Experimental comparison of cylindrical and plane parallel ionization chambers for reference dosimetry in continuous and pulsed scanned proton beams.

Objective. In this experimental work we compared the determination of absorbed dose to water using four ionization chambers (ICs), a PTW-34045 Advanced Markus, a PTW-34001 Roos, an IBA-PPC05 and a PTW-30012 Farmer, irradiated under the same conditions in one continuous- and in two pulsed-scanned proton beams.Approach. The ICs were positioned at 2 cm depth in a water phantom in four square-field single-energy scanned-proton beams with nominal energies between 80 and 220 MeV and in the middle of 10 × 10 × 10 cm3dose cubes centered at 10 cm or 12.5 cm depth in water. The water-equivalent thickness (WET) of the entrance window and the effective point of measurement was considered when positioning the plane parallel (PP) ICs and the cylindrical ICs, respectively. To reduce uncertainties, all ICs were calibrated at the same primary standards laboratory. We used the beam quality (kQ) correction factors for the ICs under investigation from IAEA TRS-398, the newly calculated Monte Carlo (MC) values and the anticipated IAEA TRS-398 updated recommendations.Main results. Dose differences among the four ICs ranged between 1.5% and 3.7% using both the TRS-398 and the newly recommendedkQvalues. The spread among the chambers is reduced with the newlykQvalues. The largest differences were observed between the rest of the ICs and the IBA-PPC05 IC, obtaining lower dose with the IBA-PPC05.Significance. We provide experimental data comparing different types of chambers in different proton beam qualities. The observed dose differences between the ICs appear to be related to inconsistencies in the determination of thekQvalues. For PP ICs, MC studies account for the physical thickness of the entrance window rather than the WET. The additional energy loss that the wall material invokes is not negligible for the IBA-PPC05 and might partially explain the lowkQvalues determined for this IC. To resolve this inconsistency and to benchmark MC values,kQvalues measured using calorimetry are needed.

Technical note: development of a simulation framework, enabling the investigation of locally tuned single energy proton radiography.

Range uncertainties remain a limitation for the confined dose distribution that proton therapy can offer. The uncertainty stems from the ambiguity when translating CT Hounsfield Units (HU) into proton stopping powers. Proton Radiography (PR) can be used to verify the proton range. Specifically, PR can be used as a quality-control tool for CBCT-based synthetic CTs. An essential part of the work illustrating the potential of PR has been conducted using multi-layer ionization chamber (MLIC) detectors and mono-energetic PR. Due to the dimensions of commercially available MLICs, clinical adoption is cumbersome. Here, we present a simulation framework exploring locally-tuned single energy (LTSE) proton radiography and corresponding potential compact PR detector designs. Based on a planning CT data set, the presented framework models the water equivalent thickness. Subsequently, it analyses the proton energies required to pass through the geometry within a defined ROI. In the final step, an LTSE PR is simulated using the MCsquare Monte Carlo code. In an anatomical head phantom, we illustrate that LTSE PR allows for a significantly shorter longitudinal dimension of MLICs. We compared PR simulations for two exemplary 30 × 30 mm2proton fields passing the phantom at a 90° angle at an anterior and a posterior location in an iso-centric setup. The longitudinal distance over which all spots per field range out is significantly reduced for LTSE PR compared to mono-energetic PR. In addition, we illustrate the difference in shape of integral depth dose (IDD) when using constrained PR energies. Finally, we demonstrate the accordance of simulated and experimentally acquired IDDs for an LTSE PR acquisition. As the next steps, the framework will be used to investigate the sensitivity of LTSE PR to various sources of errors. Furthermore, we will use the framework to systematically explore the dimensions of an optimized MLIC design for daily clinical use.

Technical note: Flat panel proton radiography with a patient specific imaging field for accurate WEPL assessment.

