Neutron Capture Enhances Dose and Reduces Cancer Cell Viability in and out of Beam During Helium and Carbon Ion Therapy.

PURPOSE: Neutron capture enhanced particle therapy (NCEPT) is a proposed augmentation of charged particle therapy that exploits thermal neutrons generated internally, within the treatment volume via nuclear fragmentation, to deliver a biochemically targeted radiation dose to cancer cells. This work is the first experimental demonstration of NCEPT, performed using both carbon and helium ion beams with 2 different targeted neutron capture agents (NCAs). METHODS AND MATERIALS: Human glioblastoma cells (T98G) were irradiated by carbon and helium ion beams in the presence of NCAs [10B]-BPA and [157Gd]-DOTA-TPP. Cells were positioned within a polymethyl methacrylate phantom either laterally adjacent to or within a 100 × 100 × 60 mm spread out Bragg peak (SOBP). The effect of NCAs and location relative to the SOBP on the cells was measured by cell growth and survival assays in 6 independent experiments. Neutron fluence within the phantom was characterized by quantifying the neutron activation of gold foil. RESULTS: Cells placed inside the treatment volume reached 10% survival by 2 Gy of carbon or 2 to 3 Gy of helium in the presence of NCAs compared with 5 Gy of carbon and 7 Gy of helium with no NCA. Cells placed adjacent to the treatment volume showed a dose-dependent decrease in cell growth when treated with NCAs, reaching 10% survival by 6 Gy of carbon or helium (to the treatment volume), compared with no detectable effect on cells without NCA. The mean thermal neutron fluence at the center of the SOBP was approximately 2.2 × 109 n/cm2/Gy (relative biological effectiveness) for the carbon beam and 5.8 × 109 n/cm2/Gy (relative biological effectiveness) for the helium beam and gradually decreased in all directions. CONCLUSIONS: The addition of NCAs to cancer cells during carbon and helium beam irradiation has a measurable effect on cell survival and growth in vitro. Through the capture of internally generated neutrons, NCEPT introduces the concept of a biochemically targeted radiation dose to charged particle therapy. NCEPT enables the established pharmaceuticals and concepts of neutron capture therapy to be applied to a wider range of deeply situated and diffuse tumors, by targeting this dose to microinfiltrates and cells outside of defined treatment regions. These results also demonstrate the potential for NCEPT to provide an increased dose to tumor tissue within the treatment volume, with a reduction in radiation doses to off-target tissue.

First experimental demonstration of real-time neutron capture discrimination in helium and carbon ion therapy.

This work provides the first experimental proof of an increased neutron capture photon signal following the introduction of boron to a PMMA phantom during helium and carbon ion therapies in Neutron Capture Enhanced Particle Therapy (NCEPT). NCEPT leverages [Formula: see text]B neutron capture, leading to the emission of detectable 478 keV photons. Experiments were performed at the Heavy Ion Medical Accelerator in Chiba, Japan, with two Poly(methyl methacrylate) (PMMA) targets, one bearing a boron insert. The BeNEdiCTE gamma-ray detector measured an increase in the 478 keV signal of 45 ± 7% and 26 ± 2% for carbon and helium ion irradiation, respectively. Our Geant4 Monte Carlo simulation model, developed to investigate photon origins, found less than 30% of detected photons originated from the insert, while boron in the detector's circuit boards contributed over 65%. Further, the model investigated detector sensitivity, establishing its capability to record a 10% increase in 478 keV photon detection at a target [Formula: see text]B concentration of 500 ppm using spectral windowing alone, and 25% when combined with temporal windowing. The linear response extended to concentrations up to 20,000 ppm. The increase in the signal in all evaluated cases confirm the potential of the proposed detector design for neutron capture quantification in NCEPT.

A Monte Carlo model of the Dingo thermal neutron imaging beamline.

