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Purpose: This work aims at investigating intensity corrected cone-beam x-ray computed tomography (CBCT) images for accurate dose calculation in adaptive intensity modulated proton therapy (IMPT) for prostate and head and neck (H&N) cancer. A deformable image registration (DIR)-based method and a scatter correction approach using the image data obtained from DIR as prior are characterized and compared on the basis of the same clinical patient cohort for the first time. Methods: Planning CT (pCT) and daily CBCT data (reconstructed images and measured projections) of four H&N and four prostate cancer patients have been considered in this study. A previously validated Morphons algorithm was used for DIR of the planning CT to the current CBCT image, yielding a so-called virtual CT (vCT). For the first time, this approach was translated from H&N to prostate cancer cases in the scope of proton therapy. The warped pCT images were also used as prior for scatter correction of the CBCT projections for both tumor sites. Single field uniform dose and IMPT (only for H&N cases) treatment plans have been generated with a research version of a commercial planning system. Dose calculations on vCT and scatter corrected CBCT (CBCTcor) were compared by means of the proton range and a gamma-index analysis. For the H&N cases, an additional diagnostic replanning CT (rpCT) acquired within three days of the CBCT served as additional reference. For the prostate patients, a comprehensive contour comparison of CBCT and vCT, using a trained physician's delineation, was performed. Results: A high agreement of vCT and CBCTcor was found in terms of the proton range and gamma-index analysis. For all patients and indications between 95% and 100% of the proton dose profiles in beam's eye view showed a range agreement of better than 3 mm. The pass rate in a (2%,2 mm) gamma-comparison was between 96% and 100%. For H&N patients, an equivalent agreement of vCT and CBCTcor to the reference rpCT was observed. However, for the prostate cases, an insufficient accuracy of the vCT contours retrieved from DIR was found, while the CBCTcor contours showed very high agreement to the contours delineated on the raw CBCT. Conclusions: For H&N patients, no considerable differences of vCT and CBCTcor were found. For prostate cases, despite the high dosimetric agreement, the DIR yields incorrect contours, probably due to the more pronounced anatomical changes in the abdomen and the reduced soft-tissue contrast in the CBCT. Using the vCT as prior, these inaccuracies can be overcome and images suitable for accurate delineation and dose calculation in CBCT-based adaptive IMPT can be retrieved from scatter correction of the CBCT projections. [ABSTRACT FROM AUTHOR]

Background: Intensity modulated proton therapy (IMPT) of head and neck (H&N) tumors may benefit from plan adaptation to correct for the dose perturbations caused by weight loss and tumor volume changes observed in these patients. As cone beam CT (CBCT) is increasingly considered in proton therapy, it may be possible to use available CBCT images following intensity correction for plan adaptation. This is the first study exploring IMPT plan adaptation on CBCT images corrected and delineated by deformable image registration of the planning CT (pCT) to the CBCT, yielding a virtual CT (vCT).Methods: A Morphons algorithm was used to deform the pCTs and corresponding delineations of 9 H&N cancer patients to a weekly CBCT acquired within ±3 days of a control replanning CT scan (rpCT). The IMPT treatment plans were adapted using the vCT and the adapted and original plans were recalculated on the rpCT for dose/volume parameter evaluation of the impact of adaptation.Results: On the rpCT, the adapted plans were equivalent to the original plans in terms of target volumes D 95 and V 95, but showed a significant reduction of D 2 in these volumes. OAR doses were mostly equivalent or reduced. In particular, the adapted plans did not reduce parotid gland D mean, but the dose to the optical system. For three patients the spinal cord or brain stem received higher, though well below tolerance, maximum dose. Subsequent tightening of the treatment planning constraints for these OARs on new vCT-adapted plans did not degrade target coverage and yielded pCT equivalent plans on the vCT.Conclusions: An offline automated procedure to generate an adapted IMPT plan on CBCT images was developed and investigated. When evaluating the adapted plan on a control rpCT we observed reduced D 2 in target volumes as major improvement. OAR sparing was only partially improved by the procedure. Despite potential limitations in the accuracy of the vCT approach, an improved quality of the adapted plans could be achieved. [ABSTRACT FROM AUTHOR]