BACKGROUND: Proton radiography (PR) uses highly energetic proton beams to create images where energy loss is the main contrast mechanism. Water-equivalent path length (WEPL) measurements using flat panel PR (FP-PR) have potential for in vivo range verification. However, an accurate WEPL measurement via FP-PR requires irradiation with multiple energy layers, imposing high imaging doses. PURPOSE: A FP-PR method is proposed for accurate WEPL determination based on a patient-specific imaging field with a reduced number of energies (n) to minimize imaging dose. METHODS: Patient-specific FP-PRs were simulated and measured for a head and neck (HN) phantom. An energy selection algorithm estimated spot-wise the lowest energy required to cross the anatomy (Emin) using a water-equivalent thickness map. Starting from Emin, n was restricted to certain values (n = 26, 24, 22, …, 2 for simulations, n = 10 for measurements), resulting in patient-specific FP-PRs. A reference FP-PR with a complete set of energies was compared against patient-specific FP-PRs covering the whole anatomy via mean absolute WEPL differences (MAD), to evaluate the impact of the developed algorithm. WEPL accuracy of patient-specific FP-PRs was assessed using mean relative WEPL errors (MRE) with respect to measured multi-layer ionization chamber PRs (MLIC-PR) in the base of skull, brain, and neck regions. RESULTS: MADs ranged from 2.1 mm (n = 26) to 21.0 mm (n = 2) for simulated FP-PRs, and 7.2 mm for measured FP-PRs (n = 10). WEPL differences below 1 mm were observed across the whole anatomy, except at the phantom surfaces. Measured patient-specific FP-PRs showed good agreement against MLIC-PRs, with MREs of 1.3 ± 2.0%, -0.1 ± 1.0%, and -0.1 ± 0.4% in the three regions of the phantom. CONCLUSION: A method to obtain accurate WEPL measurements using FP-PR with a reduced number of energies selected for the individual patient anatomy was established in silico and validated experimentally. Patient-specific FP-PRs could provide means of in vivo range verification.

Deep learning-based 4D-synthetic CTs from sparse-view CBCTs for dose calculations in adaptive proton therapy.

BACKGROUND: Time-resolved 4D cone beam-computed tomography (4D-CBCT) allows a daily assessment of patient anatomy and respiratory motion. However, 4D-CBCTs suffer from imaging artifacts that affect the CT number accuracy and prevent accurate proton dose calculations. Deep learning can be used to correct CT numbers and generate synthetic CTs (sCTs) that can enable CBCT-based proton dose calculations. PURPOSE: In this work, sparse view 4D-CBCTs were converted into 4D-sCT utilizing a deep convolutional neural network (DCNN). 4D-sCTs were evaluated in terms of image quality and dosimetric accuracy to determine if accurate proton dose calculations for adaptive proton therapy workflows of lung cancer patients are feasible. METHODS: A dataset of 45 thoracic cancer patients was utilized to train and evaluate a DCNN to generate 4D-sCTs, based on sparse view 4D-CBCTs reconstructed from projections acquired with a 3D acquisition protocol. Mean absolute error (MAE) and mean error were used as metrics to evaluate the image quality of single phases and average 4D-sCTs against 4D-CTs acquired on the same day. The dosimetric accuracy was checked globally (gamma analysis) and locally for target volumes and organs-at-risk (OARs) (lung, heart, and esophagus). Furthermore, 4D-sCTs were also compared to 3D-sCTs. To evaluate CT number accuracy, proton radiography simulations in 4D-sCT and 4D-CTs were compared in terms of range errors. The clinical suitability of 4D-sCTs was demonstrated by performing a 4D dose reconstruction using patient specific treatment delivery log files and breathing signals. RESULTS: 4D-sCTs resulted in average MAEs of 48.1 ± 6.5 HU (single phase) and 37.7 ± 6.2 HU (average). The global dosimetric evaluation showed gamma pass ratios of 92.3% ± 3.2% (single phase) and 94.4% ± 2.1% (average). The clinical target volume showed high agreement in D98 between 4D-CT and 4D-sCT, with differences below 2.4% for all patients. Larger dose differences were observed in mean doses of OARs (up to 8.4%). The comparison with 3D-sCTs showed no substantial image quality and dosimetric differences for the 4D-sCT average. Individual 4D-sCT phases showed slightly lower dosimetric accuracy. The range error evaluation revealed that lung tissues cause range errors about three times higher than the other tissues. CONCLUSION: In this study, we have investigated the accuracy of deep learning-based 4D-sCTs for daily dose calculations in adaptive proton therapy. Despite image quality differences between 4D-sCTs and 3D-sCTs, comparable dosimetric accuracy was observed globally and locally. Further improvement of 3D and 4D lung sCTs could be achieved by increasing CT number accuracy in lung tissues.

Experimental validation of 4D log file-based proton dose reconstruction for interplay assessment considering amplitude-sorted 4DCTs.