In this study, we present a validated Geant4 Monte Carlo simulation model of the Dingo thermal neutron imaging beamline at the Australian Centre for Neutron Scattering. The model, constructed using CAD drawings of the entire beam transport path and shielding structures, is designed to precisely predict the in-beam neutron field at the position at the sample irradiation stage. The model's performance was assessed by comparing simulation results to various experimental measurements, including planar thermal neutron distribution obtained in-beam using gold foil activation and [Formula: see text]B[Formula: see text]C-coated microdosimeters and the out-of-beam neutron spectra measured with Bonner spheres. The simulation results demonstrated that the predicted neutron fluence at the field's centre is within 8.1% and 2.1% of the gold foil and [Formula: see text]B[Formula: see text]C-coated microdosimeter measurements, respectively. The logarithms of the ratios of average simulated to experimental fluences in the thermal (E[Formula: see text] 0.414 eV), epithermal (0.414 eV < E[Formula: see text] 11.7 keV) and fast (E[Formula: see text] 11.7 keV) spectral regions were approximately - 0.03 to + 0.1, - 0.2 to + 0.15, and - 0.4 to + 0.2, respectively. Furthermore, the predicted thermal, epithermal and fast neutron components in-beam at the sample stage position constituted approximately 18%, 64% and 18% of the total neutron fluence.

An inception network for positron emission tomography based dose estimation in carbon ion therapy.

Objective. We aim to evaluate a method for estimating 1D physical dose deposition profiles in carbon ion therapy via analysis of dynamic PET images using a deep residual learning convolutional neural network (CNN). The method is validated using Monte Carlo simulations of12C ion spread-out Bragg peak (SOBP) profiles, and demonstrated with an experimental PET image.Approach. A set of dose deposition and positron annihilation profiles for monoenergetic12C ion pencil beams in PMMA are first generated using Monte Carlo simulations. From these, a set of random polyenergetic dose and positron annihilation profiles are synthesised and used to train the CNN. Performance is evaluated by generating a second set of simulated12C ion SOBP profiles (one 116 mm SOBP profile and ten 60 mm SOBP profiles), and using the trained neural network to estimate the dose profile deposited by each beam and the position of the distal edge of the SOBP. Next, the same methods are used to evaluate the network using an experimental PET image, obtained after irradiating a PMMA phantom with a12C ion beam at QST's Heavy Ion Medical Accelerator in Chiba facility in Chiba, Japan. The performance of the CNN is compared to that of a recently published iterative technique using the same simulated and experimental12C SOBP profiles.Main results. The CNN estimated the simulated dose profiles with a mean relative error (MRE) of 0.7% ± 1.0% and the distal edge position with an accuracy of 0.1 mm ± 0.2 mm, and estimate the dose delivered by the experimental12C ion beam with a MRE of 3.7%, and the distal edge with an accuracy of 1.7 mm.Significance. The CNN was able to produce estimates of the dose distribution with comparable or improved accuracy and computational efficiency compared to the iterative method and other similar PET-based direct dose quantification techniques.

Detection and discrimination of neutron capture events for NCEPT dose quantification.

