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Monte Carlo patient study on the comparison of prompt gamma and PET imaging for range verification in proton therapy

The purpose of this work was to compare the clinical adaptation of prompt gamma (PG) imaging and positron emission tomography (PET) as independent tools for non-invasive proton beam range verification and treatment validation. The PG range correlation and its differences with PET have been modeled for the first time in a highly heterogeneous tissue environment, using different field sizes and configurations. Four patients with different tumor locations (head and neck, prostate, spine and abdomen) were chosen to compare the site-specific behaviors of the PG and PET images, using both passive scattered and pencil beam fields. Accurate reconstruction of dose, PG and PET distributions was achieved by using the planning computed tomography (CT) image in a validated GEANT4-based Monte Carlo code capable of modeling the treatment nozzle and patient anatomy in detail. The physical and biological washout phenomenon and decay half-lives for PET activity for the most abundant isotopes such as (11)C, (15)O, (13)N, (30)P and (38)K were taken into account in the data analysis. The attenuation of the gamma signal after traversing the patient geometry and respective detection efficiencies were estimated for both methods to ensure proper comparison. The projected dose, PG and PET profiles along many lines in the beam direction were analyzed to investigate the correlation consistency across the beam width. For all subjects, the PG method showed on average approximately 10 times higher gamma production rates than the PET method before, and 60 to 80 times higher production after including the washout correction and acquisition time delay. This rate strongly depended on tissue density and elemental composition. For broad passive scattered fields, it was demonstrated that large differences exist between PG and PET signal falloff positions and the correlation with the dose distribution for different lines in the beam direction. These variations also depended on the treatment site and the particular subject. Thus, similar to PET, direct range verification with PG in passive scattering is not easily viable. However, upon development of an optimized 3D PG detector, indirect range verification by comparing measured and simulated PG distributions (currently being explored for the PET method) would be more beneficial because it can avoid the inherent biological challenges of the PET imaging. The improved correlation of PG and PET with dose when using pencil beams was evident. PG imaging was found to be potentially advantageous especially for small tumors in the presence of high tissue heterogeneities. Including the effects of detector acceptance and efficiency may hold PET superior in terms of the amplitude of the detected signal (depending on the future development of PG detection technology), but the ability to perform online measurements and avoid signal disintegration (due to washout) with PG are important factors that can outweigh the benefits of higher detection sensitivity.

Monitoring proton radiation therapy with in-room PET imaging

We used a mobile positron emission tomography (PET) scanner positioned within the proton therapy treatment room to study the feasibility of proton range verification with an in-room, stand-alone PET system, and compared with off-line equivalent studies. Two subjects with adenoid cystic carcinoma were enrolled into a pilot study in which in-room PET scans were acquired in list-mode after a routine fractionated treatment session. The list-mode PET data were reconstructed with different time schemes to generate in-room short, in-room long and off-line equivalent (by skipping coincidences from the first 15 min during the list-mode reconstruction) PET images for comparison in activity distribution patterns. A phantom study was followed to evaluate the accuracy of range verification for different reconstruction time schemes quantitatively. The in-room PET has a higher sensitivity compared to the off-line modality so that the PET acquisition time can be greatly reduced from 30 to <5 min. Features in deep-site, soft-tissue regions were better retained with in-room short PET acquisitions because of the collection of (15)O component and lower biological washout. For soft tissue-equivalent material, the distal fall-off edge of an in-room short acquisition is deeper compared to an off-line equivalent scan, indicating a better coverage of the high-dose end of the beam. In-room PET is a promising low cost, high sensitivity modality for the in vivo verification of proton therapy. Better accuracy in Monte Carlo predictions, especially for biological decay modeling, is necessary.

The reliability of proton-nuclear interaction cross-section data to predict proton-induced PET images in proton therapy.

In vivo PET range verification relies on the comparison of measured and simulated activity distributions. The accuracy of the simulated distribution depends on the accuracy of the Monte Carlo code, which is in turn dependent on the accuracy of the available cross-section data for β(+) isotope production. We have explored different cross-section data available in the literature for the main reaction channels ((16)O(p,pn)(15)O, (12)C(p,pn)(11)C and (16)O(p,3p3n)(11)C) contributing to the production of β(+) isotopes by proton beams in patients. Available experimental and theoretical values were implemented in the simulation and compared with measured PET images obtained with a high-resolution PET scanner. Each reaction channel was studied independently. A phantom with three different materials was built, two of them with high carbon or oxygen concentration and a third one with average soft tissue composition. Monoenergetic and SOBP field irradiations of the phantom were accomplished and measured PET images were compared with simulation results. Different cross-section values for the tissue-equivalent material lead to range differences below 1 mm when a 5 min scan time was employed and close to 5 mm differences for a 30 min scan time with 15 min delay between irradiation and scan (a typical off-line protocol). The results presented here emphasize the need of more accurate measurement of the cross-section values of the reaction channels contributing to the production of PET isotopes by proton beams before this in vivo range verification method can achieve mm accuracy.