Purpose: Intrafractional organ motion imposes considerable challenges to scanned ion beam therapy and demands for a thorough verification of the applied treatment. At the Heidelberg Ion-Beam Therapy Center (HIT), the scanned ion beam delivery is verified by means of postirradiation positronemission- tomography (PET) imaging. This work presents a first clinical evaluation of PET-based treatment monitoring in ion beam therapy under consideration of target motion. Methods: Three patients with mobile liver lesions underwent scanned carbon ion irradiation at HIT and postirradiation PET/CT (x-ray-computed-tomography) imaging with a commercial scanner. Respiratory motion was recorded during irradiation and subsequent image acquisition. This enabled a time-resolved (4D) calculation of the expected irradiation-induced activity pattern and, for one patient where an additional 4D CT was acquired at the PET/CT scanner after treatment, a motioncompensated PET image reconstruction. For the other patients, PET data were reconstructed statically. To verify the treatment, calculated prediction and reconstructed measurement were compared with a focus on the ion beam range. Results: Results in the current three patients suggest that for motion amplitudes in the order of 2mm there is no benefit from incorporating respiratory motion information into PET-based treatment monitoring. For a target motion in the order of 10 mm, motion-related effects become more severe and a time-resolved modeling of the expected activity distribution can lead to an improved data interpretation if a sufficient number of true coincidences is detected. Benefits from motion-compensated PET image reconstruction could not be shown conclusively at the current stage. Conclusions: The feasibility of clinical PET-based treatment verification under consideration of organ motion has been shown for the first time. Improvements in noise-robust 4D PET image reconstruction are deemed necessary to enhance the clinical potential. [ABSTRACT FROM AUTHOR]

Purpose: External beam radiotherapy with protons and heavier ions enables a tighter conformation of the applied dose to arbitrarily shaped tumor volumes with respect to photons, but is more sensitive to uncertainties in the radiotherapeutic treatment chain. Consequently, an independent verification of the applied treatment is highly desirable. For this purpose, the irradiation-induced β+-emitter distribution within the patient is detected shortly after irradiation by a commercial full-ring positron emission tomography/x-ray computed tomography (PET/CT) scanner installed next to the treatment rooms at the Heidelberg Ion-Beam Therapy Center (HIT). A major challenge to this approach is posed by the small number of detected coincidences. This contribution aims at characterizing the performance of the used PET/CT device and identifying the best-performing reconstruction algorithm under the particular statistical conditions of PET-based treatment monitoring. Moreover, this study addresses the impact of radiation background from the intrinsically radioactive lutetium-oxyorthosilicate (LSO)-based detectors at low counts. Methods: The authors have acquired 30 subsequent PET scans of a cylindrical phantom emulating a patientlike activity pattern and spanning the entire patient counting regime in terms of true coincidences and random fractions (RFs). Accuracy and precision of activity quantification, image noise, and geometrical fidelity of the scanner have been investigated for various reconstruction algorithms and settings in order to identify a practical, well-suited reconstruction scheme for PET-based treatment verification. Truncated listmode data have been utilized for separating the effects of small true count numbers and high RFs on the reconstructed images. A corresponding simulation study enabled extending the results to an even wider range of counting statistics and to additionally investigate the impact of scatter coincidences. Eventually, the recommended reconstruction scheme has been applied to exemplary postirradiation patient data-sets. Results: Among the investigated reconstruction options, the overall best results in terms of image noise, activity quantification, and accurate geometrical recovery were achieved using the ordered subset expectation maximization reconstruction algorithm with time-of-flight (TOF) and point-spread function (PSF) information. For this algorithm, reasonably accurate (better than 5%) and precise (uncertainty of the mean activity below 10%) imaging can be provided down to 80 000 true coincidences at 96% RF. Image noise and geometrical fidelity are generally improved for fewer iterations. The main limitation for PET-based treatment monitoring has been identified in the small number of true coincidences, rather than the high intrinsic random background. Application of the optimized reconstruction scheme to patient data-sets results in a 25%-50% reduced image noise at a comparable activity quantification accuracy and an improved geometrical performance with respect to the formerly used reconstruction scheme at HIT, adopted from nuclear medicine applications. Conclusions: Under the poor statistical conditions in PET-based treatment monitoring, improved results can be achieved by considering PSF and TOF information during image reconstruction and by applying less iterations than in conventional nuclear medicine imaging. Geometrical fidelity and image noise are mainly limited by the low number of true coincidences, not the high LSO-related random background. The retrieved results might also impact other emerging PET applications at low counting statistics. [ABSTRACT FROM AUTHOR]