PURPOSE: The unpredictable interplay between dynamic proton therapy delivery and target motion in the thorax can lead to severe dose distortions. A fraction-wise four-dimensional (4D) dose reconstruction workflow allows for the assessment of the applied dose after patient treatment while considering the actual beam delivery sequence extracted from machine log files, the recorded breathing pattern and the geometric information from a 4D computed tomography scan (4DCT). Such an algorithm capable of accounting for amplitude-sorted 4DCTs was implemented and its accuracy as well as its sensitivity to input parameter variations was experimentally evaluated. METHODS: An anthropomorphic thorax phantom with a movable insert containing a target surrogate and a radiochromic film was irradiated with a monoenergetic field for various 1D target motion forms (sin, sin4 ) and peak-to-peak amplitudes (5/10/15/20/30 mm). The measured characteristic film dose distributions were compared to the respective sections in the 4D reconstructed doses using a 2D γ-analysis (3 mm, 3%); γ-pass rates were derived for different dose grid resolutions (1 mm/3 mm) and deformable image registrations (DIR, automatic/manual) applied during the 4D dose reconstruction process. In an additional analysis, the sensitivity of reconstructed dose distributions against potential asynchronous timing of the motion and machine log files was investigated for both a monoenergetic field and more realistic 4D robustly optimized fields by artificially introduced offsets of ±1/5/25/50/250 ms. The resulting dose distributions with asynchronized log files were compared to those with synchronized log files by means of a 3D γ-analysis (1 mm, 1%) and the evaluation of absolute dose differences. RESULTS: The induced characteristic interplay patterns on the films were well reproduced by the 4D dose reconstruction with 2D γ-pass rates ≥95% for almost all cases with motion magnitudes ≤15 mm. In general, the 2D γ-pass rates showed a significant decrease for larger motion amplitudes and increase when using a finer dose grid resolution but were not affected by the choice of motion form (sin, sin4 ). There was also a trend, though not statistically significant, toward the manually defined DIR for better quality of the reconstructed dose distributions in the area imaged by the film. The 4D dose reconstruction results for the monoenergetic as well as the 4D robustly optimized fields were robust against small asynchronies between motion and machine log files of up to 5 ms, which is in the order of potential network latencies. CONCLUSIONS: We have implemented a 4D log file-based proton dose reconstruction that accounts for amplitude-sorted 4DCTs. Its accuracy was proven to be clinically acceptable for target motion magnitudes of up to 15 mm. Particular attention should be paid to the synchronization of the log file generating systems as the reconstructed dose distribution may vary with log file asynchronies larger than those caused by realistic network delays.

Clinical necessity of multi-image based (4DMIB) optimization for targets affected by respiratory motion and treated with scanned particle therapy - A comprehensive review.

4D multi-image-based (4DMIB) optimization is a form of robust optimization where different uncertainty scenarios, due to anatomy variations, are considered via multiple image sets (e.g., 4DCT). In this review, we focused on providing an overview of different 4DMIB optimization implementations, introduced various frameworks to evaluate the robustness of scanned particle therapy affected by breathing motion and summarized the existing evidence on the necessity of using 4DMIB optimization clinically. Expected potential benefits of 4DMIB optimization include more robust and/or interplay-effect-resistant doses for the target volume and organs-at-risk for indications affected by anatomical variations (e.g., breathing, peristalsis, etc.). Although considerable literature is available on the research and technical aspects of 4DMIB, clinical studies are rare and often contain methodological limitations, such as, limited patient number, motion amplitude, motion and delivery time structure considerations, number of repeat CTs, etc. Therefore, the data are not conclusive. In addition, multiple studies have found that robust 3D optimized plans result in dose distributions within the set clinical tolerances and, therefore, are suitable for a treatment of moving targets with scanned particle therapy. We, therefore, consider the clinical necessity of 4DMIB optimization, when treating moving targets with scanned particle therapy, as still to be demonstrated.

Anthropomorphic lung phantom based validation of in-room proton therapy 4D-CBCT image correction for dose calculation.