The impact of uncertainties in the CT conversion algorithm when predicting proton beam ranges in patients from dose and PET-activity distributions

The advantages of a finite range of proton beams can only be partly exploited in radiation therapy unless the range can be predicted in patient anatomy with <2 mm accuracy (for non-moving targets). Monte Carlo dose calculation aims at 1-2 mm accuracy in dose prediction, and proton-induced PET imaging aims at ∼2 mm accuracy in range verification. The latter is done using Monte Carlo predicted PET images. Monte Carlo methods are based on CT images to describe patient anatomy. The dose calculation algorithm and the CT resolution/artifacts might affect dose calculation accuracy. Additionally, when using Monte Carlo for PET range verification, the biological decay model and the cross sections for positron emitter production affect predicted PET images. The goal of this work is to study the effect of uncertainties in the CT conversion on the proton beam range predicted by Monte Carlo dose calculations and proton-induced PET signals. Conversion schemes to assign density and elemental composition based on a CT image of the patient define a unique Hounsfield unit (HU) to tissue parameters relationship. Uncertainties are introduced because there is no unique relationship between HU and tissue parameters. In this work, different conversion schemes based on a stoichiometric calibration method as well as different numbers of tissue bins were considered in three head and neck patients. For Monte Carlo dose calculation, the results show close to zero (<0.5 mm) differences in range using different conversion schemes. Further, a reduction of the number of bins used to define individual tissues down to 13 did not affect the accuracy. In the case of simulated PET images we found a more pronounced sensitivity on the CT conversion scheme with a mean fall-off position variation of about 1 mm. We conclude that proton dose distributions based on Monte Carlo calculation are only slightly affected by the uncertainty on density and elemental composition introduced by unique assignment to each HU if a stoichiometric calibration is used. Calculated PET images used for range verification are more sensitive to conversion uncertainties causing an intrinsic limitation due to CT conversion alone of at least 1 mm.

Design and performance evaluation of a coplanar multimodality scanner for rodent imaging

This work reports on the development and performance evaluation of the VrPET/CT, a new multimodality scanner with coplanar geometry for in vivo rodent imaging. The scanner design is based on a partial-ring PET system and a small-animal CT assembled on a rotatory gantry without axial displacement between the geometric centers of both fields of view (FOV). We report on the PET system performance based on the NEMA NU-4 protocol; the performance characteristics of the CT component are not included herein. The accuracy of inter-modality alignment and the imaging capability of the whole system are also evaluated on phantom and animal studies. Tangential spatial resolution of PET images ranged between 1.56 mm at the center of the FOV and 2.46 at a radial offset of 3.5 cm. The radial resolution varies from 1.48 mm to 1.88 mm, and the axial resolution from 2.34 mm to 3.38 mm for the same positions. The energy resolution was 16.5% on average for the entire system. The absolute coincidence sensitivity is 2.2% for a 100-700 keV energy window with a 3.8 ns coincident window. The scatter fraction values for the same settings were 11.45% for a mouse-sized phantom and 23.26% for a rat-sized phantom. The peak noise equivalent count rates were also evaluated for those phantoms obtaining 70.8 kcps at 0.66 MBq/cc and 31.5 kcps at 0.11 MBq/cc, respectively. The accuracy of inter-modality alignment is below half the PET resolution, and the image quality of biological specimens agrees with measured performance parameters. The assessment presented in this study shows that the VrPET/CT system is a good performance small-animal imager, while the cost derived from a partial ring detection system is substantially reduced as compared with a full-ring PET tomograph.

Clinical consequences of relative biological effectiveness variations in proton radiotherapy of the prostate, brain and liver.

Proton relative biological effectiveness (RBE) is known to depend on the (α/β)x of irradiated tissues, with evidence of ∼60% variation over (α/β)x values from 1-10 Gy. The range of (α/β)x values reported for prostate tumors (1.2-5.0 Gy), brain tumors (10-15 Gy) and liver tumors (13-17 Gy) imply that the proton RBE for these tissues could vary significantly compared to the commonly used generic value of 1.1. Our aim is to evaluate the impact of this uncertainty on the proton dose in Gy(RBE) absorbed in normal and tumor tissues. This evaluation was performed for standard and hypofractionated regimens. RBE-weighted total dose (RWTD) distributions for 15 patients (five prostate tumors, five brain tumors and five liver tumors) were calculated using an in-house developed RBE model as a function of dose, dose-averaged linear energy transfer (LETd) and (α/β)x. Variations of the dose-volume histograms (DVHs) for the gross tumor volume (GTV) and the organs at risk due to changes of (α/β)x and fractionation regimen were calculated and the RWTD received by 10% and 90% of the organ volume reported. The goodness of the plan, bearing the uncertainties, was then evaluated compared to the delivered plan, which considers a constant RBE of 1.1. For standard fractionated regimens, the prostate tumors, liver tumors and all critical structures in the brain showed typically larger RBE values than 1.1. However, in hypofractionated regimens lower values of RBE than 1.1 were observed in most cases. Based on DVH analysis we found that the RBE variations were clinically significant in particular for the prostate GTV and the critical structures in the brain. Despite the uncertainties in the biological input parameters when estimating RBE values, the results show that the use of a variable RBE with dose, LETd and (α/β)x could help to further optimize the target dose in proton treatment planning. Most importantly, this study shows that the consideration of RBE variations could influence the comparison of proton and photon treatments in clinical trials, in particular in the case of the prostate.

