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Purpose: 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 [D-98%]). 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 (D-98%: 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. (C) 2021 Elsevier Inc. All rights reserved.

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.

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.

BACKGROUND AND PURPOSE: Intensity-modulated proton therapy (IMPT) is expected to result in clinical benefits by lowering radiation dose to organs-at-risk (OARs). However, there are concerns about plan robustness due to motion. To address this uncertainty we evaluated the robustness of IMPT compared to the widely clinically used volumetric modulated arc therapy (VMAT) on weekly repeated computed tomographies (CT).MATERIALS AND METHODS: 19 patients with oesophageal cancer were evaluated. IMPT and VMAT plans were created on a planning 4-Dimensional CT (p4DCT) and evaluated on weekly repeated 4DCTs (r4DCT). In case of inadequate target coverage or unacceptable high dose to normal tissue, re-planning was performed. Dose distributions of the r4DCTs were warped to p4DCT, resulting in an estimated actual given dose (EAGD).RESULTS: Compared to VMAT, IMPT resulted in significantly lowered dose to heart, lungs, spleen, liver and kidneys. For IMPT, target coverage was adequate (after max 1 replanning) in 17/19 cases. In two cases target coverage remained insufficient. However, in one of these patients the summed dose was insufficient (due to tumor shrinkage) while weekly coverage was adequate. For the other patient the target coverage was also insufficient by VMAT, due to large anatomical changes during treatment. For VMAT, adequate target coverage was achieved in 18/19 cases without re-planning. However, for reasons of high OAR dose re-planning was required in two cases.CONCLUSION: IMPT reduces the dose to OARs significantly, while achieving adequate target coverage in the majority of patients. Re-planning was necessary for both IMPT and VMAT due to anatomical changes.

Background and purpose Non-small cell lung cancer (NSCLC) patients show typically large anatomical changes during treatment, making recalculation or adaption necessary. For report and review, the applied treatment dose can be accumulated on the reference planning CT using deformable image registration (DIR). We investigated the dosimetric impact of using six different clinically available DIR algorithms for dose accumulation in presence of inter-fractional anatomy variations. Materials and methods For seven NSCLC patients, proton treatment plans with 66 Gy-RBE to the planning target volume (PTV) were optimised. Nine repeated CTs were registered to the planning CT using six DIR algorithms each. All CTs were acquired in visually guided deep-inspiration breath-hold. The plans were recalculated on the repeated CTs and warped back to the planning CT using the corresponding DIRs. Fraction doses warped with the same DIR were summed up to six different accumulated dose distributions per patient, and compared to the initial dose. Results The PTV-V95 of accumulated doses decreased by 16% on average over all patients, with variations due to DIR selection of 8.7%. A separation of the dose effects caused by anatomical changes and DIR uncertainty showed a good agreement between the dose degradation caused by anatomical changes and the dose predicted from the average of all DIRs (differences of only 1.6%). Conclusion The dose degradation caused by anatomical changes was more pronounced than the uncertainty of employing different DIRs for dose accumulation, with averaged results from several DIRs providing a good representation of dose degradation caused by anatomy. However, accumulated dose variations between DIRs can be substantial, leading to an additional dose uncertainty., Radiotherapy & Oncology, 147, ISSN:0167-8140, ISSN:1879-0887

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 ΔE values (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.

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 7 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 towards 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.

To optimize beam delivery and conformality of proton therapy, MRI integration has been proposed. Therefore, we investigated if proton irradiation in a magnetic field would change biological responses. Our data in cancer cell lines and stem cell-derived organoid models suggest that a magnetic field does not modify the biological response. (C) 2019 Elsevier B.V. All rights reserved.

The treatment of cancer with proton radiation therapy was first suggested in 1946 followed by the first treatments in the 1950s. As of 2020, almost 200 000 patients have been treated with proton beams worldwide and the number of operating proton therapy (PT) facilities will soon reach one hundred. PT has long moved from research institutions into hospital-based facilities that are increasingly being utilized with workflows similar to conventional radiation therapy. While PT has become mainstream and has established itself as a treatment option for many cancers, it is still an area of active research for various reasons: the advanced dose shaping capabilities of PT cause susceptibility to uncertainties, the high degrees of freedom in dose delivery offer room for further improvements, the limited experience and understanding of optimizing pencil beam scanning, and the biological effect difference compared to photon radiation. In addition to these challenges and opportunities currently being investigated, there is an economic aspect because PT treatments are, on average, still more expensive compared to conventional photon based treatment options. This roadmap highlights the current state and future direction in PT categorized into four different themes, ‘improving efficiency’, ‘improving planning and delivery’, ‘improving imaging’, and ‘improving patient selection’.