PURPOSE: Ventilation-induced tumour motion remains a challenge for the accuracy of proton therapy treatments in lung patients. We investigated the feasibility of using a 4D virtual CT (4D-vCT) approach based on deformable image registration (DIR) and motion-aware 4D CBCT reconstruction (MA-ROOSTER) to enable accurate daily proton dose calculation using a gantry-mounted CBCT scanner tailored to proton therapy. METHODS: Ventilation correlated data of 10 breathing phases were acquired from a porcine ex-vivo functional lung phantom using CT and CBCT. 4D-vCTs were generated by (1) DIR of the mid-position 4D-CT to the mid-position 4D-CBCT (reconstructed with the MA-ROOSTER) using a diffeomorphic Morphons algorithm and (2) subsequent propagation of the obtained mid-position vCT to the individual 4D-CBCT phases. Proton therapy treatment planning was performed to evaluate dose calculation accuracy of the 4D-vCTs. A robust treatment plan delivering a nominal dose of 60Gy was generated on the average intensity image of the 4D-CT for an approximated internal target volume (ITV). Dose distributions were then recalculated on individual phases of the 4D-CT and the 4D-vCT based on the optimized plan. Dose accumulation was performed for 4D-vCT and 4D-CT using DIR of each phase to the mid position, which was chosen as reference. Dose based on the 4D-vCT was then evaluated against the dose calculated on 4D-CT both, phase-by-phase as well as accumulated, by comparing dose volume histogram (DVH) values (Dmean, D2%, D98%, D95%) for the ITV, and by a 3D-gamma index analysis (global, 3%/3mm, 5Gy, 20Gy and 30Gy dose thresholds). RESULTS: Good agreement was found between the 4D-CT and 4D-vCT-based ITV-DVH curves. The relative differences ((CT-vCT)/CT) between accumulated values of ITV Dmean, D2%, D95% and D98% for the 4D-CT and 4D-vCT-based dose distributions were -0.2%, 0.0%, -0.1% and -0.1%, respectively. Phase specific values varied between -0.5% and 0.2%, -0.2% and 0.5%, -3.5% and 1.5%, and -5.7% and 2.3%. The relative difference of accumulated Dmean over the lungs was 2.3% and Dmean for the phases varied between -5.4% and 5.8%. The gamma pass-rates with 5Gy, 20Gy and 30Gy thresholds for the accumulated doses were 96.7%, 99.6% and 99.9%, respectively. Phase-by-phase comparison yielded pass-rates between 86% and 97%, 88% and 98%, and 94% and 100%. CONCLUSIONS: Feasibility of the suggested 4D-vCT workflow using proton therapy specific imaging equipment was shown. Results indicate the potential of the method to be applied for daily 4D proton dose estimation.

Executive Summary of Clinical and Technical Guidelines for Esophageal Cancer Proton Beam Therapy From the Particle Therapy Co-Operative Group Thoracic and Gastrointestinal Subcommittees.

Radiation therapy (RT) is an integral component of potentially curative management of esophageal cancer (EC). However, RT can cause significant acute and late morbidity due to excess radiation exposure to nearby critical organs, especially the heart and lungs. Sparing these organs from both low and high radiation dose has been demonstrated to achieve clinically meaningful reductions in toxicity and may improve long-term survival. Accruing dosimetry and clinical evidence support the consideration of proton beam therapy (PBT) for the management of EC. There are critical treatment planning and delivery uncertainties that should be considered when treating EC with PBT, especially as there may be substantial motion-related interplay effects. The Particle Therapy Co-operative Group Thoracic and Gastrointestinal Subcommittees jointly developed guidelines regarding patient selection, treatment planning, clinical trials, and future directions of PBT for EC.

Clinical suitability of deep learning based synthetic CTs for adaptive proton therapy of lung cancer.

PURPOSE: Adaptive proton therapy (APT) of lung cancer patients requires frequent volumetric imaging of diagnostic quality. Cone-beam CT (CBCT) can provide these daily images, but x-ray scattering limits CBCT-image quality and hampers dose calculation accuracy. The purpose of this study was to generate CBCT-based synthetic CTs using a deep convolutional neural network (DCNN) and investigate image quality and clinical suitability for proton dose calculations in lung cancer patients. METHODS: A dataset of 33 thoracic cancer patients, containing CBCTs, same-day repeat CTs (rCT), planning-CTs (pCTs), and clinical proton treatment plans, was used to train and evaluate a DCNN with and without a pCT-based correction method. Mean absolute error (MAE), mean error (ME), peak signal-to-noise ratio, and structural similarity were used to quantify image quality. The evaluation of clinical suitability was based on recalculation of clinical proton treatment plans. Gamma pass ratios, mean dose to target volumes and organs at risk, and normal tissue complication probabilities (NTCP) were calculated. Furthermore, proton radiography simulations were performed to assess the HU-accuracy of sCTs in terms of range errors. RESULTS: On average, sCTs without correction resulted in a MAE of 34 ± 6 HU and ME of 4 ± 8 HU. The correction reduced the MAE to 31 ± 4HU (ME to 2 ± 4HU). Average 3%/3 mm gamma pass ratios increased from 93.7% to 96.8%, when the correction was applied. The patient specific correction reduced mean proton range errors from 1.5 to 1.1 mm. Relative mean target dose differences between sCTs and rCT were below ± 0.5% for all patients and both synthetic CTs (with/without correction). NTCP values showed high agreement between sCTs and rCT (<2%). CONCLUSION: CBCT-based sCTs can enable accurate proton dose calculations for APT of lung cancer patients. The patient specific correction method increased the image quality and dosimetric accuracy but had only a limited influence on clinically relevant parameters.

