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Objective . Image-guided and adaptive proton therapy rely on daily CBCT or CT imaging, which increases radiation dose and radiation-induced cancer risk. Online adaptation however also reduces setup uncertainty, and the additional risk might be compensated by reducing the setup robustness margin. This work developed a framework to investigate how much this robustness margin should be reduced to offset the secondary cancer risk from additional imaging dose and applied it to proton therapy for head-and-neck cancer. Approach . For five patients with head-and-neck cancer, voxel-wise CT and CBCT imaging doses were estimated with Monte Carlo radiation transport simulations, calibrated with air and PMMA phantom measurements. The total dose of several image-guided and adaptive treatments protocols was calculated by summing the planning CT dose, daily and weekly CBCT or CT dose, and therapy dose, robustly optimized with setup margins between 0 and 4 mm. These were compared to a reference protocol with 4 mm setup margin without daily imaging. All plans further used 3% range robustness. Organ-wise excess absolute risk (EAR) of cancer was calculated with three models to determine at which setup margin the total EAR of image-guided and adaptive treatment protocols was equal to the total EAR of the reference. Results . The difference between the simulated and measured CT and CBCT doses was within 10%. Using the Monte Carlo models, we found that a 1 mm setup margin reduction was sufficient for most patients, treatment protocols, and cancer risk models to compensate the additional risk imposed by daily and weekly imaging. For some protocols, even a smaller reduction sufficed, depending on the imaging frequency and type. The risk reduction by reducing the margin was mainly due to reducing the risk for carcinomas in the brain and, for some patients, the oral cavity. Significance . Our framework allows to compare an increased imaging dose with the reduced treatment dose from margin reductions in terms of radiation-induced cancer risk. It is extendable to different treatment sites, modalities, and imaging protocols, in clinic-specific or even patient-specific assessments., (Creative Commons Attribution license.)

Objective. This study presents the first clinical implementation of an efficient online daily adaptive proton therapy workflow (DAPT). Approach. The DAPT workflow includes a pre-treatment phase, where a template and a fallback plan are optimized on the planning computed tomography (CT). In the online phase , the adapted plan is re-optimized on daily images from an in-room CT. Daily structures are rigidly propagated from the planning CT. Automated Quality Assurance (QA) involves geometric, sanity checks and an independent dose calculation from the machine files. Differences from the template plan are analyzed field-by-field, and clinical plan is assessed by reviewing the achieved clinical goals using a traffic light protocol. If the daily adapted plan fails any QA or clinical goals, the fallback plan is used. In the offline phase the delivered dose is recalculated from log-files onto the daily CT, and a gamma analysis is performed (3%/3 mm). The DAPT workflow has been applied to selected adult patients treated in rigid anatomy for the last serie of the treatment between October 2023 and April 2024. Main Results. DAPT treatment sessions averaged around 23 min [range: 15-30 min] and did not exceed the typical 30 minute time slot. Treatment adaptation, including QA and clinical plan assessment, averaged just under 7 min [range: 3:30-16 min] per fraction. All plans passed the online QAs steps. In the offline phase a good agreement with the log-files reconstructed dose was achieved (minimum gamma pass rate of 97.5%). The online adapted plan was delivered for >85% of the fractions. In 92% of total fractions, adapted plans exhibited improved individual dose metrics to the targets and/or organs at risk. Significance. This study demonstrates the successful implementation of an online daily DAPT workflow. Notably, the duration of a DAPT session did not exceed the time slot typically allocated for non-DAPT treatment. As far as we are aware, this is a first clinical implementation of daily online adaptive proton therapy., (Creative Commons Attribution license.)

Introduction. This study aims to assess the effective lateral margin requirements for target coverage in ocular proton therapy (OPT), considering the unique challenges posed by eye motion and hypofractionation. It specifically addresses the previously unaccounted-for uncertainty contribution of intra-fractional motion, in conjunction with setup uncertainties, on dosimetric determination of lateral margin requirements. Method. The methodology integrates dose calculations from the in-house developed treatment planning system OCULARIS with measured intra-fractional motion, patient models from EyePlan and Monte Carlo (MC) sampling of setup uncertainties. The study is conducted on 16 uveal melanoma patients previously treated in the OPTIS2 treatment room at the Paul Scherrer Institute (PSI). Result. The retrospective simulation analysis highlights a significant impact of non-systematic factors on lateral margin requirements in OPT. Simulations indicate that reducing the 2.5 mm clinical lateral margin, represented by a 2.1 mm margin in this work, would have resulted in inadequate target coverage for two patients, revealing a greater impact of non-systematic factors on lateral margin requirements. Conclusions. This work characterizes intra-fractional motion in 16 OPT patients and identifies limitations of clinical margin selection protocols for OPT applications. A novel framework was introduced to assess margin sufficiency for target coverage. The findings suggest that prior research underestimated non-systematic factors and overestimated systematic contributions to lateral margin components. This re-evaluation highlights the critical need to prioritize the management of non-systematic uncertainty contributions in OPT., (Creative Commons Attribution license.)