Objectives: Deep learning-based auto-segmentation of head and neck cancer (HNC) tumors is expected to have better reproducibility than manual delineation. Positron emission tomography (PET) and computed tomography (CT) are commonly used in tumor segmentation. However, current methods still face challenges in handling whole-body scans where a manual selection of a bounding box may be required. Moreover, different institutions might still apply different guidelines for tumor delineation. This study aimed at exploring the auto-localization and segmentation of HNC tumors from entire PET/CT scans and investigating the transferability of trained baseline models to external real world cohorts. Methods: We employed 2D Retina Unet to find HNC tumors from whole-body PET/CT and utilized a regular Unet to segment the union of the tumor and involved lymph nodes. In comparison, 2D/3D Retina Unets were also implemented to localize and segment the same target in an end-to-end manner. The segmentation performance was evaluated via Dice similarity coefficient (DSC) and Hausdorff distance 95th percentile (HD95). Delineated PET/CT scans from the HECKTOR challenge were used to train the baseline models by 5-fold cross-validation. Another 271 delineated PET/CTs from three different institutions (MAASTRO, CRO, BERLIN) were used for external testing. Finally, facility-specific transfer learning was applied to investigate the improvement of segmentation performance against baseline models. Results: Encouraging localization results were observed, achieving a maximum omnidirectional tumor center difference lower than 6.8 cm for external testing. The three baseline models yielded similar averaged cross-validation (CV) results with a DSC in a range of 0.71–0.75, while the averaged CV HD95 was 8.6, 10.7 and 9.8 mm for the regular Unet, 2D and 3D Retina Unets, respectively. More than a 10% drop in DSC and a 40% increase in HD95 were observed if the baseline models were tested on the three external cohorts directly. After the facility-specific training, an improvement in external testing was observed for all models. The regular Unet had the best DSC (0.70) for the MAASTRO cohort, and the best HD95 (7.8 and 7.9 mm) in the MAASTRO and CRO cohorts. The 2D Retina Unet had the best DSC (0.76 and 0.67) for the CRO and BERLIN cohorts, and the best HD95 (12.4 mm) for the BERLIN cohort. Conclusion: The regular Unet outperformed the other two baseline models in CV and most external testing cohorts. Facility-specific transfer learning can potentially improve HNC segmentation performance for individual institutions, where the 2D Retina Unets could achieve comparable or even better results than the regular Unet. [ABSTRACT FROM AUTHOR]

Introduction: The recent developments of magnetic resonance (MR) based adaptive strategies for photon and, potentially for proton therapy, require a fast and reliable conversion of MR images to X-ray computed tomography (CT) values. CT values are needed for photon and proton dose calculation. The improvement of conversion results employing a 3D deep learning approach is evaluated. Material and methods: A database of 89 T1-weighted MR head scans with about 100 slices each, including rigidly registered CTs, was created. Twenty-eight validation patients were randomly sampled, and four patients were selected for application. The remaining patients were used to train a 2D and a 3D U-shaped convolutional neural network (Unet). A stack size of 32 slices was used for 3D training. For all application cases, volumetric modulated arc therapy photon and single-field uniform dose pencil-beam scanning proton plans at four different gantry angles were optimized for a generic target on the CT and recalculated on 2D and 3D Unet-based pseudoCTs. Mean (absolute) error (MAE/ME) and a gradient sharpness estimate were used to quantify the image quality. Three-dimensional gamma and dose difference analyses were performed for photon (gamma criteria: 1%, 1 mm) and proton dose distributions (gamma criteria: 2%, 2 mm). Range (80% fall off) differences for beam's eye view profiles were evaluated for protons. Results: Training 36 h for 1000 epochs in 3D (6 h for 200 epochs in 2D) yielded a maximum MAE of 147 HU (135 HU) for the application patients. Except for one patient gamma pass rates for photon and proton dose distributions were above 96% for both Unets. Slice discontinuities were reduced for 3D training at the cost of sharpness. Conclusions: Image analysis revealed a slight advantage of 2D Unets compared to 3D Unets. Similar dose calculation performance was reached for the 2D and 3D network. [ABSTRACT FROM AUTHOR]