Neutron Capture Enhanced Particle Therapy (NCEPT) boosts the effectiveness of particle therapy by capturing thermal neutrons produced by beam-target nuclear interactions in and around the treatment site, using tumour-specific [Formula: see text]B or [Formula: see text]Gd-based neutron capture agents. Neutron captures release high-LET secondary particles together with gamma photons with energies of 478 keV or one of several energies up to 7.94 MeV, for [Formula: see text]B and [Formula: see text]Gd, respectively. A key requirement for NCEPT's translation is the development of in vivo dosimetry techniques which can measure both the direct ion dose and the dose due to neutron capture. In this work, we report signatures which can be used to discriminate between photons resulting from neutron capture and those originating from other processes. A Geant4 Monte Carlo simulation study into timing and energy thresholds for discrimination of prompt gamma photons resulting from thermal neutron capture during NCEPT was conducted. Three simulated [Formula: see text] mm[Formula: see text] cubic PMMA targets were irradiated by [Formula: see text]He or [Formula: see text]C ion beams with a spread out Bragg peak (SOBP) depth range of 60 mm; one target is homogeneous while the others include [Formula: see text] mm[Formula: see text] neutron capture inserts (NCIs) of pure [Formula: see text]B or [Formula: see text]Gd located at the distal edge of the SOBP. The arrival times of photons and neutrons entering a simulated [Formula: see text] mm[Formula: see text] ideal detector were recorded. A temporal mask of 50-60 ns was found to be optimal for maximising the discrimination of the photons resulting from the neutron capture by boron and gadolinium. A range of candidate detector and thermal neutron shielding materials were simulated, and detections meeting the proposed acceptance criteria (i.e. falling within the target energy window and arriving 60 ns post beam-off) were classified as true or false positives, depending on their origin. The ratio of true/false positives ([Formula: see text]) was calculated; for targets with [Formula: see text]B and [Formula: see text]Gd NCIs, the detector materials which resulted in the highest [Formula: see text] were cadmium-shielded CdTe and boron-shielded LSO, respectively. The optimal irradiation period for both carbon and helium ions was 1 µs for the [Formula: see text]B NCI and 1 ms for the [Formula: see text]Gd NCI.

A Monte Carlo simulation study of scatter fraction and the impact of patient BMI on scatter in long axial field-of-view PET scanners.

The NEMA NU-2 standard describes a protocol for measurement of scatter fraction (SF) using an axially-aligned line source, offset at 45mm from the central axis, in a cylindrical polyethylene phantom. In this work, which is an extension of our preliminary results previuosly published in the Proceedings of IEEE NSS/MIC 2018 [1], we aim to evaluate the performance of the NEMA NU-2 SF protocol in a Siemens Biograph mCT PET/CT whole-body scanner and a long axial field-of-view (LAFOV) total-body PET scanner to determine whether modifications to the NEMA NU-2 SF protocol are needed for the characterisation of scatter in such scanners. In addition, we evaluate the impact of patient body mass index (BMI) on SF in a LAFOV scanner. The Siemens Biograph mCT and a typical LAFOV PET scanner were modelled in GATE. Monte Carlo simulations were performed to validate the mCT scanner model against published experimental results. SF was estimated using a modified NEMA NU-2 protocol with variable radial offsets on both scanners and compared to ground truth SF measurements obtained with a uniform-activity cylindrical phantom. Correlation between BMI and SF in the LAFOV scanner was evaluated by simulating anthropomorphic phantoms with different BMIs and realistic 18F-FDG distributions, together with uniformly-filled 200cm long cylindrical phantoms with equivalent effective diameters. The optimal offset was found to be either 60mm or 80mm, depending on the chosen optimality metric. We conclude that modifications to NEMA NU-2 are required for accurate SF characterisation in whole-body and LAFOV scanners. Finally, SF in anthropomorphic phantoms with realistic tissue concentrations of 18F-FDG was found to be strongly correlated with SF in an equivalent-volume cylindrical phantom for the LAFOV PET scanner; BMI was also found to strongly positively correlate with the SF.

A validated Geant4 model of a whole-body PET scanner with four-layer DOI detectors.