There is a rising interest in developing and utilizing arc delivery techniques with charged particle beams, e.g., proton, carbon or other ions, for clinical implementation. In this work, perspectives from the European Society for Radiotherapy and Oncology (ESTRO) 2022 physics workshop on particle arc therapy are reported. This outlook provides an outline and prospective vision for the path forward to clinically deliverable proton, carbon, and other ion arc treatments. Through the collaboration among industry, academic, and clinical research and development, the scientific landscape and outlook for particle arc therapy are presented here to help our community understand the physics, radiobiology, and clinical principles. The work is presented in three main sections: (i) treatment planning, (ii) treatment delivery, and (iii) clinical outlook., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Sophie Wuyckens is funded by the Walloon Region as part of the Arc Proton Therapy convention (Pôles Mecatech et Biowin). Liu Hong and Guillaume Jansens are employed by ION BEAM APPLICATIONS SA (IBA Ltd). Research by Bas De Jong and Stefan Both is partly funded byION BEAM APPLICATIONS SA (IBA Ltd). Thomas Mackie is on the Board and has a financialinterest(stocks) and salary from Leo Cancer Care.Erik Engwall is employed by RaySearch. Martin Soukup is employed by Elekta. Xuanfeng Ding and Xiaoqiang Li have patents related to the particle arc therapy and it has been licensed to IBA. Xuanfeng Ding received honorium from IBA and Elekta’s speaker Bureau and the research project on proton arc therapy is in part supported by IBA and Elekta., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

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 mm 2 proton 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., (Creative Commons Attribution license.)

Background and Purpose: Deep learning techniques excel in MR-based CT synthesis, but missing uncertainty prediction limits its clinical use in proton therapy. We developed an uncertainty-aware framework and evaluated its efficiency in robust proton planning., Materials and Methods: A conditional generative-adversarial network was trained on 64 brain tumour patients with paired MR-CT images to generate synthetic CTs (sCT) from combined T1-T2 MRs of three orthogonal planes. A Bayesian neural network predicts Laplacian distributions for all voxels with parameters (μ, b). A robust proton plan was optimized using three sCTs of μ and μ±b. The dosimetric differences between the plan from sCT (sPlan) and the recalculated plan (rPlan) on planning CT (pCT) were quantified for each patient. The uncertainty-aware robust plan was compared to conventional robust (global ± 3 %) and non-robust plans., Results: In 8-fold cross-validation, sCT-pCT image differences (Mean-Absolute-Error) were 80.84 ± 9.84HU (body), 35.78 ± 6.07HU (soft tissues) and 221.88 ± 31.69HU (bones), with Dice scores of 90.33 ± 2.43 %, 95.13 ± 0.80 %, and 85.53 ± 4.16 %, respectively. The uncertainty distribution positively correlated with absolute prediction error (Correlation Coefficient: 0.62 ± 0.01). The uncertainty-conditioned robust optimisation improved the rPlan-sPlan agreement, e.g., D95 absolute difference (CTV) was 1.10 ± 1.24 % compared to conventional (1.64 ± 2.71 %) and non-robust (2.08 ± 2.96 %) optimisation. This trend was consistent across all target and organs-at-risk indexes., Conclusion: The enhanced framework incorporates 3D uncertainty prediction and generates high-quality sCTs from MR images. The framework also facilitates conditioned robust optimisation, bolstering proton plan robustness against network prediction errors. The innovative feature of uncertainty visualisation and robust analyses contribute to evaluating sCT clinical utility for individual patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objective. Anatomical and daily set-up uncertainties impede high precision delivery of proton therapy. With online adaptation, the daily plan is reoptimized on an image taken shortly before the treatment, reducing these uncertainties and, hence, allowing a more accurate delivery. This reoptimization requires target and organs-at-risk (OAR) contours on the daily image, which need to be delineated automatically since manual contouring is too slow. Whereas multiple methods for autocontouring exist, none of them are fully accurate, which affects the daily dose. This work aims to quantify the magnitude of this dosimetric effect for four contouring techniques. Approach. Plans reoptimized on automatic contours are compared with plans reoptimized on manual contours. The methods include rigid and deformable registration (DIR), deep-learning based segmentation and patient-specific segmentation. Main results. It was found that independently of the contouring method, the dosimetric influence of using automatic OAR contours is small (<5% prescribed dose in most cases), with DIR yielding the best results. Contrarily, the dosimetric effect of using the automatic target contour was larger (>5% prescribed dose in most cases), indicating that manual verification of that contour remains necessary. However, when compared to non-adaptive therapy, the dose differences caused by automatically contouring the target were small and target coverage was improved, especially for DIR. Significance. The results show that manual adjustment of OARs is rarely necessary and that several autocontouring techniques are directly usable. Contrarily, manual adjustment of the target is important. This allows prioritizing tasks during time-critical online adaptive proton therapy and therefore supports its further clinical implementation., (Creative Commons Attribution license.)