This study evaluates the suitability of convolutional neural networks (CNNs) to automatically process proton radiography (PR)-based images. CNNs are used to classify PR images impaired by several sources of error affecting the proton range, more precisely setup and calibration curve errors. PR simulations were performed in 40 head and neck cancer patients, at three different anatomical locations (fields A, B and C, centered for head and neck, neck and base of skull coverage). Field sizes were 26 × 26cm2 for field A and 4.5 × 4.5cm2 for fields B and C. Range shift maps were obtained by comparing an unperturbed reference PR against a PR where one or more sources of error affected the proton range. CT calibration curve errors in soft, bone and fat tissues and setup errors in the anterior–posterior and inferior–superior directions were simulated individually and in combination. A CNN was trained for each type of PR field, leading to three CNNs trained with a mixture of range shift maps arising from one or more sources of range error. To test the full/partial/wrong agreement between predicted and actual sources of range error in the range shift maps, exact, partial and wrong match percentages were computed for an independent test dataset containing range shift maps arising from isolated or combined errors, retrospectively. The CNN corresponding to field A showed superior capability to detect isolated and combined errors, with exact matches of 92% and 71% respectively. Field B showed exact matches of 80% and 54%, and field C resulted in exact matches of 77% and 41%. The suitability of CNNs to classify PR-based images containing different sources of error affecting the proton range was demonstrated. This procedure enables the detection of setup and calibration curve errors when they appear individually or in combination, providing valuable information for the interpretation of PR images.

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 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.

Background The targeting accuracy of proton therapy (PT) for moving soft-tissue tumours is expected to greatly improve by real-time magnetic resonance imaging (MRI) guidance. The integration of MRI and PT at the treatment isocenter would offer the opportunity of combining the unparalleled soft-tissue contrast and real-time imaging capabilities of MRI with the most conformal dose distribution and best dose steering capability provided by modern PT. However, hybrid systems for MR-integrated PT (MRiPT) have not been realized so far due to a number of hitherto open technological challenges. In recent years, various research groups have started addressing these challenges and exploring the technical feasibility and clinical potential of MRiPT. The aim of this contribution is to review the different aspects of MRiPT, to report on the status quo and to identify important future research topics. Methods Four aspects currently under study and their future directions are discussed: modelling and experimental investigations of electromagnetic interactions between the MRI and PT systems, integration of MRiPT workflows in clinical facilities, proton dose calculation algorithms in magnetic fields, and MRI-only based proton treatment planning approaches. Conclusions Although MRiPT is still in its infancy, significant progress on all four aspects has been made, showing promising results that justify further efforts for research and development to be undertaken. First non-clinical research solutions have recently been realized and are being thoroughly characterized. The prospect that first prototype MRiPT systems for clinical use will likely exist within the next 5 to 10 years seems realistic, but requires significant work to be performed by collaborative efforts of research groups and industrial partners.

In this review article, we introduced the importance of “motion management” in advanced particle therapy. Several publications have reported that organ motion causes dose distribution disturbances due to interplay and blurring effects. Furthermore, motion can result in target dose miss and unwanted dose to healthy structures around the target. To avoid these problems, motion should be assessed and monitored prior and during treatment. In this review article, we give an overview about clinically available motion monitoring systems. Based on the acquired motion information an adequate motion mitigation technique should be chosen. This article reviews the clinical status of motion mitigation techniques like rescanning, gating and tracking. A limited number of centers have now started the treatment of targets in the thorax and abdomen using scanned particle beams. Therefore, the establishment of guidelines for motion monitoring and motion mitigation will be essential in the coming years.

In 2016 and 2017, the 8th and 9th 4D treatment planning workshop took place in Groningen (the Netherlands) and Vienna (Austria), respectively. This annual workshop brings together international experts to discuss re- search, advances in clinical implementation as well as problems and challenges in 4D treatment planning, mainly in spot scanned proton therapy. In the last two years several aspects like treatment planning, beam delivery, Monte Carlo simulations, motion modeling and monitoring, QA phantoms as well as 4D imaging were thor- oughly discussed. This report provides an overview of discussed topics, recent findings and literature review from the last two years. Its main focus is to highlight translation of 4D research into clinical practice and to discuss remaining challenges and pitfalls that still need to be addressed and to be overcome.