The purpose of this work is to develop a validated Geant4 simulation model of a whole-body prototype PET scanner constructed from the four-layer depth-of-interaction detectors developed at the National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Japan. The simulation model emulates the behaviour of the unique depth of interaction sensing capability of the scanner without needing to directly simulate optical photon transport in the scintillator and photodetector modules. The model was validated by evaluating and comparing performance metrics from the NEMA NU 2-2012 protocol on both the simulated and physical scanner, including spatial resolution, sensitivity, scatter fraction, noise equivalent count rates and image quality. The results show that the average sensitivities of the scanner in the field-of-view were 5.9 cps kBq-1 and 6.0 cps kBq-1 for experiment and simulation, respectively. The average spatial resolutions measured for point sources placed at several radial offsets were 5.2± 0.7 mm and 5.0± 0.8 mm FWHM for experiment and simulation, respectively. The peak NECR was 22.9 kcps at 7.4 kBq ml-1 for the experiment, while the NECR obtained via simulation was 23.3 kcps at the same activity. The scatter fractions were 44% and 41.3% for the experiment and simulation, respectively. Contrast recovery estimates performed in different regions of a simulated image quality phantom matched the experimental results with an average error of -8.7% and +3.4% for hot and cold lesions, respectively. The results demonstrate that the developed Geant4 model reliably reproduces the key NEMA NU 2-2012 performance metrics evaluated on the prototype PET scanner. A simplified version of the model is included as an advanced example in Geant4 version 10.5.

Dose quantification in carbon ion therapy using in-beam positron emission tomography.

This work presents an iterative method for the estimation of the absolute dose distribution in patients undergoing carbon ion therapy, via analysis of the distribution of positron annihilations resulting from the decay of positron-emitting fragments created in the target volume. The proposed method relies on the decomposition of the total positron-annihilation distributions into profiles of the three principal positron-emitting fragment species - 11C, 10C and 15O. A library of basis functions is constructed by simulating a range of monoenergetic 12C ion irradiations of a homogeneous polymethyl methacrylate phantom and measuring the resulting one-dimensional positron-emitting fragment profiles and dose distributions. To estimate the dose delivered during an arbitrary polyenergetic irradiation, a linear combination of factors from the fragment profile library is iteratively fitted to the decomposed positron annihilation profile acquired during the irradiation, and the resulting weights combined with the corresponding monoenergetic dose profiles to estimate the total dose distribution. A total variation regularisation term is incorporated into the fitting process to suppress high-frequency noise. The method was evaluated with 14 different polyenergetic 12C dose profiles in a polymethyl methacrylate target: one which produces a flat biological dose, 10 with randomised energy weighting factors, and three with distinct dose maxima or minima within the spread-out Bragg peak region. The proposed method is able to calculate the dose profile with mean relative errors of 0.8%, 1.0% and 1.6% from the 11C, 10C, 15O fragment profiles, respectively, and estimate the position of the distal edge of the SOBP to within an average of 0.7 mm, 1.9 mm and 1.2 mm of its true location.

Experimental investigation of the characteristics of radioactive beams for heavy ion therapy.