Background and Purpose: Studies have shown large variations in stopping-power ratio (SPR) prediction from computed tomography (CT) across European proton centres. To standardise this process, a step-by-step guide on specifying a Hounsfield look-up table (HLUT) is presented here., Materials and Methods: The HLUT specification process is divided into six steps: Phantom setup, CT acquisition, CT number extraction, SPR determination, HLUT specification, and HLUT validation. Appropriate CT phantoms have a head- and body-sized part, with tissue-equivalent inserts in regard to X-ray and proton interactions. CT numbers are extracted from a region-of-interest covering the inner 70% of each insert in-plane and several axial CT slices in scan direction. For optimal HLUT specification, the SPR of phantom inserts is measured in a proton beam and the SPR of tabulated human tissues is computed stoichiometrically at 100 MeV. Including both phantom inserts and tabulated human tissues increases HLUT stability. Piecewise linear regressions are performed between CT numbers and SPRs for four tissue groups (lung, adipose, soft tissue, and bone) and then connected with straight lines. Finally, a thorough but simple validation is performed., Results: The best practices and individual challenges are explained comprehensively for each step. A well-defined strategy for specifying the connection points between the individual line segments of the HLUT is presented. The guide was tested exemplarily on three CT scanners from different vendors, proving its feasibility., Conclusion: The presented step-by-step guide for CT-based HLUT specification with recommendations and examples can contribute to reduce inter-centre variations in SPR prediction., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective. 4D dose reconstruction in proton therapy with pencil beam scanning (PBS) typically relies on a single pre-treatment 4DCT (p4DCT). However, breathing motion during the fractionated treatment can vary considerably in both amplitude and frequency. We present a novel 4D dose reconstruction method combining delivery log files with patient-specific motion models, to account for the dosimetric effect of intra- and inter-fractional breathing variability. Approach. Correlation between an external breathing surrogate and anatomical deformations of the p4DCT is established using principal component analysis. Using motion trajectories of a surface marker acquired during the dose delivery by an optical tracking system, deformable motion fields are retrospectively reconstructed and used to generate time-resolved synthetic 4DCTs ('5DCTs') by warping a reference CT. For three abdominal/thoracic patients, treated with respiratory gating and rescanning, example fraction doses were reconstructed using the resulting 5DCTs and delivery log files. The motion model was validated beforehand using leave-one-out cross-validation (LOOCV) with subsequent 4D dose evaluations. Moreover, besides fractional motion, fractional anatomical changes were incorporated as proof of concept. Main results. For motion model validation, the comparison of 4D dose distributions for the original 4DCT and predicted LOOCV resulted in 3%/3 mm gamma pass rates above 96.2%. Prospective gating simulations on the p4DCT can overestimate the target dose coverage V 95% by up to 2.1% compared to 4D dose reconstruction based on observed surrogate trajectories. Nevertheless, for the studied clinical cases treated with respiratory-gating and rescanning, an acceptable target coverage was maintained with V 95% remaining above 98.8% for all studied fractions. For these gated treatments, larger dosimetric differences occurred due to CT changes than due to breathing variations. Significance. To gain a better estimate of the delivered dose, a retrospective 4D dose reconstruction workflow based on motion data acquired during PBS proton treatments was implemented and validated, thus considering both intra- and inter-fractional motion and anatomy changes., (Creative Commons Attribution license.)

Objective. 4D dose calculation (4DDC) for pencil beam scanned (PBS) proton therapy is typically based on phase-sorting of individual pencil beams onto phases of a single breathing cycle 4DCT. Understanding the dosimetric limitations and uncertainties of this approach is essential, especially for the realistic treatment scenario with irregular free breathing motion. Approach. For three liver and three lung cancer patient CTs, the deformable multi-cycle motion from 4DMRIs was used to generate six synthetic 4DCT(MRI)s, providing irregular motion (11/15 cycles for liver/lung; tumor amplitudes ∼4-18 mm). 4DDCs for two-field plans were performed, with the temporal resolution of the pencil beam delivery (4-200 ms) or with 8 phases per breathing cycle (500-1000 ms). For the phase-sorting approach, the tumor center motion was used to determine the phase assignment of each spot. The dose was calculated either using the full free breathing motion or individually repeating each single cycle. Additionally, the use of an irregular surrogate signal prior to 4DDC on a repeated cycle was simulated. The CTV volume with absolute dose differences >5% ( V dosediff>5% ) and differences in CTV V 95% and D Compared to 4DDC considering the full free breathing motion with finer spot-wise temporal resolution, 4DDC based on a repeated single 4DCT resulted in 5% - D up to 24%. However, surrogate based phase-sorting prior to 4DDC on a single cycle 4DCT, reduced the average 95% compared to the free breathing scenario were evaluated. Main results. Compared to 4DDC considering the full free breathing motion with finer spot-wise temporal resolution, 4DDC based on a repeated single 4DCT resulted in V dosediff>5% of on average 34%, which resulted in an overestimation of V It is important to properly consider motion irregularity in 4D dosimetric evaluations of PBS proton treatments, as 4DDC based on a single 4DCT can lead to an underestimation of motion effects.95% up to 24%. However, surrogate based phase-sorting prior to 4DDC on a single cycle 4DCT, reduced the average V dosediff>5% to 16% (overestimation V 95% up to 19%). The 4DDC results were greatly influenced by the choice of reference cycle ( V dosediff>5% up to 55%) and differences due to temporal resolution were much smaller ( V dosediff>5% up to 10%). Significance. It is important to properly consider motion irregularity in 4D dosimetric evaluations of PBS proton treatments, as 4DDC based on a single 4DCT can lead to an underestimation of motion effects., (Creative Commons Attribution license.)