BACKGROUND: The interplay effect might degrade the dose of pencil beam scanning proton therapy to a degree that free-breathing treatment might be impossible without further motion mitigation techniques, which complicate and prolong the treatment. We assessed whether treatment of free-breathing patients without motion mitigation is feasible.MATERIAL AND METHODS: For 40 lung cancer patients, 4DCT datasets and individual breathing patterns were used to simulate 4D dynamic dose distributions of 3D treatment plans over 33 fractions delivered with an IBA universal nozzle. Evaluation was done by assessing under- and overdosage in the target structure using the parameters V90, V95, V98, D98, D2, V107 and V110. The impact of using beam-specific target volumes and the impact of changes in motion and patient anatomy in control 4DCTs were assessed.RESULTS: Almost half of the patients had tumour motion amplitudes of less than 5 mm. Under- and overdosage was significantly smaller for patients with tumour motion below 5 mm compared to patients with larger motion (2% vs. 13% average absolute reduction of V95, 2% vs. 8% average increase in V107, p CONCLUSION: Tumour motion amplitude is an indicator of dose degradation caused by the interplay effect. Fractionation reduces the dose degradation allowing the unmitigated treatment of patients with small tumour motions of less than 5 mm. The beam-specific target approach improves the dose coverage. The tumour motion and position needs to be assessed during treatment for all patients, to quickly react to possible changes, which might require treatment adaptation.

Pencil-beam scanning (PBS) proton therapy (PT), particularly intensity modulated PT, represents the latest advanced PT technology for treating cancers, including thoracic malignancies. On the basis of virtual clinical studies, PBS-PT appears to have great potential in its ability to tightly tailor the dose to the target while sparing critical structures, thereby reducing treatment-related toxicities, particularly for tumors in areas with complicated anatomy. However, implementing PBS-PT for moving targets has several additional technical challenges compared with intensity modulated photon radiation therapy or passive scattering PT. Four-dimensional computed tomographye based motion management and robust optimization and evaluation are crucial for minimizing uncertainties associated with beam range and organ motion. Rigorous quality assurance is required to validate dose delivery both before and during the course of treatment. Active motion management (eg, breath hold), beam gating, rescanning, tracking, or adaptive planning may be needed for cases involving significant motion or changes in motion or anatomy over the course of treatment. (C) 2017 The Authors. Published by Elsevier Inc.

Background: The aim of this study was to compare adaptive intensity modulated proton therapy (IMPT) robustness and organ sparing capabilities with that of adaptive volumetric arc photon therapy (VMAT). Material and methods: Eighteen lung cancer patients underwent a planning 4DCT (p4DCT) and 5 weekly repeated 4DCT (r4DCT) scans. Target volumes and organs at risk were manually delineated on the three-dimensional (3D) average scans of the p4DCT (av_p4DCT) and of the r4DCT scans (av_r4DCT). Planning target volume (PTV)-based VMAT plans and internal clinical target volume (ICTV)-based robust IMPT plans were optimized in 3D on the av_p4DCT and re-calculated on the av_r4DCTs. Re-planning on av_r4DCTs was performed when indicated and accumulated doses were evaluated on the av_p4DCT. Results: Adaptive VMAT and IMPT resulted in adequate ICTV coverage on av_r4DCT in all patients and adequate accumulated-dose ICTV coverage on av_p4DCT in 17/18 patients (due to a shrinking target in one patient). More frequent re-planning was needed for IMPT than for VMAT. The average mean heart dose reduction with IMPT compared with VMAT was 4.6 Gy (p = .001) and it was >5 Gy for five patients (6, 7, 8, 15, and 22 Gy). The average mean lung dose reduction was 3.2 Gy (p

Purpose Respiratory impacts in pencil beam scanned proton therapy (PBS-PT) are accounted by extensive 4D dose calculations, where deformable image registration (DIR) is necessary for estimating deformation vector fields (DVFs). We aim here to evaluate the dosimetric errors induced by different DIR algorithms in their resulting 4D dose calculations by using ground truth(GT)-DVFs from 4DMRI. Materials and methods Six DIR methods: ANACONDA, Morfeus, B-splines, Demons, CT Deformable, and Total Variation, were respectively applied to nine 4DCT-MRI liver data sets. The derived DVFs were then used as input for 4D dose calculation. The DIR induced dosimetric error was assessed by individually comparing the resultant 4D dose distributions to those obtained with GT-DVFs. Both single-/three-field plans and single/rescanned strategies were investigated. Results Differences in 4D dose distributions among different DIR algorithms, and compared to the results using GT-DVFs, were pronounced. Up to 40 % of clinically relevant dose calculation points showed dose differences of 10 % or more between the GT. Differences in V95(CTV) reached up to 11.34 ± 12.57 %. The dosimetric errors became in general less substantial when applying multiple-field plans or using rescanning. Conclusion Intrinsic geometric errors by DIR can influence the clinical evaluation of liver 4D PBS-PT plans. We recommend the use of an error bar for correctly interpreting individual 4D dose distributions., Radiotherapy & Oncology, 128 (1), ISSN:0167-8140, ISSN:1879-0887