Abstract: The purpose of this paper is to describe the experiments and methods that led to the geometrical interpretation of new-generation commercial PET-CT scanners, finalized to off-line PET-based treatment verification in ion beam therapy. Typically, the geometrical correspondence between the image domain (i.e., the dicom PET) and the sinogram domain (i.e., the PET raw data) is not explicitly described by scanner vendors. Hence, the proposed characterization can be applied to commercial PET-CT scanners used in biomedical research, for the development of technologies and methods requiring the use of PET raw data, without having access to confidential information from the vendors. [Copyright &y& Elsevier]

Proton therapy treatment for lungs remains challenging as images enabling the detection of inter- and intra-fractional motion, which could be used for proton dose adaptation, are not readily available. 4D computed tomography (4DCT) provides high image quality but is rarely available in-room, while in-room 4D cone beam computed tomography (4DCBCT) suffers from image quality limitations stemming mostly from scatter detection. This study investigated the feasibility of using virtual 4D computed tomography (4DvCT) as a prior for a phase-per-phase scatter correction algorithm yielding a 4D scatter corrected cone beam computed tomography image (4DCBCTcor), which can be used for proton dose calculation. 4DCT and 4DCBCT scans of a porcine lung phantom, which generated reproducible ventilation, were acquired with matching breathing patterns. Diffeomorphic Morphons, a deformable image registration algorithm, was used to register the mid-position 4DCT to the mid-position 4DCBCT and yield a 4DvCT. The 4DCBCT was reconstructed using motion-aware reconstruction based on spatial and temporal regularization (MA-ROOSTER). Successively for each phase, digitally reconstructed radiographs of the 4DvCT, simulated without scatter, were exploited to correct scatter in the corresponding CBCT projections. The 4DCBCTcor was then reconstructed with MA-ROOSTER using the corrected CBCT projections and the same settings and deformation vector fields as those already used for reconstructing the 4DCBCT. The 4DCBCTcor and the 4DvCT were evaluated phase-by-phase, performing proton dose calculations and comparison to those of a ground truth 4DCT by means of dose-volume-histograms (DVH) and gamma pass-rates (PR). For accumulated doses, DVH parameters deviated by at most 1.7% in the 4DvCT and 2.0% in the 4DCBCTcor case. The gamma PR for a (2%, 2 mm) criterion with 10% threshold were at least 93.2% (4DvCT) and 94.2% (4DCBCTcor), respectively. The 4DCBCTcor technique enabled accurate proton dose calculation, which indicates the potential for applicability to clinical 4DCBCT scans. [ABSTRACT FROM AUTHOR]