Introduction: Ocular biometry in Ocular Proton Therapy (OPT) currently relies on a generic geometrical eye model built by referencing surgically implanted markers. An alternative approach based on image fusion of volumetric Magnetic Resonance Imaging (MRI) and panoramic fundus photography was investigated., Materials and Methods: Eighteen non-consecutive uveal melanoma (UM) patients, who consented for an MRI and had their tumour base visible on panoramic fundus photography, were included in this comparative analysis. Through generating digitally-reconstructed projections from MRI images using the Lambert azimuthal equal-area projection, 2D-3D image fusion between fundus photography and an eye model delineated on MRI scans was achieved and allowed for a novel definition of the target base (MRI + F CTV ). MRI + F CTV was compared with MRI-only delineation (MRI GTV ) and the conventional (EyePlan) target definition (EP CTV )., Results: The combined use of fundus photography and MRI to define tumour volumes reduced the average discrepancies by almost 65% with respect to the MRI only tumour definitions when comparing with the conventionally planned EP CTV . With the proposed method, shallow sub-retinal tumour infiltration, otherwise invisible on MRI, can be included in the target volume definition. Moreover, a novel definition of the fovea location improves the accuracy and personalisation of the 3D eye model., Conclusion: MRI and fundus image fusion overcomes some of the limitations of ophthalmological MRI for tumour volume definition in OPT. This novel eye tumour modelling method might improve treatment planning personalisation, allowing to better anticipate which patients could benefit from prophylactic treatment protocols for radiation induced maculopathy., Competing Interests: Declaration of Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: Experimental assessment of inter-centre variation and absolute accuracy of stopping-power-ratio (SPR) prediction within 17 particle therapy centres of the European Particle Therapy Network., Material and Methods: A head and body phantom with seventeen tissue-equivalent materials were scanned consecutively at the participating centres using their individual clinical CT scan protocol and translated into SPR with their in-house CT-number-to-SPR conversion. Inter-centre variation and absolute accuracy in SPR prediction were quantified for three tissue groups: lung, soft tissues and bones. The integral effect on range prediction for typical clinical beams traversing different tissues was determined for representative beam paths for the treatment of primary brain tumours as well as lung and prostate cancer., Results: An inter-centre variation in SPR prediction (2σ) of 8.7%, 6.3% and 1.5% relative to water was determined for bone, lung and soft-tissue surrogates in the head setup, respectively. Slightly smaller variations were observed in the body phantom (6.2%, 3.1%, 1.3%). This translated into inter-centre variation of integral range prediction (2σ) of 2.9%, 2.6% and 1.3% for typical beam paths of prostate-, lung- and primary brain-tumour treatments, respectively. The absolute error in range exceeded 2% in every fourth participating centre. The consideration of beam hardening and the execution of an independent HLUT validation had a positive effect, on average., Conclusion: The large inter-centre variations in SPR and range prediction justify the currently clinically used margins accounting for range uncertainty, which are of the same magnitude as the inter-centre variation. This study underlines the necessity of higher standardisation in CT-number-to-SPR conversion., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Recently, proton therapy treatments delivered with ultra-high dose rates have been of high scientific interest, and the Faraday cup (FC) is a promising dosimetry tool for such experiments. Different institutes use different FC designs, and either a high voltage guard ring, or the combination of an electric and a magnetic field is employed to minimize the effect of secondary electrons. The authors first investigate these different approaches for beam energies of 70, 150, 230 and 250 MeV, magnetic fields between 0 and 24 mT and voltages between -1000 and 1000 V. When applying a magnetic field, the measured signal is independent of the guard ring voltage, indicating that this setting minimizes the effect of secondary electrons on the reading of the FC. Without magnetic field, applying the negative voltage however decreases the signal by an energy dependent factor up to 1.3% for the lowest energy tested and 0.4% for the highest energy, showing an energy dependent response. Next, the study demonstrates the application of the FC up to ultra-high dose rates. FC measurements with cyclotron currents up to 800 nA (dose rates of up to approximately 1000 Gy s -1 ) show that the FC is indeed dose rate independent. Then, the FC is applied to commission the primary gantry monitor for high dose rates. Finally, short-term reproducibility of the monitor calibration is quantified within single days, showing a standard deviation of 0.1% (one sigma). In conclusion, the FC is a promising, dose rate independent tool for dosimetry up to ultra-high dose rates. Caution is however necessary when using a FC without magnetic field, as a guard ring with high voltage alone can introduce an energy dependent signal offset., (© 2021 Institute of Physics and Engineering in Medicine.)

Arc-therapy is a dose delivery technique regularly applied in photon radiation therapy, and is currently subject of great interest for proton therapy as well. In this technique, proton beams are aimed at a tumor from different continuous ranges of incident directions (so called 'arcs'). This technique can potentially yield a better dose conformity around the tumor and a very low dose in the surrounding healthy tissue. Currently, proton-arc therapy is performed by rotating a proton gantry around the patient, adapting the normally used dose-delivery method to the arc-specific motion of the gantry. Here we present first results from a feasibility study of the conceptual design of a new static fast beam delivery device/system for proton-arc therapy, which could be used instead of a gantry. In this novel concept, the incident angle of proton beams can be set rapidly by only changing field strengths of small magnets. This device eliminates the motion of the heavy gantry and related hardware. Therefore, a reduction of the total treatment time is expected. In the feasibility study presented here, we concentrate on the concept of the beam transport. Based on several simple, but realistic assumptions and approximations, proton tracking calculations were performed in a 3D magnetic field map, to calculate the beam transport in this device and to investigate and address several beam-optics challenges. We propose and simulate corresponding solutions and discuss their outcomes. To enable the implementation of some usually applied techniques in proton therapy, such as pencil beam scanning, energy modulation and beam shaping, we present and discuss our proposals. Here we present the concept of a new idea to perform fast proton arc-scanning and we report on first results of a feasibility study. Based on these results, we propose several options and next steps in the design.

Introduction: Ocular proton therapy (OPT) for the treatment of uveal melanoma has a long and remarkably successful history. This is despite that, for the majority of patients treated, the definition of the eye anatomy is based on a simplified geometrical model embedded in the treatment planning system EyePlan. In this study, differences in anatomical and tumor structures from EyePlan, and those based on 1.5T magnetic resonance imaging (MRI) are assessed., Materials and Methods: Thirty-three uveal melanoma patients treated with OPT at our institution were subject to eye MRI. The target volumes were manually delineated on those images by two radiation oncologists. The resulting volumes were geometrically compared to the clinical standard. In addition, the dosimetric impact of using different models for treatment planning were evaluated., Results: Two patients (6%) presented lesions too small to be visible on MRI. Target volumes identified on MRI scans were on average smaller than EyePlan with discrepancies arising mostly from the definition of the tumor base. Clip-to-tumor base distances measured on MRI models exhibited higher discrepancy to ophthalmological measurements than EyePlan. For 53% of cases, treatment plans optimized for lesions identified on MRI only, failed to achieve sufficient target coverage for EyePlan volumes., Discussion: The analysis has shown that 1.5T MRI might be more susceptible to misses of flat tumor extension of the clinical target volume than the current clinical standard. Thus, a proper integration of ancillary imaging modalities, leading to a better characterization of the full lesion, is required., (Copyright © 2020 Elsevier B.V. All rights reserved.)