Background and purpose: The treatment of moving targets with scanned proton beams is challenging. For motion mitigation, an Active Breathing Coordinator (ABC) can be used to assist with breath-holding. We evaluated the robustness of scanned proton therapy against anatomical uncertainties when treating lung patients during ABC controlled breath-hold. Materials and methods: Four subsequent MRIs of five healthy volunteers were acquired under ABC controlled breath-hold during two simulated treatment fractions. Deformation vector fields between these MRIs were used to deform CTs of three non-small-cell lung cancer patients. Per patient eight cases with different tumour sizes and locations were modeled. Intensity-modulated proton plans were created and split into sub-plans of 20 seconds duration (assumed breath-hold duration), and recalculated on the deformed CTs. Results: Dosimetric evaluation showed

Tumour tracking with scanned particle beams potentially requires accurate 3D information on both tumour motion and related density variations. We have previously developed a model-based motion reconstruction method, which allows for the prediction of deformable motions from sparsely sampled surrogate motions tracked via an on-board imaging system (Zhang et al (2013 Phys. Med. Biol. 58 8621)). Here, we investigate the potential effectiveness of tumour tracking for scanned proton beam therapy using such an approach to guide scanned beam tracking, together with the effectiveness of 're-tracking' for reducing residual motion effects due to tracking uncertainties. Three different beam tracking strategies (2D, 2D deformable and 3D) have been applied to three different liver motion cases, with mean magnitudes ranging from 10-20 mm. All simulations have been performed using simulated 4DCTs derived from 4DMRI datasets, whereby inter-breath-cycle motion variability is taken into account. The results show that, without beam tracking, large interplay effects are observed for all motion cases, resulting in CTV D5-95 values of 34.9/58.5/79.4% for the three cases, respectively. These can be reduced to 16.9/18.8/29.1% with 2D tracking, to 15.5/17.9/23.3% with 2D deformable tracking and to 15.1/17.8/21.0% with 3D tracking. Clear 'inverse interplay' effects have also been observed in the proximal portion of the field. However, with three-times re-tracking, D5-95 for the largest motions (20 mm) can be reduced to 13.0/12.8% for 2D and 3D tracking, respectively, and 'hot spots' resulting from the 'inverse interplay' effect can be substantially reduced. In summary, we have found that, for motions over 10 mm, tracking alone cannot fully mitigate motion effects, and can lead to substantially increased doses to normal tissues in the entrance path of the field. However, three-times re-tracking substantially improves the effectiveness of all types of beam tracking, with substantial advantages of 3D over 2D re-tracking only being observed for the largest motion scenario investigated.