Optimizing calibration settings for accurate water equivalent path length assessment using flat panel proton radiography.

OBJECTIVE: Proton range uncertainties can compromise the effectiveness of proton therapy treatments. Water equivalent path length (WEPL) assessment by flat panel detector proton radiography (FP-PR) can provide means of range uncertainty detection. Since WEPL accuracy intrinsically relies on the FP-PR calibration parameters, the purpose of this study is to establish an optimal calibration procedure that ensures high accuracy of WEPL measurements. To that end, several calibration settings were investigated. APPROACH: FP-PR calibration datasets were obtained simulating PR fields with different proton energies, directed towards water-equivalent material slabs of increasing thickness. The parameters investigated were the spacing between energy layers (ΔE) and the increment in thickness of the water-equivalent material slabs (ΔX) used for calibration. 30 calibrations were simulated, as a result of combining ΔE = 9, 7, 5, 3, 1 MeV and ΔX = 10, 8, 5, 3, 2, 1 mm. FP-PRs through a CIRS electron density phantom were simulated, and WEPL images corresponding to each calibration were obtained. Ground truth WEPL values were provided by range probing multi-layer ionization chamber simulations on each insert of the phantom. Relative WEPL errors between FP-PR simulations and ground truth were calculated for each insert. Mean relative WEPL errors and standard deviations across all inserts were computed for WEPL images obtained with each calibration. MAIN RESULTS: Large mean and standard deviations were found in WEPL images obtained with large ΔEvalues (ΔE = 9 or 7 MeV), for any ΔX. WEPL images obtained with ΔE ≤ 5 MeV and ΔX ≤ 5 mm resulted in a WEPL accuracy with mean values within ±0.5% and standard deviations around 1%. SIGNIFICANCE: An optimal FP calibration in the framework of this study was established, characterized by 3 MeV ≤ ΔE ≤ 5 MeV and 2 mm ≤ ΔX ≤ 5 mm. Within these boundaries, highly accurate WEPL acquisitions using FP-PR are feasible and practical, holding the potential to assist future online range verification quality control procedures.

Assessment of a diaphragm override strategy for robustly optimized proton therapy planning for esophageal cancer patients.

PURPOSE: To ensure target coverage in the treatment of esophageal cancer, a density override to the region of diaphragm motion can be applied in the optimization process. Here, we evaluate the benefit of this approach during robust optimization for intensity modulated proton therapy (IMPT) planning. MATERIALS AND METHODS: For 10 esophageal cancer patients, two robustly optimized IMPT plans were created either using (WDO) or not using (NDO) a diaphragm density override of 1.05 g/cm3 during plan optimization. The override was applied to the excursion of the diaphragm between exhale and inhale. Initial robustness evaluation was performed for plan acceptance (setup errors of 8 mm, range errors of ±3%), and subsequently, on all weekly repeated 4DCTs (setup errors of 2 mm, range errors of ±3%). Target coverage and hotspots were analyzed on the resulting voxel-wise minimum (Vwmin ) and voxel-wise maximum (Vwmax ) dose distributions. RESULTS: The nominal dose distributions were similar for both WDO and NDO plans. However, visual inspection of the Vwmax of the WDO plans showed hotspots behind the right diaphragm override region. For one patient, target coverage and hotspots improved by applying the diaphragm override. We found no differences in target coverage in the weekly evaluations between the two approaches. CONCLUSION: The diaphragm override approach did not result in a clinical benefit in terms of planning and interfractional robustness. Therefore, we do not see added value in employing this approach as a default option during robust optimization for IMPT planning in esophageal cancer.

Range probing as a quality control tool for CBCT-based synthetic CTs: In vivo application for head and neck cancer patients.