High-density materials, such as titanium, used for spinal stabilization, introduces several critical issues in proton therapy (PT). Artefacts affect both contouring and dose calculation. Subsequently, artefacts need to be corrected which is a time-consuming process. Besides, titanium causes proton interactions that are unaccounted for in dose calculation. The result is a suboptimal treatment plan, and indeed decreased local controls have been reported for these patients. Carbon fiber reinforced polyetheretherketone (CFR-PEEK) implant material, which is of low density, potentially solves these issues. For this study, we designed a unique phantom to compare the effects of titanium and CFR-PEEK implants in PT. The phantom contains four interchangeable spinal inserts representing a native spine, and three different spinal stabilizations consisting of titanium only, CFR-PEEK only, and a combination of titanium and CFR-PEEK. All phantom scenarios received the standard treatment workup. Two planning approaches were investigated: a single field plan and a multi-field optimized plan with spinal cord sparing. For both plans we analyzed the following aspects: total volume of artefacts on CT images, time required for artefact correction, effect of planning CT correction on dose calculation, plan robustness to range and set up uncertainties, and finally the discrepancy between the calculated dose and the delivered dose with Gafchromic® film. The CFR-PEEK implant had a 90% reduction of artefacts on CT images and subsequently severely reduced the time for artefact correction with respect to the titanium-only implant. Furthermore, the CFR-PEEK as opposed to titanium did not influence the robustness of the plan. Finally, the titanium implants led to hardware-related discrepancies between the planned and the measured dose while the CFR-PEEK implant showed good agreement. As opposed to titanium, CFR-PEEK has none to minor effects on PT. The use of CFR-PEEK is expected to optimize treatment and possibly improve outcomes for patients that require spinal stabilization.

Background: Despite combined modality treatment involving surgery and radiotherapy, a relevant proportion of skull-base chordoma and chondrosarcoma patients develop a local recurrence (LR). This study aims to analyze patterns of recurrence and correlate LR with a detailed dosimetric analysis., Methods: 222 patients were treated with proton radiotherapy for chordoma (n = 151) and chondrosarcoma (n = 71) at the PSI between 1998 and 2012. All patients underwent surgery, followed by pencil-beam scanning proton therapy to a mean dose of 72.5 ± 2.2Gy RBE . A retrospective patterns of recurrence analysis was performed: LR were contoured on follow-up MRI, registered with planning-imaging and the overlap with initial target structures (GTV, PTV high-dose , PTV low-dose ) was calculated. DVH parameters of planning structures and recurrences were calculated and correlated with LR using univariate and multivariate cox regression., Results: After a median follow-up of 50 months, 35 (16%) LR were observed. Follow-up MRI imaging was available for 27 (77%) of these recurring patients. Only one (3.7%) recurrence was located completely outside the initial PTV (surgical pathway recurrence). The mean proportions of LR covered by the initial target structures were 48% (range 0-86%) for the GTV, 70% (range 0-100%) for PTV high and 83% (range 0-100%) for PTV low . In the univariate analysis, the following DVH parameters were significantly associated with LR: GTV(V < 66Gy RBE , p = 0.01), GTV(volume, p = 0.02), PTV high (max, p = 0.02), PTV high (V < 66Gy RBE , p = 0.03), PTV high (V < 59Gy RBE , p = 0.02), PTV high (volume, p = 0.01) and GTV(D95, p = 0.05). In the multivariate analysis, only histology (chordoma vs. chondrosarcoma, p = 0.01), PTV high (volume, p = 0.05) and GTV(V < 66Gy RBE , p = 0.02) were independent prognostic factors for LR., Conclusion: This study identified DVH parameters, which are associated with the risk of local recurrence after proton therapy using pencil-beam scanning for patients with skull-base chordoma and chondrosarcoma.

In daily adaptive proton therapy (DAPT), the treatment plan is re-optimized on a daily basis. It is a straightforward idea to incorporate information from the previous deliveries during the optimization to refine this daily proton delivery. A feedback signal was used to correct for delivery errors and errors from an inaccurate dose calculation used for plan optimization. This feedback signal consisted of a dose distribution calculated with a Monte Carlo algorithm and was based on the spot delivery information from the previous deliveries in the form of log-files. We therefore called the method Update On Yesterday's Dose (UYD). The UYD method was first tested with a simulated DAPT treatment and second with dose measurements using an anthropomorphic phantom. For both, the simulations and the measurements, a better agreement between the delivered and the intended dose distribution could be observed using UYD. Gamma pass rates (1%/1 mm) increased from around 75% to above 90%, when applying the closed-loop correction for the simulations, as well as the measurements. For a DAPT treatment, positioning errors or anatomical changes are incorporated during the optimization and therefore are less dominant in the overall dose uncertainty. Hence, the relevance of algorithm or delivery machine errors even increases compared to standard therapy. The closed-loop process described here is a method to correct for these errors, and potentially further improve DAPT.