PURPOSE: This work has two related objectives. The first is to estimate the relative biological effectiveness of two radioactive heavy ion beams based on experimental measurements, and compare these to the relative biological effectiveness of corresponding stable isotopes to determine whether they are therapeutically equivalent. The second aim is to quantitatively compare the quality of images acquired postirradiation using an in-beam whole-body positron emission tomography scanner for range verification quality assurance. METHODS: The energy deposited by monoenergetic beams of 11 C at 350 MeV/u, 15 O at 250 MeV/u, 12 C at 350 MeV/u, and 16 O at 430 MeV/u was measured using a cruciform transmission ionization chamber in a water phantom at the Heavy Ion Medical Accelerator in Chiba (HIMAC), Japan. Dose-mean lineal energy was measured at various depths along the path of each beam in a water phantom using a silicon-on-insulator mushroom microdosimeter. Using the modified microdosimetric kinetic model, the relative biological effectiveness at 10% survival fraction of the radioactive ion beams was evaluated and compared to that of the corresponding stable ions along the path of the beam. Finally, the postirradiation distributions of positron annihilations resulting from the decay of positron-emitting nuclei were measured for each beam in a gelatin phantom using the in-beam whole-body positron emission tomography scanner at HIMAC. The depth of maximum positron-annihilation density was compared with the depth of maximum dose deposition and the signal-to-background ratios were calculated and compared for images acquired over 5 and 20 min postirradiation of the phantom. RESULTS: In the entrance region, the h b o x RBE 10 was 1.2 ± 0.1 for both 11 C and 12 C beams, while for 15 O and 16 O it was 1.4 ± 0.1 and 1.3 ± 0.1, respectively. At the Bragg peak, the RBE 10 was 2.7 ± 0.4 for 11 C and 2.9 ± 0.4 for 12 C, while for 15 O and 16 O it was 2.7 ± 0.4 and 2.8 ± 0.4, respectively. In the tail region, RBE 10 could only be evaluated for carbon; the RBE 10 was 1.6 ± 0.2 and 1.5 ± 0.1 for 11 C and 12 C, respectively. Positron emission tomography images obtained from gelatin targets irradiated by radioactive ion beams exhibit markedly improved signal-to-background ratios compared to those obtained from targets irradiated by nonradioactive ion beams, with 5-fold and 11-fold increases in the ratios calculated for the 15 O and 11 C images compared with the values obtained for 16 O and 12 C, respectively. The difference between the depth of maximum dose and the depth of maximum positron annihilation density is 2.4 ± 0.8 mm for 11 C, compared to -5.6 ± 0.8 mm for 12 C and 0.9 ± 0.8 mm for 15 O vs -6.6 ± 0.8 mm for 16 O. CONCLUSIONS: The RBE 10 values for 11 C and 15 O were found to be within the 95% confidence interval of the RBEs estimated for their corresponding stable isotopes across each of the regions in which it was evaluated. Furthermore, for a given dose, 11 C and 15 O beams produce much better quality images for range verification compared with 12 C and 16 O, in particular with regard to estimating the location of the Bragg peak.

Optimisation of monolithic nanocomposite and transparent ceramic scintillation detectors for positron emission tomography.

High-resolution arrays of discrete monocrystalline scintillators used for gamma photon coincidence detection in PET are costly and complex to fabricate, and exhibit intrinsically non-uniform sensitivity with respect to emission angle. Nanocomposites and transparent ceramics are two alternative classes of scintillator materials which can be formed into large monolithic structures, and which, when coupled to optical photodetector arrays, may offer a pathway to low cost, high-sensitivity, high-resolution PET. However, due to their high optical attenuation and scattering relative to monocrystalline scintillators, these materials exhibit an inherent trade-off between detection sensitivity and the number of scintillation photons which reach the optical photodetectors. In this work, a method for optimising scintillator thickness to maximise the probability of locating the point of interaction of 511 keV photons in a monolithic scintillator within a specified error bound is proposed and evaluated for five nanocomposite materials (LaBr3:Ce-polystyrene, Gd2O3-polyvinyl toluene, LaF3:Ce-polystyrene, LaF3:Ce-oleic acid and YAG:Ce-polystyrene) and four ceramics (GAGG:Ce, GLuGAG:Ce, GYGAG:Ce and LuAG:Pr). LaF3:Ce-polystyrene and GLuGAG:Ce were the best-performing nanocomposite and ceramic materials, respectively, with maximum sensitivities of 48.8% and 67.8% for 5 mm localisation accuracy with scintillator thicknesses of 42.6 mm and 27.5 mm, respectively.

Comparative study of alternative Geant4 hadronic ion inelastic physics models for prediction of positron-emitting radionuclide production in carbon and oxygen ion therapy.

The distribution of fragmentation products predicted by Monte Carlo simulations of heavy ion therapy depend on the hadronic physics model chosen in the simulation. This work aims to evaluate three alternative hadronic inelastic fragmentation physics options available in the Geant4 Monte Carlo radiation physics simulation framework to determine which model most accurately predicts the production of positron-emitting fragmentation products observable using in-beam PET imaging. Fragment distributions obtained with the BIC, QMD, and INCL + + physics models in Geant4 version 10.2.p03 are compared to experimental data obtained at the HIMAC heavy-ion treatment facility at NIRS in Chiba, Japan. For both simulations and experiments, monoenergetic beams are applied to three different block phantoms composed of gelatin, poly(methyl methacrylate) and polyethylene. The yields of the positron-emitting nuclei 11C, 10C and 15O obtained from simulations conducted with each model are compared to the experimental yields estimated by fitting a multi-exponential radioactive decay model to dynamic PET images using the normalised mean square error metric in the entrance, build up/Bragg peak and tail regions. Significant differences in positron-emitting fragment yield are observed among the three physics models with the best overall fit to experimental 12C and 16O beam measurements obtained with the BIC physics model.