PURPOSE: Cone-beam CT (CBCT)-based synthetic CTs (sCT) produced with a deep convolutional neural network (DCNN) show high image quality, suggesting their potential usability in adaptive proton therapy workflows. However, the nature of such workflows involving DCNNs prevents the user from having direct control over their output. Therefore, quality control (QC) tools that monitor the sCTs and detect failures or outliers in the generated images are needed. This work evaluates the potential of using a range-probing (RP)-based QC tool to verify sCTs generated by a DCNN. Such a RP QC tool experimentally assesses the CT number accuracy in sCTs. METHODS: A RP QC dataset consisting of repeat CTs (rCT), CBCTs, and RP acquisitions of seven head and neck cancer patients was retrospectively assessed. CBCT-based sCTs were generated using a DCNN. The CT number accuracy in the sCTs was evaluated by computing relative range errors between measured RP fields and RP field simulations based on rCT and sCT images. RESULTS: Mean relative range errors showed agreement between measured and simulated RP fields, ranging from -1.2% to 1.5% in rCTs, and from -0.7% to 2.7% in sCTs. CONCLUSIONS: The agreement between measured and simulated RP fields suggests the suitability of sCTs for proton dose calculations. This outcome brings sCTs generated by DCNNs closer toward clinical implementation within adaptive proton therapy treatment workflows. The proposed RP QC tool allows for CT number accuracy assessment in sCTs and can provide means of in vivo range verification.

Towards the clinical implementation of intensity-modulated proton therapy for thoracic indications with moderate motion: Robust optimised plan evaluation by means of patient and machine specific information.

PURPOSE: Compared to volumetric modulated arc therapy (VMAT), clinical benefits are anticipated when treating thoracic tumours with intensity-modulated proton therapy (IMPT). However, the current concern of plan robustness as a result of motion hampers its wide clinical implementation. To define an optimal protocol to treat lung and oesophageal cancers, we present a comprehensive evaluation of IMPT planning strategies, based on patient 4DCTs and machine log files. MATERIALS AND METHODS: For ten lung and ten oesophageal cancer patients, a planning 4DCT and weekly repeated 4DCTs were collected. For these twenty patients, the CTV volume and motion were assessed based on the 4DCTs. In addition to clinical VMAT plans, layered rescanned 3D and 4D robust optimised IMPT plans (IMPT_3D and IMPT_4D respectively) were generated, and approved clinically, for all patients. The IMPT plans were then delivered in dry runs at our proton facility to obtain log files, and subsequently evaluated through our 4D robustness evaluation method (4DREM). With this method, for each evaluated plan, fourteen 4D accumulated scenario doses were obtained, representing 14 possible fractionated treatment courses. RESULTS: From VMAT to IMPT_3D, nominal Dmean(lungs-GTV) decreased 2.75 ± 0.56 GyRBE and 3.76 ± 0.92 GyRBE over all lung and oesophageal cancer patients, respectively. A more pronounced reduction was verified for Dmean(heart): 5.38 ± 7.36 GyRBE (lung cases) and 9.51 ± 2.25 GyRBE (oesophagus cases). Target coverage robustness of IMPT_3D was sufficient for 18/20 patients. Averaged dose in critical structures over all 4DREM scenarios changed only slightly for both IMPT_3D and IMPT_4D. Relative to IMPT_3D, no gain in IMPT_4D was observed. CONCLUSION: The dosimetric superiority of IMPT over VMAT has been established. For most thoracic tumours, our IMPT_3D planning protocol showed to be robust and clinically suitable. Nevertheless, accurate patient positioning and adapting to anatomical variations over the course of treatment remain compulsory.

Clinical practice vs. state-of-the-art research and future visions: Report on the 4D treatment planning workshop for particle therapy - Edition 2018 and 2019.

The 4D Treatment Planning Workshop for Particle Therapy, a workshop dedicated to the treatment of moving targets with scanned particle beams, started in 2009 and since then has been organized annually. The mission of the workshop is to create an informal ground for clinical medical physicists, medical physics researchers and medical doctors interested in the development of the 4D technology, protocols and their translation into clinical practice. The 10th and 11th editions of the workshop took place in Sapporo, Japan in 2018 and Krakow, Poland in 2019, respectively. This review report from the Sapporo and Krakow workshops is structured in two parts, according to the workshop programs. The first part comprises clinicians and physicists review of the status of 4D clinical implementations. Corresponding talks were given by speakers from five centers around the world: Maastro Clinic (The Netherlands), University Medical Center Groningen (The Netherlands), MD Anderson Cancer Center (United States), University of Pennsylvania (United States) and The Proton Beam Therapy Center of Hokkaido University Hospital (Japan). The second part is dedicated to novelties in 4D research, i.e. motion modelling, artificial intelligence and new technologies which are currently being investigated in the radiotherapy field.

Technical Note: First report on an in vivo range probing quality control procedure for scanned proton beam therapy in head and neck cancer patients.