Aims: The outcome of chordoma patients with local or distant failure after proton therapy is not well established. We assessed the disease-specific (DSS) and overall survival of patients recurring after proton therapy and evaluated the prognostic factors affecting DSS., Materials and Methods: A retrospective analysis was carried out of 71 recurring skull base (n = 36) and extracranial (n = 35) chordoma patients who received adjuvant proton therapy at initial presentation (n = 42; 59%) or after post-surgical recurrence (n = 29; 41%). The median proton therapy dose delivered was 74 GyRBE (range 62-76). The mean age was 55 ± 14.2 years and the male/female ratio was about one., Results: The median time to first failure after proton therapy was 30.8 months (range 3-152). Most patients (n = 59; 83%) presented with locoregional failure only. There were only 12 (17%) distant failures, either with (n = 5) or without (n = 7) synchronous local failure. Eight patients (11%) received no salvage therapy for their treatment failure after proton therapy. Salvage treatments after proton therapy failure included surgery, systemic therapy and additional radiotherapy in 45 (63%), 20 (28%) and eight (11%) patients, respectively. Fifty-three patients (75%) died, most often from disease progression (47 of 53 patients; 89%). The median DSS and overall survival after failure was 3.9 (95% confidence interval 3.1-5.1) and 3.4 (95% confidence interval 2.5-4.4) years, respectively. On multivariate analysis, extracranial location and late failure (≥31 months after proton therapy) were independent favourable prognostic factors for DSS., Conclusion: The survival of chordoma patients after a treatment failure following proton therapy is poor, particularly for patients who relapse early or recur in the skull base. Although salvage treatment is administered to most patients with uncontrolled disease, they will ultimately die as a result of disease progression in most cases., (Copyright © 2020 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Aims: More efforts are required to minimise late radiation side-effects for paediatric patients. Pencil beam scanning proton beam therapy (PBS-PT) allows increased sparing of normal tissues while maintaining conformality, but is prone to dose degradation from interplay effects due to respiratory motion. We report our clinical experience of motion mitigation with volumetric rescanning (vRSC) and outcomes of children with neuroblastoma., Materials and Methods: Nineteen patients with high-risk (n = 16) and intermediate-risk (n = 3) neuroblastoma received PBS-PT. The median age at PBS-PT was 3.5 years (range 1.2-8.6) and the median PBS-PT dose was 21 Gy (relative biological effectiveness). Most children (89%) were treated under general anaesthesia. Seven patients (37%) underwent four-dimensional computed tomography for motion assessment and were treated with vRSC for motion mitigation., Results: The mean result of maximum organ motion was 2.7 mm (cranial-caudal), 1.2 mm (left-right), 1.0 mm (anterior-posterior). Four anaesthetised children (21%) showing <5 mm motion had four-dimensional dose calculations (4DDC) to guide the number of vRSC. The mean deterioration or improvement to the planning target volume covered by 95% of the prescribed dose compared with static three-dimensional plans were: 4DDC no vRSC, -0.6%; 2 vRSC, +0.3%; 4 vRSC, +0.3%; and 8 vRSC, +0.1%. With a median follow-up of 14.9 months (range 2.7-49.0) there were no local recurrences. The 2-year overall survival was 94% and distant progression-free survival was 76%. Acute grade 2-4 toxicity was 11%. During the limited follow-up time, no late toxicities were observed., Conclusions: The early outcomes of mainly high-risk patients with neuroblastoma treated with PBS-PT were excellent. With a subset of our cohort undergoing PBS-PT with vRSC we have shown that it is logistically feasible and safe. The clinical relevance of vRSC is debatable in anaesthetised children with small pre-PBS-PT motion of <5 mm., (Copyright © 2020 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Purpose: Ocular proton therapy is an effective therapeutic option for patients affected with uveal melanomas. An optical eye-tracking system (ETS) aiming at noninvasive motion monitoring was developed and tested in a clinical scenario., Materials and Methods: The ETS estimates eye position and orientation at 25 frames per second using the three-dimensional position of pupil and cornea curvature centers identified, in the treatment room, through stereoscopic optical imaging and infrared eye illumination. Its capabilities for automatic detection of eye motion were retrospectively evaluated on 60 treatment fractions. Then, the ETS performance was benchmarked against the clinical standard based on visual control and manual beam interruption., Results: Eye-tracking system detected eye position successfully in 97% of all available frames. Eye-tracking system-based eye monitoring during therapy guarantees quicker response to involuntary eye motions than manual beam interruptions and avoids unnecessary beam interruptions., Conclusions: Eye-tracking system shows promise for on-line monitoring of eye motion. Its introduction in the clinical workflow will guarantee a swifter treatment course for the patient and the clinical personnel., (© 2020 American Association of Physicists in Medicine.)

It is recognized that the use of a single plan calculated on an image acquired some time before the treatment is generally insufficient to accurately represent the daily dose to the target and to the organs at risk. This is particularly true for protons, due to the physical finite range. Although this characteristic enables the generation of steep dose gradients, which is essential for highly conformal radiotherapy, it also tightens the dependency of the delivered dose to the range accuracy. In particular, the use of an outdated patient anatomy is one of the most significant sources of range inaccuracy, thus affecting the quality of the planned dose distribution. A plan should be ideally adapted as soon as anatomical variations occur, ideally online. In this review, we describe in detail the different steps of the adaptive workflow and discuss the challenges and corresponding state-of-the art developments in particular for an online adaptive strategy.