Purpose: In photon radiotherapy, respiratory‐induced target motion can be accounted for by internal target volumes (ITV) or mid‐ventilation target volumes (midV) defined on the basis of four‐dimensional computed tomography (4D‐CT). Intrinsic limitations of these approaches can result in target volumes that are not representative for the gross tumor volume (GTV) motion over the course of treatment. To address these limitations, we propose a novel patient‐specific ITV definition method based on real‐time 4D magnetic resonance imaging (rt‐4DMRI). Methods: Three lung cancer patients underwent weekly rt‐4DMRI scans. A total of 24 datasets were included in this retrospective study. The GTV was contoured on breath‐hold MR images and propagated to all rt‐4DMRI images by deformable image registration. Different targets were created for the first (reference) imaging sessions: ITVs encompassing all GTV positions over the complete (ITV80s) or partial acquisition time (ITV10s), ITVs including only voxels with a GTV probability‐of‐presence (POP) of at least 5% (ITV5%) or 10% (ITV10%), and the mid‐ventilation GTV position. Reference planning target volumes (PTVr) were created by adding margins around the ITVs and midV target volumes. The geometrical overlap of the PTVr with ITVn5% from the six to eight subsequent imaging sessions on days n was quantified in terms of the Dice similarity coefficient (DSC), sensitivity [SE: (PTVr∩ITVn5%)/ITVn5%] and precision [PRE: (PTVr∩ITVn5%)/PTVr] as surrogates for target coverage and normal tissue sparing. Results: Patient‐specific analysis yielded a high variance of the overlap values of PTVr10s, when different periods within the reference imaging session were sampled. The mid‐ventilation‐based PTVs were smaller than the ITV‐based PTVs. While the SE was high for patients with small breathing pattern variations, changes of the median breathing amplitudes in different imaging sessions led to inferior SE values for the mid‐ventilation PTV for one patient. In contrast, PTVr5% and PTVr10% showed higher SE values with a higher robustness against interfractional changes, at the cost of larger target volumes. Conclusions: The results indicate that rt‐4DMRI could be valuable for the definition of target volumes based on the GTV POP to achieve a higher robustness against interfractional changes than feasible with today's 4D‐CT‐based target definition concepts. [ABSTRACT FROM AUTHOR]

Purpose: To compare treatment plans for interstitial high dose rate (HDR) liver brachytherapy with 192Ir calculated according to current-standard TG-43U1 protocol with model-based dose calculation following TG-186 protocol.Methods: We retrospectively evaluated dose volume histogram (DVH) parameters for liver, organs at risk (OARs) and clinical target volumes (CTVs) of 20 patient cases diagnosed with hepatocellular carcinoma (HCC) or metastatic colorectal cancer (mCRC). Dose calculations on a homogeneous water geometry (TG-43U1 surrogate) and on a computed tomography (CT) based geometry (TG-186) were performed using Monte Carlo (MC) simulations. The CTs were segmented based on a combination of assigning TG-186 recommended tissues to fixed Hounsfield Unit (HU) ranges and using organ contours delineated by physicians. For the liver, V5Gy and V10Gy were analysed, and for OARs the dose to 1 cubic centimeter (D1cc). Target coverage was assessed by calculating V150, V100, V95 and V90 as well as D95 and D90. For every DVH parameter, median, minimum and maximum values of the deviations of TG-186 from TG-43U1 were analysed.Results: TG-186-calculated dose was found to be on average lower than dose calculated with TG-43U1. The deviation of highest magnitude for liver parameters was -6.2% of the total liver volume. For OARs, the deviations were all smaller than or equal to -0.5 Gy. Target coverage deviations were as high as -1.5% of the total CTV volume and -3.5% of the prescribed dose.Conclusions: In this study we found that TG-43U1 overestimates dose to liver tissue compared to TG-186. This finding may be of clinical importance for cases where dose to the whole liver is the limiting factor. [ABSTRACT FROM AUTHOR]

A novel strategy for 4D PET optimization in the sinogram domain is proposed, aiming at motion model application before image reconstruction ("sinogram warping" strategy). Compared to state-of-the-art 4D-MLEM reconstruction, the proposed strategy is able to optimize the image SNR, avoiding iterative direct and inverse warping procedures, which are typical of the 4D-MLEM algorithm. A full-count statistics sinogram of the motion-compensated 4D PET reference phase is generated by warping the sinograms corresponding to the different PET phases. This is achieved relying on a motion model expressed in the sinogram domain. The strategy was tested on the anthropomorphic 4D PET-CT NCAT phantom in comparison with the 4D-MLEM algorithm, with particular reference to robustness to PET-CT co-registrations artefacts. The MLEM reconstruction of the warped sinogram according to the proposed strategy exhibited better accuracy (up to +40.90 % with respect to the ideal value), whereas images reconstructed according to the 4D-MLEM reconstruction resulted in less noisy (down to -26.90 % with respect to the ideal value) but more blurred. The sinogram warping strategy demonstrates advantages with respect to 4D-MLEM algorithm. These advantages are paid back by introducing approximation of the deformation field, and further efforts are required to mitigate the impact of such an approximation in clinical 4D PET reconstruction. [ABSTRACT FROM AUTHOR]