Monte Carlo investigation of the characteristics of radioactive beams for heavy ion therapy.

This work presents a simulation study evaluating relative biological effectiveness at 10% survival fraction (RBE10) of several different positron-emitting radionuclides in heavy ion treatment systems, and comparing these to the RBE10s of their non-radioactive counterparts. RBE10 is evaluated as a function of depth for three positron-emitting radioactive ion beams (10C, 11C and 15O) and two stable ion beams (12C and 16O) using the modified microdosimetric kinetic model (MKM) in a heterogeneous skull phantom subject to a rectangular 50 mm × 50 mm × 60 mm spread out Bragg peak. We demonstrate that the RBE10 of the positron-emitting radioactive beams is almost identical to the corresponding stable isotopes. The potential improvement in PET quality assurance image quality which is obtained when using radioactive beams is evaluated by comparing the signal to background ratios of positron annihilations at different intra- and post-irradiation time points. Finally, the incidental dose to the patient resulting from the use of radioactive beams is also quantified and shown to be negligible.

Localisation of the Lines of Response in a Continuous Cylindrical Shell PET Scanner.

This work presents a technique for localising the endpoints of the lines of response in a PET scanner based on a continuous cylindrical shell scintillator. The technique is demonstrated by applying it to a simulation of a sensitivity-optimised continuous cylindrical shell PET system using two novel scintillator materials - a transparent ceramic garnet, GLuGAG:Ce, and a LuF3:Ce-polystyrene nanocomposite. Error distributions for the endpoints of the lines of response in the axial, tangential and radial dimension as well as overall endpoint spatial error are calculated for three source positions; the resultant distribution of error in the placement of the lines of response is also estimated.

Opportunistic dose amplification for proton and carbon ion therapy via capture of internally generated thermal neutrons.

This paper presents Neutron Capture Enhanced Particle Therapy (NCEPT), a method for enhancing the radiation dose delivered to a tumour relative to surrounding healthy tissues during proton and carbon ion therapy by capturing thermal neutrons produced inside the treatment volume during irradiation. NCEPT utilises extant and in-development boron-10 and gadolinium-157-based drugs from the related field of neutron capture therapy. Using Monte Carlo simulations, we demonstrate that a typical proton or carbon ion therapy treatment plan generates an approximately uniform thermal neutron field within the target volume, centred around the beam path. The tissue concentrations of neutron capture agents required to obtain an arbitrary 10% increase in biological effective dose are estimated for realistic treatment plans, and compared to concentrations previously reported in the literature. We conclude that the proposed method is theoretically feasible, and can provide a worthwhile improvement in the dose delivered to the tumour relative to healthy tissue with readily achievable concentrations of neutron capture enhancement drugs.

A simulation study of BrachyShade, a shadow-based internal source tracking system for HDR prostate brachytherapy.

This paper presents a simulation study of BrachyShade, a proposed internal source-tracking system for real time quality assurance in high dose rate prostate brachytherapy. BrachyShade consists of a set of spherical tungsten occluders located above a pixellated silicon photodetector. The source location is estimated by minimising the mean squared error between a parametric model of the shadow image and acquired images of the shadows projected on the detector plane. A novel algorithm is finally employed to correct the systemic error resulting from Compton scattering in the medium. The worst-case error obtained with BrachyShade for a 13.5 ms image acquisition is less than 1.3 mm in the most distant part of the treatment volume, while for 75% of source locations an error of less than 0.42 mm was achieved.