PURPOSE: The capability of proton therapy to provide highly conformal dose distributions is impaired by range uncertainties. The aim of this work is to apply range probing (RP), a form of a proton radiography-based quality control (QC) procedure for range accuracy assessment in head and neck cancer (HNC) patients in a clinical setting. METHODS AND MATERIALS: This study included seven HNC patients. RP acquisition was performed using a multi-layer ionization chamber (MLIC). Per patient, two RP frames were acquired within the first two weeks of treatment, on days when a repeated CT scan was obtained. Per RP frame, integral depth dose (IDD) curves of 81 spots around the treatment isocenter were acquired. Range errors are determined as a discrepancy between calculated IDDs in the treatment planning system and measured residual ranges by the MLIC. Range errors are presented relative to the water equivalent path length of individual proton spots. In addition to reporting results for complete measurement frames, an analysis, excluding range error contributions due to anatomical changes, is presented. RESULTS: Discrepancies between measured and calculated ranges are smaller when performing RP calculations on the day-specific patient anatomy rather than the planning CT. The patient-specific range evaluation shows an agreement between calculated and measured ranges for spots in anatomically consistent areas within 3% (1.5 standard deviation). CONCLUSIONS: The results of an RP-based QC procedure implemented in the clinical practice for HNC patients have been demonstrated. The agreement of measured and simulated proton ranges confirms the 3% uncertainty margin for robust optimization. Anatomical variations show a predominant effect on range accuracy, motivating efforts towards the implementation of adaptive radiotherapy.

Consensus Statement on Proton Therapy in Mesothelioma.

PURPOSE: Radiation therapy for mesothelioma remains challenging, as normal tissue toxicity limits the amount of radiation that can be safely delivered to the pleural surfaces, especially radiation dose to the contralateral lung. The physical properties of proton therapy result in better sparing of normal tissues when treating the pleura, both in the postpneumonectomy setting and the lung-intact setting. Compared with photon radiation, there are dramatic reductions in dose to the contralateral lung, heart, liver, kidneys, and stomach. However, the tissue heterogeneity in the thorax, organ motion, and potential for changing anatomy during the treatment course all present challenges to optimal irradiation with protons. METHODS: The clinical data underlying proton therapy in mesothelioma are reviewed here, including indications, advantages, and limitations. RESULTS: The Particle Therapy Cooperative Group Thoracic Subcommittee task group provides specific guidelines for the use of proton therapy for mesothelioma. CONCLUSIONS: This consensus report can be used to guide clinical practice, insurance approval, and future research.

Head and neck IMPT probabilistic dose accumulation: Feasibility of a 2 mm setup uncertainty setting.

OBJECTIVE: To establish optimal robust optimization uncertainty settings for clinical head and neck cancer (HNC) patients undergoing 3D image-guided pencil beam scanning (PBS) proton therapy. METHODS: We analyzed ten consecutive HNC patients treated with 70 and 54.25 GyRBE to the primary and prophylactic clinical target volumes (CTV) respectively using intensity-modulated proton therapy (IMPT). Clinical plans were generated using robust optimization with 5 mm/3% setup/range uncertainties (RayStation v6.1). Additional plans were created for 4, 3, 2 and 1 mm setup and 3% range uncertainty and for 3 mm setup and 3%, 2% and 1% range uncertainty. Systematic and random error distributions were determined for setup and range uncertainties based on our quality assurance program. From these, 25 treatment scenarios were sampled for each plan, each consisting of a systematic setup and range error and daily random setup errors. Fraction doses were calculated on the weekly verification CT closest to the date of treatment as this was considered representative of the daily patient anatomy. RESULTS: Plans with a 2 mm/3% setup/range uncertainty setting adequately covered the primary and prophylactic CTV (V95 ≥ 99% in 98.8% and 90.8% of the treatment scenarios respectively). The average organ-at-risk dose decreased with 1.1 GyRBE/mm setup uncertainty reduction and 0.5 GyRBE/1% range uncertainty reduction. Normal tissue complication probabilities decreased by 2.0%/mm setup uncertainty reduction and by 0.9%/1% range uncertainty reduction. CONCLUSION: The results of this study indicate that margin reduction below 3 mm/3% is possible but requires a larger cohort to substantiate clinical introduction.

Comparison of the suitability of CBCT- and MR-based synthetic CTs for daily adaptive proton therapy in head and neck patients.