• Deep learning PET and CT-based DM and OS time-to-event models showed predictive capability. • PET-only achieved the best prognosis performance. • Unlike CT, GTV segmentation is not necessary for PET-based prognosis. Recent studies have shown that deep learning based on pre-treatment positron emission tomography (PET) or computed tomography (CT) is promising for distant metastasis (DM) and overall survival (OS) prognosis in head and neck cancer (HNC). However, lesion segmentation is typically required, resulting in a predictive power susceptible to variations in primary and lymph node gross tumor volume (GTV) segmentation. This study aimed at achieving prognosis without GTV segmentation, and extending single modality prognosis to joint PET/CT to allow investigating the predictive performance of combined- compared to single-modality inputs. We employed a 3D-Resnet combined with a time-to-event outcome model to incorporate censoring information. We focused on the prognosis of DM and OS for HNC patients. For each clinical endpoint, five models with PET and/or CT images as input were compared: PET-GTV, PET-only, CT-GTV, CT-only, and PET/CT-GTV models, where -GTV indicates that the corresponding images were masked using the GTV contour. Publicly available delineated CT and PET scans from 4 different Canadian hospitals (293) and the MAASTRO clinic (74) were used for training by 3-fold cross-validation (CV). For independent testing, we used 110 patients from a collaborating institution. The predictive performance was evaluated via Harrell's Concordance Index (HCI) and Kaplan-Meier curves. In a 5-year time-to-event analysis, all models could produce CV HCIs with median values around 0.8 for DM and 0.7 for OS. The best performance was obtained with the PET-only model, achieving a median testing HCI of 0.82 for DM and 0.69 for OS. Compared with the PET/CT-GTV model, the PET-only still had advantages of up to 0.07 in terms of testing HCI. The Kaplan-Meier curves and corresponding log-rank test results also demonstrated significant stratification capability of our models for the testing cohort. Deep learning-based DM and OS time-to-event models showed predictive capability and could provide indications for personalized RT. The best predictive performance achieved by the PET-only model suggested GTV segmentation might be less relevant for PET-based prognosis. [ABSTRACT FROM AUTHOR]

Abstract: Background and purpose: We report on the implementation of offline PET/CT-based treatment verification at the Heidelberg Ion Beam Therapy Centre (HIT) and present first clinical cases for post-activation measurements after scanned carbon ion irradiation. Key ingredient of this in-vivo treatment verification is the comparison of irradiation-induced patient activation measured by a PET scanner with a prediction simulated by means of Monte Carlo techniques. Material and methods: At HIT, a commercial full-ring PET/CT scanner has been installed in close vicinity to the treatment rooms. After selected irradiation fractions, the patient either walks to the scanner for acquisition of the activation data or is transported using a shuttle system. The expected activity distribution is obtained from the production of β+-active isotopes simulated by the FLUKA code on the basis of the patient-specific treatment plan, post-processed considering the time course of the respective treatment fraction, the estimated biological washout of the induced activity and a simplified model of the imaging process. Results: We present four patients with different indications of head, head/neck, liver and pelvic tumours. A clear correlation between the measured PET signal and the simulated activity pattern is observed for all patients, thus supporting a proper treatment delivery. In the case of a pelvic tumour patient it was possible to detect minor treatment delivery inaccuracies. Conclusions: The initial clinical experience proves the feasibility of the implemented strategy for offline confirmation of scanned carbon ion irradiation and therefore constitutes a first step towards a comprehensive PET/CT-based treatment verification in the clinical routine at HIT. [Copyright &y& Elsevier]