Performance evaluation of SiPM detectors for PET imaging in the presence of magnetic fields

The multi-pixel photon counter (MPPC) or silicon photo-multiplier (SiPM), recently introduced as a solid-state photodetector, consists of an array of Geiger-mode photodiodes (microcells). It is a promising device for PET thanks to its potential for high photon detection efficiency (PDE) and immunity to high magnetic fields. It is also very easy to use, with simple electronic read-out, high gain and small size. In this work we evaluate the performance of three 1 × 1 mm2 and one 6 × 6 mm2 (2 × 2 array) SiPMs offered by Hamamatsu for their use in PET. We examine the dependence of the energy resolution and the gain of these devices on the thermal and reverse bias when coupled to LYSO scintillator crystals. We find that the 400 and 1600 microcells models and the 2 × 2 array are suitable for small size crystals, like those employed in high resolution small animal scanners. The good performance of these devices up to 7 Tesla has also been confirmed.

Positron range estimations with PeneloPET

Technical advances towards high resolution PET imaging try to overcome the inherent physical limitations to spatial resolution. Positrons travel in tissue until they annihilate into the two gamma photons detected. This range is the main detector-independent contribution to PET imaging blurring. To a large extent, it can be remedied during image reconstruction if accurate estimates of positron range are available. However, the existing estimates differ, and the comparison with the scarce experimental data available is not conclusive. In this work we present positron annihilation distributions obtained from Monte Carlo simulations with the PeneloPET simulation toolkit, for several common PET isotopes ((18)F, (11)C, (13)N, (15)O, (68)Ga and (82)Rb) in different biological media (cortical bone, soft bone, skin, muscle striated, brain, water, adipose tissue and lung). We compare PeneloPET simulations against experimental data and other simulation results available in the literature. To this end the different positron range representations employed in the literature are related to each other by means of a new parameterization for positron range profiles. Our results are generally consistent with experiments and with most simulations previously reported with differences of less than 20% in the mean and maximum range values. From these results, we conclude that better experimental measurements are needed, especially to disentangle the effect of positronium formation in positron range. Finally, with the aid of PeneloPET, we confirm that scaling approaches can be used to obtain universal, material and isotope independent, positron range profiles, which would considerably simplify range correction.

Positron range effects in high resolution 3D PET imaging

Positron range limits the spatial resolution of PET images. It has a different effect for different isotopes and propagation materials, therefore it is important to consider it during image reconstruction, in order to obtain the best image quality. Positron range distribution was computed using Monte Carlo simulations with PeneloPET. The simulation models positron trajectories and computes the spatial distribution of the annihilation coordinates for the most common isotopes used in PET: 18F, 11C, 13N, 15O, 68Ga and 82Rb. Range profiles are computed for different positron propagation materials, obtaining one kernel profile for each isotope-material combination. These range kernels were introduced in FIRST, a 3D-OSEM image reconstruction software, and employed to blur the object during forward projection. The blurring introduced takes into account the material in which the positron is annihilated, obtained for instance from a CT image. In this way, different positron range corrections for each material in the phantom are considered. We compare resolution and noise properties of the images reconstructed with and without positron range modelling. For this purpose, acquisitions of an Image Quality phantom filled with different isotopes have been simulated for the ARGUS small animal PET scanner.

GPU-Based Fast Iterative Reconstruction of Fully 3-D PET Sinograms

This work presents a graphics processing unit (GPU)-based implementation of a fully 3-D PET iterative reconstruction code, FIRST (Fast Iterative Reconstruction Software for [PET] Tomography), which was developed by our group. We describe the main steps followed to convert the FIRST code (which can run on several CPUs using the message passing interface [MPI] protocol) into a code where the main time-consuming parts of the reconstruction process (forward and backward projection) are massively parallelized on a GPU. Our objective was to obtain significant acceleration of the reconstruction without compromising the image quality or the flexibility of the CPU implementation. Therefore, we implemented a GPU version using an abstraction layer for the GPU, namely, CUDA C. The code reconstructs images from sinogram data, and with the same System Response Matrix obtained from Monte Carlo simulations than the CPU version. The use of memory was optimized to ensure good performance in the GPU. The code was adapted for the VrPET small-animal PET scanner. The CUDA version is more than 70 times faster than the original code running in a single core of a high-end CPU, with no loss of accuracy.