Cone-beam computed tomography (CBCT)- and magnetic resonance (MR)-images allow a daily observation of patient anatomy but are not directly suited for accurate proton dose calculations. This can be overcome by creating synthetic CTs (sCT) using deep convolutional neural networks. In this study, we compared sCTs based on CBCTs and MRs for head and neck (H&N) cancer patients in terms of image quality and proton dose calculation accuracy. A dataset of 27 H&N-patients, treated with proton therapy (PT), containing planning CTs (pCTs), repeat CTs, CBCTs and MRs were used to train two neural networks to convert either CBCTs or MRs into sCTs. Image quality was quantified by calculating mean absolute error (MAE), mean error (ME) and Dice similarity coefficient (DSC) for bones. The dose evaluation consisted of a systematic non-clinical analysis and a clinical recalculation of actually used proton treatment plans. Gamma analysis was performed for non-clinical and clinical treatment plans. For clinical treatment plans also dose to targets and organs at risk (OARs) and normal tissue complication probabilities (NTCP) were compared. CBCT-based sCTs resulted in higher image quality with an average MAE of 40 ± 4 HU and a DSC of 0.95, while for MR-based sCTs a MAE of 65 ± 4 HU and a DSC of 0.89 was observed. Also in clinical proton dose calculations, sCTCBCT achieved higher average gamma pass ratios (2%/2 mm criteria) than sCTMR (96.1% vs. 93.3%). Dose-volume histograms for selected OARs and NTCP-values showed a very small difference between sCTCBCT and sCTMR and a high agreement with the reference pCT. CBCT- and MR-based sCTs have the potential to enable accurate proton dose calculations valuable for daily adaptive PT. Significant image quality differences were observed but did not affect proton dose calculation accuracy in a similar manner. Especially the recalculation of clinical treatment plans showed high agreement with the pCT for both sCTCBCT and sCTMR.

Technical Note: 4D cone-beam CT reconstruction from sparse-view CBCT data for daily motion assessment in pencil beam scanned proton therapy (PBS-PT).

PURPOSE: The number of pencil beam scanned proton therapy (PBS-PT) facilities equipped with cone-beam computed tomography (CBCT) imaging treating thoracic indications is constantly rising. To enable daily internal motion monitoring during PBS-PT treatments of thoracic tumors, we assess the performance of Motion-Aware RecOnstructiOn method using Spatial and Temporal Regularization (MA-ROOSTER) four-dimensional CBCT (4DCBCT) reconstruction for sparse-view CBCT data and a realistic data set of patients treated with proton therapy. METHODS: Daily CBCT projection data for nine non-small cell lung cancer (NSCLC) patients and one SCLC patient were acquired at a proton gantry system (IBA Proteus® One). Four-dimensional CBCT images were reconstructed applying the MA-ROOSTER and the conventional phase-correlated Feldkamp-Davis-Kress (PC-FDK) method. Image quality was assessed by visual inspection, contrast-to-noise ratio (CNR), signal-to-noise ratio (SNR), and the structural similarity index measure (SSIM). Furthermore, gross tumor volume (GTV) centroid motion amplitudes were evaluated. RESULTS: Image quality for the 4DCBCT reconstructions using MA-ROOSTER was superior to the PC-FDK reconstructions and close to FDK images (median CNR: 1.23 [PC-FDK], 1.98 [MA-ROOSTER], and 1.98 [FDK]; median SNR: 2.56 [PC-FDK], 4.76 [MA-ROOSTER], and 5.02 [FDK]; median SSIM: 0.18 [PC-FDK vs FDK], 0.31 [MA-ROOSTER vs FDK]). The improved image quality of MA-ROOSTER facilitated GTV contour warping and realistic motion monitoring for most of the reconstructions. CONCLUSION: MA-ROOSTER based 4DCBCTs performed well in terms of image quality and appear to be promising for daily internal motion monitoring in PBS-PT treatments of (N)SCLC patients.

Evaluation of continuous beam rescanning versus pulsed beam in pencil beam scanned proton therapy for lung tumours.

The treatment of moving targets with pencil beam scanned proton therapy (PBS-PT) may rely on rescanning strategies to smooth out motion induced dosimetric disturbances. PBS-PT machines, such as Proteus®Plus (PPlus) and Proteus®One (POne), deliver a continuous or a pulsed beam, respectively. In PPlus, scaled (or no) rescanning can be applied, while POne implies intrinsic 'rescanning' due to its pulsed delivery. We investigated the efficacy of these PBS-PT delivery types for the treatment of lung tumours. In general, clinically acceptable plans were achieved, and PPlus and POne showed similar effectiveness.