Linear Energy Transfer Measurements and Estimation of Relative Biological Effectiveness in Proton and Helium Ion Beams Using Fluorescent Nuclear Track Detectors.

PURPOSE: Our objective was to develop a methodology for assessing the linear energy transfer (LET) and relative biological effectiveness (RBE) in clinical proton and helium ion beams using fluorescent nuclear track detectors (FNTDs). METHODS AND MATERIALS: FNTDs were exposed behind solid water to proton and helium (4He) ion spread-out Bragg peaks. Detectors were imaged with a confocal microscope, and the LET spectra were derived from the fluorescence intensity. The track- and dose-averaged LET (LETF and LETD, respectively) were calculated from the LET spectra. LET measurements were used as input on RBE models to estimate the RBE. Human alveolar adenocarcinoma cells (A549) were exposed at the same positions as the FNTDs. The RBE was calculated from the resulting survival curves. All measurements were compared with Monte Carlo simulations. RESULTS: For protons, average relative differences between measurements and simulations were 6% and 19% for LETF and LETD, respectively. For helium ions, the same differences were 11% for both quantities. The position of the experimental LET spectra primary peaks agreed with the simulations within 9% and 14% for protons and helium ions, respectively. For the RBE models using LETD as input, FNTD-based RBE values ranged from 1.02 ± 0.01 to 1.25 ± 0.04 and from 1.08 ± 0.09 to 2.68 ± 1.26 for protons and helium ions, respectively. The average relative differences between these values and simulations were 2% and 4%. For A549 cells, the RBE ranged from 1.05 ± 0.07 to 1.47 ± 0.09 and from 0.89 ± 0.06 to 3.28 ± 0.20 for protons and helium ions, respectively. Regarding the RBE-weighted dose (2.0 Gy at the spread-out Bragg peak), the differences between simulations and measurements were below 0.10 Gy. CONCLUSIONS: This study demonstrates for the first time that FNTDs can be used to perform direct LET measurements and to estimate the RBE in clinical proton and helium ion beams.

Proton beam dosimetry in the presence of magnetic fields using Farmer-type ionization chambers of different radii.

BACKGROUND: Magnetic resonance-guided proton therapy is promising, as it combines high-contrast imaging of soft tissue with highly conformal dose delivery. However, proton dosimetry in magnetic fields using ionization chambers is challenging since the dose distribution as well as the detector response are perturbed. PURPOSE: This work investigates the effect of the magnetic field on the ionization chamber response, and on the polarity and ion recombination correction factors, which are essential for the implementation of a proton beam dosimetry protocol in the presence of magnetic fields. METHODS: Three Farmer-type cylindrical ionization chambers, the 30013 with 3 mm inner radius (PTW, Freiburg, Germany) and two custom built chambers "R1" and "R6" with 1 and 6 mm inner radii respectively were placed at the center of an experimental electromagnet (Schwarzbeck Mess - Elektronik, Germany) 2 cm depth of an in-house developed 3D printed water phantom. The detector response was measured for a 3 × 10 cm2 field of mono-energetic protons 221.05 MeV/u for the three chambers, and with an additional proton beam of 157.43 MeV/u for the chamber PTW 30013. The magnetic flux density was varied between 0.1 and 1.0 Tesla in steps of 0.1 Tesla. RESULTS: At both energies, the ionization chamber PTW 30013 showed a non-linear response as a function of the magnetic field strength, with a decrease of the ionization chamber response of up to 0.27% ± 0.06% (1 SD) at 0.2 Tesla, followed by a smaller effect at higher magnetic field strength. For the chamber R1, the response decreased slightly with the magnetic field strength up to 0.45% ± 0.12% at 1 Tesla, and for the chamber R6, the response decreased up to 0.54% ± 0.13% at 0.1 Tesla, followed by a plateau up to 0.3 Tesla, and a weaker effect at higher magnetic field strength. The dependence of the polarity and recombination correction factor on the magnetic field was ⩽0.1% for the chamber PTW 30013. CONCLUSIONS: The magnetic field has a small but significant effect on the chamber response in the low magnetic field region for the chamber PTW 30013 and for R6, and in the high magnetic field region for the chamber R1. Corrections may be necessary for ionization chamber measurements, depending on both the chamber volume and the magnetic flux density. No significant effect of the magnetic field on the polarity and recombination correction factor was detected in this work for the ionization chamber PTW 30013.

Sensitivity correction of fluorescent nuclear track detectors using alpha particles: Determining LET spectra of light ions with enhanced accuracy.