The literature is controversial about the scan direction dependency of interplay effects in pencil beam scanning (PBS) treatment of moving targets. A directional effect is supported by many simulation studies, whereas the experimental data are mostly limited to simple geometries, not reflecting realistically clinical treatment plans. We have compared increasingly complex treatment fields, from a homogeneous single energy layer to a more modulated lung plan, under identical experimental settings, seeking evidence for differences in motion mitigation due to the selection of primary scanning direction. In total, 120 experimental samples were taken, combining two primary scan directions and three rescanning regimes with different motion scenarios. 4D dose distributions were measured in water with a moving ionisation chamber array and compared to those of a stationary delivery using 2D gamma analysis. Each plan has been verified twice for the same rescanning regime and motion scenario, changing the meandering direction in between to scan perpendicularly to, or along, the target motion. Additionally, machine log files of the lung plan, together with 4DCT data, were used to calculate the dose distribution that such deliveries would have produced in the patient. The primary meandering direction has a clear influence on measured dose distributions when considering a single energy layer. Introducing spot weight modulation and multiple energy layers however, makes the dynamic of interplay more complex and difficult to predict. Overall, gamma (3%/3 mm) differences between scanning along or orthogonal to the target motion follow a normal distribution [Formula: see text] when considering multiple motion scenarios and rescanning regimes. Nevertheless, data spread [Formula: see text] is significant enough such that, for individual experiments and set-ups, a dependency may be observed even if this is not a general result. Patient reconstructed doses follow the same trend, the two primary scan directions producing statistically insignificant differences in dose distributions in terms of conformity or homogeneity. Except for extremely simplified cases of mono-energetic and homogeneous treatment fields, the interplay effect has been found to be only marginally influenced by the choice of the primary scanning direction.

For pencil beam scanned (PBS) proton therapy, analytical dose calculation engines are still typically used for the optimisation process, and often for the final evaluation of the plan. Recently however, the suitability of analytical calculations for planning PBS treatments has been questioned. Conceptually, the two main approaches for these analytical dose calculations are the ray-casting (RC) and the pencil-beam (PB) method. In this study, we compare dose distributions and dosimetric indices, calculated on both the clinical dose calculation grid and as a function of dose grid resolution, to Monte Carlo (MC) calculations. The analysis is done using a comprehensive set of clinical plans which represent a wide choice of treatment sites. When analysing dose difference histograms for relative treatment plans, pencil beam calculations with double grid resolution perform best, with on average 97.7%/91.9% (RC), 97.9%/92.7% (RC, double grid resolution), 97.6%/91.0% (PB) and 98.6%/94.0% (PB, double grid resolution) of voxels agreeing within  ±5%/±  3% between the analytical and the MC calculations. Even though these point-to-point dose comparison shows differences between analytical and MC calculations, for all algorithms, clinically relevant dosimetric indices agree within  ±4% for the PTV and within  ±5% for critical organs. While the clinical agreement depends on the treatment site, there is no substantial difference of indices between the different algorithms. The pencil-beam approach however comes at a higher computational cost than the ray-casting calculation. In conclusion, we would recommend using the ray-casting algorithm for fast dose optimization and subsequently combine it with one MC calculation to scale the absolute dose and assure the quality of the treatment plan.

We present a proof of principle, experimental validation of the potential of proton 'Range Probes' (RP) for patient positioning verification in proton therapy. In this work, we have evaluated experimentally the accuracy of RP by using tissue-like samples and an in-house developed multilayer ionization chamber (MLIC). In addition we build on our previous, simulation based work to present first experimental measurements of RP through anthropomorphic phantoms to detect either rotational or translational positioning errors. For this, a technique has been proposed to characterize the residual integral depth dose curve (RIDDC) after range mixing. This parametrization has been used to evaluate the similarity between Monte Carlo calculated error scenarios of the database and the measured RIDDC, while considering the intrinsic uncertainties of both modalities in order to deduce the positioning error. Finally, the additional dose applied to the patient when using clinical RP with known fluence has been estimated by measuring the local dose of a single RP. In tissue phantoms, the prediction accuracy of the water equivalent path length was 0.70%, with the highest deviations being found in low density samples (up to 5.67%). In addition, the results of the patient positioning verification measurements demonstrated that using carefully selected RPs, 1D translational or rotational errors could be detected with an accuracy of 1 mm and 2°, respectively, and that these would be associated with a low additional dose burden to the patient. In summary, these promising results suggest that the RP method could be a simple, fast and low-dose tool for verifying patient set-up during proton therapy treatment.

Despite growing rapidly, proton therapy is still a relatively immature treatment modality, at least in comparison to conventional radiotherapy using photons. As such, in this article, the author gives a very personal view of some of the potential areas for development in medical physics for proton therapy in the next 10 yr by identifying six topics for detailed discussion. The first of these are all related to reducing various "parameters" of proton therapy treatments (size and cost, treatment times, penumbras, and margins), while the second group are related to providing more quantitative "knowledge" about the quality of the treatments we are delivering. In conclusion, there is much interesting and important work still to be done in many areas of medical physics related to proton therapy, of which, the topics selected here are just the tip of the iceberg., (© 2018 American Association of Physicists in Medicine.)

Patient specific verification (PSV) measurements for pencil beam scanning (PBS) proton therapy are resource-consuming and necessitate substantial beam time outside of clinical hours. As such, efforts to safely reduce the PSV-bottleneck in the clinical work-flow are of great interest. Here, capabilities of current PSV methods to ensure the treatment integrity were investigated and compared to an alternative approach of reconstructing the dose distribution directly from the machine control- or delivery log files with the help of an independent dose calculation (IDC). Scenarios representing a wide range of delivery or work-flow failures were identified (e.g. error in spot position, air gap or pre-absorber setting) and machine files were altered accordingly. This yielded 21 corrupted treatment files, which were delivered and measured with our clinical PSV protocol. IDC machine- and log file checks were also conducted and their sensitivity at detecting the errors compared to the measurements. Although some of the failure scenarios induced clinically relevant dose deviations in the patient geometry, the PSV measurement protocol only detected one out of 21 error scenarios. However, 11 and all 21 error scenarios were detected using dose reconstructions based on the log and machine files respectively. Our data suggests that, although commonly used in particle therapy centers, PSV measurements do a poor job detecting data transfer failures and imperfect delivery machine performance. Machine- and log-file IDCs have been shown to successfully detect erroneous work-flows and to represent a reliable addition to the QA procedure, with the potential to replace PSV.