Purpose/Objective Proton therapy is a highly conformal way to treat cancer. For the treatment of moving targets, scanned proton therapy delivery is a challenge, as it is sensitive to motion. The use of breath hold mitigates motion effects. Due to the treatment delivery over several fractions with delivery times extending the feasible breath hold duration, high reproducibility of breath holds is required. Active Breathing Control (ABC) is used to perform breath holds with controlled volumes. We investigated whether the lung anatomy is as reproducible as lung volumes under ABC, to consider ABC for scanned proton treatments. Material/Methods For five representative volunteers (3 male, 2 female, age: 25-58, BMI: 19 – 29) MR imaging was performed during ABC at two separate fractions. The image voxel size was 0.7x0.7x3.0 mm3. Each fraction consisted of four subsequent breath holds, resulting in a total of eight MRIs per volunteer. The interval between fractions was 1-4 weeks, keeping the same positioning. The intra-fraction reproducibility of the lung anatomy during breath hold was investigated, by comparing the MRI of the first breath hold with the three other MRIs of the same session. The inter-fraction anatomical reproducibility was investigated by comparing the first breath hold MRI of the first session with the four MRIs during the second session. To avoid any influence of setup variation, first a global rigid image registration was performed. Then the lung volume was semi-automatically segmented to define a region of interest for the deformable image registration (DIR). DIR was performed using Mirada RTx v1.2 (Mirada Medical, Ltd.), with a DIR grid resolution of 3.5x2x3 mm3. The deformation vector fields were analyzed using MATLAB v2014b. Magnitudes of the deformation vectors were calculated and combined for all five volunteers. The lung volumes were divided into six segments, to analyze the anatomical displacements on a local level. A boxplot showing the intra- and inter-fraction displacements with a schematic view of the six segments can be seen in figure 1. Results The lung volumes for all breath holds varied by 2% within and 7% between fractions. Looking at all five volunteers, up to 2 mm median intra- and inter-fraction displacements were found for all lung segments. The anatomical reproducibility decreased towards the caudal regions. Inter-fraction displacements were larger than intra-fractional displacements. Maximum displacements (99.3% of the magnitude vectors) reached 6 mm intra-fractionally and did not exceed 7 mm inter-fractionally. Conclusion While the lung volume differences were insignificant, relevant anatomical displacements were found. Moreover, a trend of increased displacements over time could be seen. ABC mitigates motion to some extent. Nevertheless, the remaining reproducibility uncertainties need to be considered during scanned proton therapy treatments. As next step, we aim to include this knowledge in a model to estimate their dosimetric influence for scanning proton therapy.

Purpose or Objective With the increase of proton therapy facilities worldwide featuring Pencil Beam Scanning (PBS) as their only treatment modality, PBS is on the way of becoming the standard for proton therapy. However, for some indications in the thoracic region PBS is not widely used due to uncertainties in the planned dose, which can be caused by combined effects of setup errors, range uncertainty, interplay effect, breathing irregularity, anatomical variations, delivery machine uncertainties, etc. By performing pre-treatment plan robustness evaluation that includes these effects, it is evident that actual delivered fractional dose at any instance is highly uncertain to predict. 4D dose accumulation is able to control some of the uncertainties that are affecting pretreatment evaluation of the plan quality. Therefore, the purpose of this proof-of-concept study is to investigate the feasibility of monitoring and assessing the quality of delivered treatment fractions throughout the treatment course. Material and Methods 4D dose accumulation is performed by utilizing (1) delivery machine log files (IBA, Belgium), (2) breathing pattern records (ANZAI, Japan) and (3) planning 4DCT scans or repeated 4D control CT scans (Siemens, Germany). Dose computation is performed in the RayStation (RaySearch, Sweden) treatment planning system (TPS). For every spot that is delivered during a particular fraction, the spot energy, position, dose (as charge) and absolute time of delivery is retrieved from the machine log file using a dedicated script. Patient’s breathing pattern is analyzed and inhale peaks are determined. Subsequently, all breathing cycles are divided in 10 phases and each phase is associated with absolute time. PBS spots are split in 10 groups according to their corresponding phase and written to 10 treatment sub-plans (DICOM), where every sub-plan corresponds to a particular phase of the 4DCT. Using scripting capabilities of the TPS, sub-plans are imported for dose computation. Eventually dose warping to the reference phase is performed to estimate the delivered fractional dose. Data sets used for the proof-of-concept were not collected during the same treatment fraction. Results By using the described method the timeline of a PBS delivery can be correlated with patient’s breathing pattern as shown in Figure 1. Computation of log based sub-plans on 4DCT results in an accumulated fractional 4D dose distribution as shown in Figure 2. Based on the exemplary case, the method allows to assess the conformity between planned and delivered doses (i.e., CTV V95 has dropped to 96.7% from nominal 100%). Conclusion The availability of a real-time 4D dose accumulation based treatment assessment tool allows to assess the quality of the delivered dose during progress of the treatment course and to take appropriate actions, as for example, plan adaptation, in cases of significant deviations. It is foreseen to extend this study for a full treatment course of a broader population of patients.

