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Publikation A survey of practice patterns for adaptive particle therapy for interfractional changes(Elsevier, 04/2023) Trnkova, Petra; Zhang, Ye; Toshito, Toshiyuki; Heijmen, Ben; Richter, Christian; Aznar, Marianne C.; Albertini, Francesca; Bolsi, Alessandra; Daartz, Juliane; Knopf, Antje; Bertholet, Jenny01A - Beitrag in wissenschaftlicher ZeitschriftPublikation A survey of practice patterns for real-time intrafractional motion-management in particle therapy(Elsevier, 26.04.2023) Zhang, Ye; Trnkova, Petra; Toshito, Toshiyuki; Heijmen, Ben; Richter, Christian; Aznar, Marianne; Albertini, Francesca; Bolsi, Alexandra; Daartz, Juliane; Bertholet, Jenny; Knopf, Antje01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Diaphragm-based position verification to improve daily target dose coverage in proton and photon radiation therapy treatment of distal esophageal cancer(Elsevier, 01.02.2022) Visser, Sabine; den Otter, Lydia A.; Ribeiro, Cássia O.; Korevaar, Erik W.; Both, Stefan; Langendijk, Johannes A.; Muijs, Christina T.; Sijtsema, Nanna M.; Knopf, AntjePurpose In modern conformal radiation therapy of distal esophageal cancer, target coverage can be affected by variations in the diaphragm position. We investigated if daily position verification (PV) extended by a diaphragm position correction would optimize target dose coverage for esophageal cancer treatment. Methods and Materials For 15 esophageal cancer patients, intensity modulated proton therapy (IMPT) and volumetric modulated arc therapy (VMAT) plans were computed. Displacements of the target volume were correlated with diaphragm displacements using repeated 4-dimensional computed tomography images to determine the correction needed to account for diaphragm variations. Afterwards, target coverage was evaluated for 3 PV approaches based on: (1) bony anatomy (PV_B), (2) bony anatomy corrected for the diaphragm position (PV_BD) and (3) target volume (PV_T). Results The cranial-caudal mean target displacement was congruent with almost half of the diaphragm displacement (y = 0.459x), which was used for the diaphragm correction in PV_BD. Target dose coverage using PV_B was adequate for most patients with diaphragm displacements up till 10 mm (≥94% of the dose in 98% of the volume [D98%]). For larger displacements, the target coverage was better maintained by PV_T and PV_BD. Overall, PV_BD accounted best for target displacements, especially in combination with tissue density variations (D98%: IMPT 94% ± 5%, VMAT 96% ± 5%). Diaphragm displacements of more than 10 mm were observed in 22% of the cases. Conclusions PV_B was sufficient to achieve adequate target dose coverage in case of small deviations in diaphragm position. However, large deviations of the diaphragm were best mitigated by PV_BD. To detect the cases where target dose coverage could be compromised due to diaphragm position variations, we recommend monitoring of the diaphragm position before treatment through online imaging.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Management of motion and anatomical variations in charged particle therapy. Past, present, and into the future(Frontiers, 09.03.2022) Pakela, Julia M.; Dong, Lei; Rucinski, Antoni; Zou, Wei; Knopf, AntjeThe major aim of radiation therapy is to provide curative or palliative treatment to cancerous malignancies while minimizing damage to healthy tissues. Charged particle radiotherapy utilizing carbon ions or protons is uniquely suited for this task due to its ability to achieve highly conformal dose distributions around the tumor volume. For these treatment modalities, uncertainties in the localization of patient anatomy due to inter- and intra-fractional motion present a heightened risk of undesired dose delivery. A diverse range of mitigation strategies have been developed and clinically implemented in various disease sites to monitor and correct for patient motion, but much work remains. This review provides an overview of current clinical practices for inter and intra-fractional motion management in charged particle therapy, including motion control, current imaging and motion tracking modalities, as well as treatment planning and delivery techniques. We also cover progress to date on emerging technologies including particle-based radiography imaging, novel treatment delivery methods such as tumor tracking and FLASH, and artificial intelligence and discuss their potential impact towards improving or increasing the challenge of motion mitigation in charged particle therapy.