BACKGROUND: Radiation fields encountered in proton therapy (PT) and ion-beam therapy (IBT) are characterized by a variable linear energy transfer (LET), which lead to a variation of relative biological effectiveness and also affect the response of certain dosimeters. Therefore, reliable tools to measure LET are advantageous to predict and correct LET effects. Fluorescent nuclear track detectors (FNTDs) are suitable to measure LET spectra within the range of interest for PT and IBT, but so far the accuracy and precision have been challenged by sensitivity variations between individual crystals. PURPOSE: To develop a novel methodology to correct changes in the fluorescent intensity due to sensitivity variations among FNTDs. This methodology is based on exposing FNTDs to alpha particles in order to derive a detector-specific correction factor. This will allow us to improve the accuracy and precision of LET spectra measurements with FNTDs. METHODS: FNTDs were exposed to alpha particles. Afterward, the detectors were irradiated to monoenergetic protons, 4 He-, 12 C-, and 16 O-ions. At each step, the detectors were imaged with a confocal laser scanning microscope. The tracks were reconstructed and analyzed using in-house developed tools. Alpha-particle tracks were used to derive a detector-specific sensitivity correction factor ( k s , i ${k_{s,i}}$ ). Proton, 4 He-, 12 C-, and 16 O-ion tracks were used to establish a traceable calibration curve that relates the fluorescence intensity with the LET in water ( L E T H 2 O $LE{T_{{{\rm{H}}_2}{\rm{O}}}}$ ). FNTDs from a second batch were exposed and analyzed following the same procedures, to test if k s , i ${k_{s,i}}$ can be used to extend the applicability of the calibration curve to detectors from different batches. Finally, a set of blind tests was performed to assess the accuracy of the proposed methodology without user bias. Throughout all stages, the main sources of uncertainty were evaluated. RESULTS: Based on a sample of 100 FNTDs, our findings show a high sensitivity heterogeneity between FNTDs, with k s , i ${k_{s,i}}$ having values between 0.57 and 2.55. The fitting quality of the calibration curve, characterized by the mean absolute percentage residuals and correlation coefficient, was improved when k s , i ${k_{s,i}}$ was considered. Results for detectors from the second batch show that, if the fluorescence signal is corrected by k s , i ${k_{s,i}}$ , the differences in the predicted L E T H 2 O $LE{T_{{{\rm{H}}_2}{\rm{O}}}}$ with respect to the reference set are reduced from 55%, 141%, 41%, and 186% to 4.2%, 6.5%, 5.0%, and 11.0%, for protons, 4 He-, 12 C-, and 16 O-ions, respectively. The blind tests showed that it is possible to measure the track- and dose-average L E T H 2 O $LE{T_{{{\rm{H}}_2}{\rm{O}}}}$ with an accuracy of 0.3%, 16%, and 9.6% and 1.7%, 28%, and 30% for protons, 12 C-ions and mixed beams, respectively. On average, the combined uncertainty of the measured L E T H 2 O $LE{T_{{{\rm{H}}_2}{\rm{O}}}}$ was 11%, 13%, 21%, and 26% for protons, 4 He-, 12 C-, and 16 O-ions, respectively. These values were increased by a mean factor of 2.0 when k s , i ${k_{s,i}}$ was not applied. CONCLUSIONS: We have demonstrated for the first time that alpha particles can be used to derive a detector-specific sensitivity correction factor. The proposed methodology allows us to measure LET spectra using FNTD-technology, with a degree of accuracy and precision unreachable before with sole experimental approaches.

Integrated MRI-guided proton therapy planning: Accounting for the full MRI field in a perpendicular system.

PURPOSE: To present a first study on the treatment planning feasibility in perpendicular field MRI-integrated proton therapy that considers the full transport of protons from the pencil beam scanning (PBS) assembly to the patient inside the MRI scanner. METHODS: A generic proton PBS gantry was modeled as being integrated with a realistic split-bore MRI system in the perpendicular orientation. MRI field strengths were modeled as 0.5, 1, and 1.5 T. The PBS beam delivery and dose calculation was modeled using the TOPAS Monte Carlo toolkit coupled with matRad as the optimizer engine. A water phantom, liver, and prostate plans were evaluated and optimized in the presence of the full MRI field distribution. A simple combination of gantry angle offset and small PBS nozzle skew was used to direct the proton beams along a path that closely follows the reference planning scenario, that is, without magnetic field. RESULTS: All planning metrics could be successfully achieved with the inclusion of gantry angle offsets in the range of 8 ∘ $^{\circ }$ -29 ∘ $^{\circ }$ when coupled with a PBS nozzle skew of 1.6 ∘ $^{\circ }$ -4.4 ∘ $^{\circ }$ . These two hardware-based corrections were selected to minimize the average Euclidean distance (AED) in the beam path enabling the proton beams to travel inside the patient in a path that is close to the original path (AED smaller than 3 mm at 1.5 T). Final dose optimization, performed through further changes in the PBS delivery, was then shown to be feasible for our selection of plans studied yielding comparable plan quality metrics to reference conditions. CONCLUSIONS: For the first time, we have shown a robust method to account for the full proton beam deflection in a perpendicular orientation MRI-integrated proton therapy. These results support the ongoing development of the current prototype systems.