Background and purpose: To evaluate the dosimetric sparing and robustness against inter-fraction anatomical changes between photon and proton dose distributions for children with abdominal tumors.Material and methods: Volumetric modulated arc therapy (VMAT) and intensity-modulated pencil beam scanning (PBS) proton dose distributions were calculated for 20 abdominal pediatric cases (average 3, range 1-8 years). VMAT plans were based on a full-arc while PBS plans on 2-3 posterior-oblique irradiation fields. Plans were robustly optimized on a patient-specific internal target volume (ITV) using a uniform 5 mm set-up uncertainty. Additionally, for the PBS plans a +/- 3% proton range uncertainty was accounted for. Fractional dose re-calculations were performed using the planning computed tomography (CT) deformably registered to the daily cone-beam CT (CBCT) images. Fractional doses were accumulated rigidly. Planned and CBCT accumulated VMAT and PBS dose distributions were compared using dose-volume histogram (DVH) parameters.Results: Significant better sparing of the organs at risk with a maximum reduction in the mean dose of 40% was achieved with PBS. Mean ITV DVH parameters differences between planned and CBCT accumulated dose distributions were smaller than 0.5% for both VMAT and PBS. However, the ITV coverage (V-95% > 99%) was not reached for one patient for the accumulated VMAT dose distribution.Conclusions: For pediatric patients with abdominal tumors, improved dosimetric sparing was obtained with PBS compared to VMAT. In addition, PBS delivered by posterior-oblique irradiation fields demonstrated to be robust against anatomical inter-fraction changes. Compared to PBS, daily anatomical changes proved to affect the target coverage of VMAT dose distributions to a higher extent. (C) 2019 Elsevier B.V. All rights reserved.

In recent years, particle therapy has become a widely accepted form of cancer treatment and technological advances in beam delivery technology (i.e. pencil beam scanning (PBS)) have enabled the application of highly conformal dose distributions to static targets. Current research focuses on the possibilities for the treatment of mobile targets with these techniques. Of different motion mitigation methods being investigated, rescanning is perhaps the easiest to apply clinically. In general however, different PBS delivery systems exhibit a different temporal parameter space between delivery and target motions, due to the system specific beam position adjustment times (BPATs). Depending on these BPATs, dosimetric effects appearing during irradiation of moving targets vary significantly. In this work, volumetric and layered rescanning were compared for four different scenarios--a combination of fast and slow BPATs laterally (4 ms and 10 ms) and in depth (80 ms and 1 s); and nine different treatment plan arrangements for two clinical liver cases. 4D dose calculations were performed assuming regular, sinusoidal rigid motion as a worst-case motion scenario to model interplay effects. Calculations were sampled over three different starting phases resulting in a total of 432 dose distributions. It was found that layered rescanning is the method of choice for slow scanning systems, both in terms of dose homogeneity (D5-95 values are lower by up to 16% with layered rescanning) and in the estimated treatment delivery times (reduction of up to 300 s with layered rescanning). Analysis of dose homogeneity showed that layered rescanning leads to a smoother decrease in dose inhomogeneity as a function of the number of rescans than volumetric rescanning, which shows larger fluctuations. However, layered rescanning appears to be more sensitive to the starting phase. When analyzing the performance of both approaches and different scanning speeds as a function of delivery time, layered rescanning appears to be the only viable approach for slow energy changing systems, even approaching the performance of fast energy changing systems, as long as lateral scanning speeds are kept high. Similar results were found for multiple field plans and when analyzing different field directions.

Organ motion is a major problem for any dynamic radiotherapy delivery technique, and is particularly so for spot scanned proton therapy. On the other hand, the use of narrow, magnetically deflected proton pencil beams is potentially an ideal delivery technique for tracking tumour motion on-line. At PSI, our new Gantry is equipped with a Beams Eye View (BEV) imaging system which will be able to acquire 2D x-ray images in fluoroscopy mode during treatment delivery. However, besides precisely tracking motion from BEVs, it is also essential to obtain information on the 3D motion vector throughout the whole region of interest, and any sparsely acquired surrogate motion is generally not sufficient to describe the deformable behaviour of the whole volume in three dimensions. In this study, we propose a method by which 3D deformable motions can be estimated from surrogate motions obtained using this monoscopic imaging system. The method assumes that example motions over a number of breathing cycles can be acquired before treatment for each patient using 4DMRI. In this study, for each of 11 different subjects, 100 continuous breathing cycles have been extracted from extended 4DMRI studies in the liver and then subject specific motion models have been built using principle component analysis (PCA). To simulate treatment conditions, a different set of 30 continuous breathing cycles from the same subjects have then been used to generate a set of simulated 4DCT data sets (so-called 4DCT(MRI) data sets), from which time-resolved digitally reconstructed radiographs (DRRs) were calculated using the BEV geometry for three treatment fields respectively. From these DRRs, surrogate motions from fiducial markers or the diaphragm have been used as a predictor to estimate 3D motions in the liver region for each subject. The prediction results have been directly compared to the 'ground truth' motions extracted from the same 30 breath cycles of the originating 4DMRI data set. Averaged over all 11 subjects, and for three field directions, for 99% of predicted positions, median (max) error magnitudes of better than 2.63(5.67) mm can be achieved when fiducial markers was chosen as predictor. Furthermore, three single fields, 4D dose calculations have been performed as a verification tool to evaluate the prediction performance of such a model in the context of scanned proton beam therapy. These show a high similarity between plans considering either PCA predicted motion or ground truth motion, where absolute dose differences of more than 5% (V(dosediff = 5%)) occur for the worst field scenarios in only 3.61% (median) or 15.13% (max) of dose calculation points in the irradiated volume. The magnitude of these dose differences were insignificantly dependent on whether surrogate motions were tracked by monoscopic or stereoscopic imaging systems, or whether fiducial markers or diaphragm were chosen as surrogate. This study has demonstrated that on-line deformable motion reconstruction from sparse surrogate motions is feasible, even when using only a monoscopic imaging system. In addition, it has also been found that diaphragm motion can be considered as a good predictor for respiratory deformable liver motion prediction, implying that fiducial markers might not be compulsory if used in conjunction with a patient specific PCA based model.