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Experimental validation of 4D log file‐based proton dose reconstruction for interplay assessment considering amplitude‐sorted 4DCTs(Wiley, 11.04.2022) Spautz, Saskia; Jakobi, Annika; Meijers, Arturs; Peters, Nils; Löck, Steffen; Troost, Esther G.C.; Richter, Christian; Stützer, Kristin; Knopf, AntjePurpose 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.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Deep learning–based 4D‐synthetic CTs from sparse‐view CBCTs for dose calculations in adaptive proton therapy(Wiley, 27.08.2022) Thummerer, Adrian; Seller Oria, Carmen; Zaffino, Paolo; Visser, Sabine; Meijers, Arturs; Guterres Marmitt, Gabriel; Wijsman, Robin; Seco, Joao; Langendijk, Johannes Albertus; Spadea, Maria Francesca; Both, Stefan; Knopf, AntjeBackground 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.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Anthropomorphic lung phantom based validation of in-room proton therapy 4D-CBCT image correction for dose calculation(Elsevier, 02/2022) Bondesson, David; Meijers, Arturs; Janssens, Guillaume; Rit, Simon; Rabe, Moritz; Kamp, Florian; Niepel, Katharina; Otter, Lydia A. den; Both, Stefan; Brousmiche, Sebastien; Dinkel, Julien; Belka, Claus; Parodi, Katia; Kurz, Christopher; Landry, Guillaume; Knopf, AntjePurpose 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 60 Gy 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%/3 mm, 5 Gy, 20 Gy and 30 Gy 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 5 Gy, 20 Gy and 30 Gy 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.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Clinical necessity of multi-image based (4DMIB) optimization for targets affected by respiratory motion and treated with scanned particle therapy – A comprehensive review(Elsevier, 02/2022) Czerska, Katarzyna; Fracchiolla, Francesco; Graeff, Christian; Molinelli, Silvia; Rinaldi, Ilaria; Rucincki, Antoni; Sterpin, Edmond; Stützer, Kristin; Trnkova, Petra; Zhang, Ye; Chang, Joe Y; Giap, Huan; Liu, Wei; Schild, Steven E; Simone, Charles B.; Lomax, Antony J; Meijers, Arturs; Knopf, Antje4D multi-image-based (4D MIB) 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 var- ious 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 opti- mized 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 4D MIB optimization, when treating moving targets with scanned particle therapy, as still to be demonstrated.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Robustness assessment of clinical adaptive proton and photon radiotherapy for oesophageal cancer in the model-based approach(Elsevier, 12/2022) Visser, Sabine; O. Ribeiro, Cássia; Dieters, Margriet; Mul, Veronique E.; Niezink, Anne G.H.; van der Schaaf, Arjen; Langendijk, Johannes A.; Korevaar, Erik W.; Both, Stefan; Muijs, Christina T.; Knopf, AntjePurpose In the Netherlands, oesophageal cancer (EC) patients are selected for intensity modulated proton therapy (IMPT) using the expected normal tissue complication probability reduction (ΔNTCP) when treating with IMPT compared to volumetric modulated arc therapy (VMAT). In this study, we evaluate the robustness of the first EC patients treated with IMPT in our clinic in terms of target and organs-at-risk (OAR) dose with corresponding NTCP, as compared to VMAT. Materials and Methods For 20 consecutive EC patients, clinical IMPT and VMAT plans were created on the average planning 4DCT. Both plans were robustly evaluated on weekly repeated 4DCTs and if target coverage degraded, replanning was performed. Target coverage was evaluated for complete treatment trajectories with and without replanning. The planned and accumulated mean lung dose (MLD) and mean heart dose (MHD) were additionally evaluated and translated into NTCP. Results Replanning in the clinic was performed more often for IMPT (15x) than would have been needed for VMAT (8x) (p = 0.11). Both adaptive treatments would have resulted in adequate accumulated target dose coverage. Replanning in the first week of treatment had most clinical impact, as anatomical changes resulting in insufficient accumulated target coverage were already observed at this stage. No differences were found in MLD between the planned dose and the accumulated dose. Accumulated MHD differed from the planned dose (p < 0.001), but since these differences were similar for VMAT and IMPT (1.0 and 1.5 Gy, respectively), the ΔNTCP remained unchanged. Conclusion Following an adaptive clinical workflow, adequate target dose coverage and stable OAR doses with corresponding NTCPs was assured for both IMPT and VMAT.01A - Beitrag in wissenschaftlicher Zeitschrift