MRI-guided proton therapy planning: accounting for an inline MRI fringe field.

MRI-guided proton therapy is being pursued for its promise to provide a more conformal, accurate proton therapy. However, the presence of the magnetic field imposes a challenge for the beam delivery as protons are deflected due to the Lorenz force. In this study, the impact of realistic inline MRI fringe field on IMPT plan delivery is investigated for a water phantom, liver tumor and prostate cancer differing in target volume, shape, and field configuration using Monte Carlo simulations. A method to correct for the shift of the beam spot positions in the presence of the inline magnetic field is presented. Results show that when not accounting for the effect of the magnetic field on the pencil beam delivery, the spot positions are substantially shifted and the quality of delivered plans is significantly deteriorated leading to dose inhomogeneities and creation of hot and cold spots. However, by correcting the pencil beam delivery, the dose quality of the IMPT plans is restored to a high degree. Nevertheless, adaptation of beam delivery alone is not robust regarding different treatment sites. By fully accounting during plan optimization for the dose distortions caused by the fringe and imaging fields, highly conformal IMPT plans are achieved. These results demonstrate proton pencil beam scanning and treatment planning can be adapted for precise delivery of state-of-the-art IMPT plans in MR-guided proton therapy in the presence of an inline MRI fringe field.

The microdosimetric extension in TOPAS: development and comparison with published data.

Microdosimetric energy depositions have been suggested as a key variable for the modeling of the relative biological effectiveness (RBE) in proton and ion radiation therapy. However, microdosimetry has been underutilized in radiation therapy. Recent advances in detector technology allow the design of new mico- and nano-dosimeters. At the same time Monte Carlo (MC) simulations have become more widely used in radiation therapy. In order to address the growing interest in the field, a microdosimetric extension was developed in TOPAS. The extension provides users with the functionality to simulate microdosimetric spectra as well as the contribution of secondary particles to the spectra, calculate microdosimetric parameters, and determine RBE with a biological weighting function approach or with the microdosimetric kinetic (MK) model. Simulations were conducted with the extension and the results were compared with published experimental data and other simulation results for three types of microdosimeters, a spherical tissue equivalent proportional counter (TEPC), a cylindrical TEPC and a solid state microdosimeter. The corresponding microdosimetric spectra obtained with TOPAS from the plateau region to the distal tail of the Bragg curve generally show good agreement with the published data.

Comparing the effectiveness and efficiency of various gating approaches for PBS proton therapy of pancreatic cancer using 4D-MRI datasets.

Abdominal organ motion may lead to considerable uncertainties in pencil-beam scanning (PBS) proton therapy of pancreatic cancer. Beam gating, where irradiation only occurs in certain breathing phases in which the gating conditions are fulfilled, may be an option to reduce the interplay effect between tumor motion and the scanning beam. This study aims to, first, determine suitable gating windows with respect to effectiveness (low interplay effect) and efficiency (high duty cycles). Second, it investigates whether beam gating allows for a better mitigation of the interplay effect along the treatment course than free-breathing irradiations. Based on synthetic 4D-CTs, generated by warping 3D-CTs with vector fields extracted from time-resolved magnetic resonance imaging (4D-MRI) for 8 pancreatic cancer patients, 4D dose calculations (4DDC) were performed to analyze the duty cycle and homogeneity index HI = d5/d95 for four different gating scenarios. These were based on either fixed threshold values of CTV (clinical target volume) mean or maximum motion amplitudes (5 mm), relative CTV motion amplitudes (30%) or CTV overlap criteria (95%), respectively. 4DDC for 28-fractions treatment courses were performed with fixed and variable initial breathing phases to investigate the fractionation-induced mitigation of the interplay effect. Gating criteria, based on patient-specific relative 30% CTV motion amplitudes, showed the significantly best HI values with sufficient duty cycles, in contrast to inferior results by either fixed gating thresholds or overlap criteria. For gated treatments with 28 fractions, less fractionation-induced mitigation of the interplay effect was observed for gating criteria with gating windows ⩾30%, compared to free-breathing treatments. The gating effectiveness for multiple fractions was improved by allowing a variable initial breathing phase. Gating with relative amplitude thresholds are effective for proton therapy of pancreatic cancer. By combining beam gating with variable initial breathing phases, a pronounced mitigation of the interplay effect by fractionation can be achieved.

Simultaneous optimization of RBE-weighted dose and nanometric ionization distributions in treatment planning with carbon ions.