Proton therapy with active scanning beam delivery has significant advantages compared to conventional radiotherapy. However, so far only static targets have been treated in this way, since moving targets potentially lead to interplay effects. For 4D treatment planning, information on the target motion is needed to calculate time-resolved dose distributions. In this study, respiratory liver motion has been extracted from 4D CT data using two deformable image registration algorithms. In moderately moving patient cases (mean motion range around 6 mm), the registration error was no more than 3 mm, while it reached 7 mm for larger motions (range around 13 mm). The obtained deformation fields have then been used to calculate different time-resolved 4D treatment plans. Averaged over both motion estimations, interplay effects can increase the D₅-D₉₅ value for the clinical target volume (CTV) from 8.8% in a static plan to 23.4% when motion is considered. It has also been found that the different deformable registration algorithms can provide different motion estimations despite performing similarly for the selected landmarks, which in turn can lead to differing 4D dose distributions. Especially for single-field treatments where no motion mitigation is used, a maximum (mean) dose difference (averaged over three cases) of 32.8% (2.9%) can be observed. However, this registration ambiguity-induced uncertainty can be reduced if rescanning is applied or if the treatment plan consists of multiple fields, where the maximum (mean) difference can decrease to 15.2% (0.57%). Our results indicate the necessity to interpret 4D dose distributions for scanned proton therapy with some caution or with error bars to reflect the uncertainties resulting from the motion estimation. On the other hand, rescanning has been found to be an appropriate motion mitigation technique and, furthermore, has been shown to be a robust approach to also deal with these motion estimation uncertainties.

The interest in positron emission tomography (PET) as a tool for treatment verification in proton therapy has become widespread in recent years, and several research groups worldwide are currently investigating the clinical implementation. After the first off-line investigation with a PET/CT scanner at MGH (Boston, USA), attention is now focused on an in-room PET application immediately after treatment in order to also detect shorter-lived isotopes, such as O15 and N13, minimizing isotope washout and avoiding patient repositioning errors. Clinical trials are being conducted by means of commercially available PET systems, and other tests are planned using application-dedicated tomographs. Parallel to the experimental investigation and new hardware development, great interest has been shown in the development of fast procedures to provide feedback regarding the delivered dose from reconstructed PET images. Since the thresholds of inelastic nuclear reactions leading to tissue β+ -activation fall within the energy range of 15-20 MeV, the distal activity fall-off is correlated, but not directly matched, to the distal fall-off of the dose distribution. Moreover, the physical interactions leading to β+ -activation and energy deposition are of a different nature. All these facts make it essential to further develop accurate and fast methodologies capable of predicting, on the basis of the planned dose distribution, expected PET images to be compared with actual PET measurements, thus providing clinical feedback on the correctness of the dose delivery and of the irradiation field position. The aim of this study has been to validate an analytical model and to implement and evaluate it in a fast and flexible framework able to locally predict such activity distributions directly taking the reference planning CT and planned dose as inputs. The results achieved in this study for phantoms and clinical cases highlighted the potential of the implemented method to predict expected activity distributions with great accuracy. Thus, the analytical model can be used as a powerful substitute method to the sensitive and time-consuming Monte Carlo approach.

