNTD irradiations with protons as well as helium, carbon and oxygen ions enables spectroscopic analysis of a detector irradiated in Bragg peak proximity of a 270 MeV u(-1) carbon ion field. Fluence-based dosimetry results agree with treatment planning software reference.

Registration procedure for spatial correlation of physical energy deposition of particle irradiation and cellular response utilizing cell-fluorescent ion track hybrid detectors.

The hybrid technology cell-fluorescent ion track hybrid detector (Cell-Fit-HD) enables the investigation of radiation-related cellular events along single ion tracks on the subcellular scale in clinical ion beams. The Cell-Fit-HD comprises a fluorescent nuclear track detector (FNTD, the physical compartment), a device for individual particle detection and a substrate for viable cell-coating, i.e. the biological compartment. To date both compartments have been imaged sequentially in situ by confocal laser scanning microscopy (CLSM). This is yet in conflict with a functional read-out of the Cell-Fit-HD utilizing a fast live-cell imaging of the biological compartment with low phototoxicity on greater time scales. The read-out of the biological from the physical compartment was uncoupled. A read-out procedure was developed to image the cell layer by conventional widefield microscopy whereas the FNTD was imaged by CLSM. Point mapping registration of the confocal and widefield imaging data was performed. Non-fluorescent crystal defects (spinels) visible in both read-outs were used as control point pairs. The accuracy achieved was on the sub-µm scale. The read-out procedure by widefield microscopy does not impair the unique ability of spatial correlation by the Cell-Fit-HD. The uncoupling will enlarge the application potential of the hybrid technology significantly. The registration allows for an ultimate correlation of microscopic physical beam parameters and cell kinetics on greater time scales. The method reported herein will be instrumental for the introduction of a novel generation of compact detectors facilitating biodosimetric research towards high-throughput analysis.

Biologically optimized helium ion plans: calculation approach and its in vitro validation.

Treatment planning studies on the biological effect of raster-scanned helium ion beams should be performed, together with their experimental verification, before their clinical application at the Heidelberg Ion Beam Therapy Center (HIT). For this purpose, we introduce a novel calculation approach based on integrating data-driven biological models in our Monte Carlo treatment planning (MCTP) tool. Dealing with a mixed radiation field, the biological effect of the primary (4)He ion beams, of the secondary (3)He and (4)He (Z = 2) fragments and of the produced protons, deuterons and tritons (Z = 1) has to be taken into account. A spread-out Bragg peak (SOBP) in water, representative of a clinically-relevant scenario, has been biologically optimized with the MCTP and then delivered at HIT. Predictions of cell survival and RBE for a tumor cell line, characterized by [Formula: see text] Gy, have been successfully compared against measured clonogenic survival data. The mean absolute survival variation ([Formula: see text]) between model predictions and experimental data was 5.3% ± 0.9%. A sensitivity study, i.e. quantifying the variation of the estimations for the studied plan as a function of the applied phenomenological modelling approach, has been performed. The feasibility of a simpler biological modelling based on dose-averaged LET (linear energy transfer) has been tested. Moreover, comparisons with biophysical models such as the local effect model (LEM) and the repair-misrepair-fixation (RMF) model were performed. [Formula: see text] values for the LEM and the RMF model were, respectively, 4.5% ± 0.8% and 5.8% ± 1.1%. The satisfactorily agreement found in this work for the studied SOBP, representative of clinically-relevant scenario, suggests that the introduced approach could be applied for an accurate estimation of the biological effect for helium ion radiotherapy.