Inverse treatment planning in intensity modulated particle therapy (IMPT) with scanned carbon-ion beams is currently based on the optimization of RBE-weighted dose to satisfy requirements of target coverage and limited toxicity to organs-at-risk (OARs) and healthy tissues. There are many feasible IMPT plans that meet these requirements, which allows the introduction of further criteria to narrow the selection of a biologically optimal treatment plan. We propose a novel treatment planning strategy based on the simultaneous optimization of RBE-weighted dose and nanometric ionization details (ID) as a new physical characteristic of the delivered plan beyond LET. In particular, we focus on the distribution of large ionization clusters (more than 3 ionizations) to enhance the biological effect across the target volume while minimizing biological effect in normal tissues. Carbon-ion treatment plans for different patient geometries and beam configurations generated with the simultaneous optimization strategy were compared against reference plans obtained with RBE-weighted dose optimization alone. Quality indicators, inhomogeneity index and planning volume histograms of RBE-weighted dose and large ionization clusters were used to evaluate the treatment plans. We show that with simultaneous optimization, ID distributions can be optimized in carbon-ion radiotherapy without compromising the RBE-weighted dose distributions. This strategy can potentially be used to account for optimization of endpoints closely related to radiation quality to achieve better tumor control and reduce risks of complications.

Fast calculation of nanodosimetric quantities in treatment planning of proton and ion therapy.

Details of the pattern of ionization formed by particle tracks extends knowledge of dose effects on the nanometer scale. Ionization detail (ID), frequently characterized by ionization cluster size distributions (ICSD), is obtained through time-consuming Monte Carlo (MC) track-structure simulations. In this work, TOPAS-nBio was used to generate a highly precise database of biologically significant ID quantities, sampled with randomly oriented 2.3 nm diameter cylinders, 3.4 nm (10 base pairs) long, inside a chromatin-size cylinder, irradiated by 1-1000 MeV/u ions of Z = 1-8. A macroscopic method developed to utilize the database using condensed-history MC was used to calculate distributions of the ICSD first moment [Formula: see text] and cumulative probability [Formula: see text] in a 20 × 20 × 40 cm3 water phantom irradiated with proton and carbon spread-out Bragg peak (SOBP) of 10.5 cm range, 2 cm width. Results were verified against detailed MC track-structure simulations using phase space scored at several depths. ID distributions were then obtained for intensity modulated proton and carbon radiotherapy plans in a digitized anthropomorphic phantom of a base of skull tumor to demonstrate clinical application of this approach. The database statistical uncertainties were 0.5% (3 standard deviations). Fluence-averaged ID as implemented proved unsuitable for macroscopic calculation. E dep-averaged ID agreed with track-structure results within 0.8% for protons. For carbon, maximum absolute differences of 2.9% ± 1.6% and 5.6% ± 1.9% for [Formula: see text], 1.7% ± 0.8% and 1.9% ± 0.4% (1 standard deviation) for [Formula: see text], were found in the plateau and SOBP, respectively, up to 11.5% ± 5.6% in the tail region. Macroscopic ID calculation was demonstrated for a realistic treatment plan. Computation times with or without ID calculation were comparable in all cases. Pre-calculated nanodosimetric data may be used for condensed-history MC for nanodosimetric ID-based treatment planning in ion radiotherapy in the future. The macroscopic approach developed has the calculation speed of condensed-history MC while approaching the accuracy of full track structure simulations.

A novel method for assessment of fragmentation and beam-material interactions in helium ion radiotherapy with a miniaturized setup.

Radiotherapy with protons and carbon ions enables to deliver dose distributions of high conformation to the target. Treatment with helium ions has been suggested due to their physical and biological advantages. A reliable benchmarking of the employed physics models with experimental data is required for treatment planning. However, experimental data for helium interactions is limited, in part due to the complexity and large size of conventional experimental setups. We present a novel method for the investigation of helium interactions with matter using miniaturized instrumentation based on highly integrated pixel detectors. The versatile setup consisted of a monitoring detector in front of the PMMA phantom of varying thickness and a detector stack for investigation of outgoing particles. The ion type downstream from the phantom was determined by high-resolution pattern recognition analysis of the single particle signals in the pixelated detectors. The fractions of helium and hydrogen ions behind the used targets were determined. As expected for the stable helium nucleus, only a minor decrease of the primary ion fluence along the target depth was found. E.g. the detected fraction of hydrogen ions on axis of a 220MeV/u 4He beam was below 6% behind 24.5cm of PMMA. Monte-Carlo simulations using Geant4 reproduce the experimental data on helium attenuation and yield of helium fragments qualitatively, but significant deviations were found for some combinations of target thickness and beam energy. The presented method is promising to contribute to the reduction of the uncertainty of treatment planning for helium ion radiotherapy.