Proton therapy is a treatment modality of increasing interest in clinical radiation oncology mostly because its dose distribution allows high dose conformality and a reduced integral dose compared to conventional radiation therapy based on X-rays and electrons. Its advantages are centered on the characteristic proton Bragg peak: a sharp maximum in the linear energy transfer of the projectile, that, if rightly positioned, makes the effect of the irradiation on the tissue more localized, thus increasing therapy efficacy and reducing side effects. The potential benefits of such physical selectivity have led to multiple studies addressed to the evaluation of uncertainty sources in the radiation therapy treatment process, from the initial treatment planning to the real patient dose delivery, thus providing insights into ways in which new imaging strategies are necessary to monitor, correct and adapt for possible errors. An interesting method to assess the geometric accuracy of the planned treatment delivery and to ensure the high quality of the proton therapy is to use Positron Emission Tomography (PET), which takes advantage of the nuclear inelastic reactions between protons and nuclei in the tissue during irradiation, producing small amounts of short-lived β+-emitting isotopes detectable soon after the irradiation. Verification of the therapy can be achieved by comparing and then quantifying differences between the PET images and the yield of the positron emitters predicted on the basis of the treatment planning system. The purpose of this study has been to extend an existing model and to implement and evaluate it in a fast and flexible framework to predict locally such activity distributions taking directly the reference planning CT and planned dose as inputs. The results achieved in this patient study highlighted the potential of the implemented analytical model, to monitor the dose delivery, proposing as a powerful substitution method to the sensitive and time-consuming Monte Carlo (MC) approach for the calculation of expected activity distributions.

A recent clinical pilot study demonstrated the feasibility of offline PET/CT range verification for proton therapy treatments. In vivo PET measurements are challenged by blood perfusion, variations of tissue compositions, patient motion and image co-registration uncertainties. Besides these biological and treatment specific factors, the accuracy of the method is constrained by the underlying physical processes. This phantom study distinguishes physical factors from other factors, assessing the reproducibility, consistency and sensitivity of the PET/CT range verification method. A spread-out Bragg-peak (SOBP) proton field was delivered to a phantom consisting of poly-methyl methacrylate (PMMA), lung and bone equivalent material slabs. PET data were acquired in listmode at a commercial PET/CT scanner available within 10 min walking distance from the proton therapy unit. The measured PET activity distributions were compared to simulations of the PET signal based on Geant4 and FLUKA Monte Carlo (MC) codes. To test the reproducibility of the measured PET signal, data from two independent measurements at the same geometrical position in the phantom were compared. Furthermore, activation depth profiles within identical material arrangements but at different positions within the irradiation field were compared to test the consistency of the measured PET signal. Finally, activation depth profiles through air/lung, air/bone and lung/bone interfaces parallel as well as at 6 degrees to the beam direction were studied to investigate the sensitivity of the PET/CT range verification method. The reproducibility and the consistency of the measured PET signal were found to be of the same order of magnitude. They determine the physical accuracy of the PET measurement to be about 1 mm. However, range discrepancies up to 2.6 mm between two measurements and range variations up to 2.6 mm within one measurement were found at the beam edge and at the edge of the field of view (FOV) of the PET scanner. PET/CT range verification was found to be able to detect small range modifications in the presence of complex tissue inhomogeneities. This study indicates the physical potential of the PET/CT verification method to detect the full-range characteristic of the delivered dose in the patient.

Ion beams offer the possibility of improved conformation of the dose delivered to the tumor with better sparing of surrounding tissue and critical structures in comparison to conventional photon and electron external radiation treatment modalities. Full clinical exploitation of this advantage can benefit from in vivo confirmation of the actual beam delivery and, in particular, of the ion range in the patient. During irradiation, positron emitters like 15 O (half-life T 1/2 ≈2 min) and 11 C ( T 1/2 ≈20 min) are formed in nuclear interactions between the ions and the tissue. Detection of this transient radioactivity via positron emission tomography (PET) and comparison with the expectation based on the prescribed beam application may serve as an in vivo, non-invasive range validation method of the whole treatment planning and delivery chain. For technical implementation, PET imaging during irradiation (in-beam) requires the development of customized, limited angle detectors with data acquisition synchronized with the beam delivery. Alternatively, commercial PET or PET/CT scanners in close proximity to the treatment site enable detection of the residual activation from long-lived emitters shortly after treatment (offline). This paper reviews two clinical examples using a dedicated in-beam PET scanner for verification of carbon ion therapy at GSI Darmstadt, Germany, as well as a commercial offline PET/CT tomograph for post-radiation imaging of proton treatments at Massachusetts General Hospital, Boston, USA. Challenges as well as pros and cons of the two imaging approaches in dependence of the different ion type and beam delivery system are discussed.