For radiotherapy, it is crucial to guarantee that the delivered dose matches the planned dose. Therefore, patient specific quality assurance (QA) of absolute dose distributions is necessary. Here, we investigate the potential of replacing patient specific QA for pencil beam scanned proton therapy with Monte Carlo simulations. First, the set-up of the automated Monte Carlo model is presented with an emphasis on the absolute dose validation. Second, the absolute dose results obtained from the Monte Carlo simulation for a comprehensive set of patient fields are compared to patient specific QA measurements. Absolute doses measured with the Farmer chamber are shown to be 1.4% higher than the doses measured with the Semiflex chamber. For single energy layers, Monte Carlo simulated doses are 2.1%  ±  0.4% lower than the ones measured with the ionization chamber and 1.1%  ±  1.0% lower than measurements compared to patient field verification measurements. After rescaling to account for this 1.1% discrepancy, 98 fields (94.2%) agree within 2% to measurements, the maximum difference being 2.3%. In conclusion, an automated, easy-to-use Monte Carlo calculation system has been set up. This system reproduced patient specific QA results over a wide range of cases, showing that the time consuming measurements could be reduced or even replaced using Monte Carlo simulations without jeopardizing treatment quality.

Therapeutic pencil beams are typically scanned using one of the following three techniques: spot scanning, raster scanning or line scanning. While providing similar dose distributions to the target, these three techniques can differ significantly in their delivery time sequence. Thus, we can expect differences in effectiveness and time efficiency when trying to mitigate interplay effects using rescanning. At the Paul Scherrer Institute, we are able to irradiate treatment plans using either of the three delivery techniques. Hence, we can compare them directly with identical underlying machine parameters such as energy switching time or minimum/maximum beam current. For this purpose, we selected three different liver targets, optimized plans for spots, and converted them to equivalent raster and line scanning plans. In addition to the scanning technique, we varied the underlying motion curve, starting phase, prescription dose and rescanning strategy, which resulted in a total of 1584 4D dose calculations and 49 measurements. They indicate that rescanning becomes effective when achieving a high number of rescans for every dose element. Fixed minimum spot weights for spot and raster scanning machines often hamper this. By introducing adaptive scaling of the beam current within iso-energy layers for line scanning, we can flexibly lower the minimum weight whenever required and achieve higher rescanning capability. Averaged over all scenarios studied, volumetric rescanning is significantly more effective than layered provided the same number of rescans are applied. Fast lateral scanning contributes to the efficiency of rescanning. We observed that in any given time window, we can always perform more rescans using raster or line scanning compared to spot scanning irradiations. Thus, we conclude that line scanning represents a promising technique for rescanning by combining both effectiveness and efficiency.

Purpose: By precalculation of an entire set of planning solutions for protons, penalizing them and providing a graphical navigator tool (Automated Treatment Planning [ATP]), we aim to improve the efficiency of the planning procedure for uveal melanoma (UM) and make it independent of treatment planner experience., Methods and Materials: A phase space of plans is evaluated by transforming the eye model in each gaze angle, calculating cumulative dose-volume histograms for each position, and defining a dose-volume constraint for each considered structure. The final result is a map of the plan phase space, displaying how many criteria are fulfilled for each gaze angle., Results: To test its usability and performance, ATP was used retrospectively on 48 UM patients treated with protons. In 36 of 48 cases (75%), the planning result was either the same (13 of 48, 27%) or comparable (23 of 48, 48%). In 11 of 48 evaluated cases (23%), ATP plans showed improvements. In 1 case (2%) the patient's visual acuity had been impaired, and an optimization was not possible., Conclusions: We have developed a dose calculation and planning engine that prepares a set of treatment plans covering a wide range of theoretical clinically feasible gaze angles for a given patient, by precalculating the dose distributions for each gaze angle. By considering different structures and adapting their constraints, the identification of the optimal gaze angle can be realized. With a better understanding of the dose-volume constraints and the development of strategies to react to the trade-offs between considered structures, ATP may lead to a complete automation of the planning process for UM treated with proton therapy., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: To evaluate the efficacy and safety of high-dose pencil-beam scanning proton therapy (PBS-PT) in the adjuvant treatment of spinal chordomas., Methods and Materials: Between 1997 and 2015, 100 patients with spinal chordomas (median age, 56 years; range, 25-81 years) were treated with adjuvant PBS-PT at the Paul Scherrer Institute: cervical (n = 46), thoracic (n = 4), lumbar (n = 12), and sacral (n = 38). The majority (88%) received PBS-PT alone rather than combined photon-proton therapy. The median radiation therapy dose prescribed was 74 Gy (relative biological effectiveness [RBE]) (range, 59.4-77 Gy [RBE]). Thirty-nine patients (39%) had undergone surgical stabilization, primarily with titanium hardware, before radiation therapy., Results: With a median follow-up of 65 months (range, 13-175 months), 5-year local control, disease control, and overall survival rates were 63% (95% confidence interval [CI] 57.7-68.7%; median, 103 months), 57% (95% CI 50.9-62.1%; median, 82 months), and 81% (95% CI 76.8-85.6%; median, 157 months), respectively. On univariate and multivariate analyses, the presence of surgical stabilization was highly prognostic for worsened outcomes. Multivariate analysis also revealed the extent of treatment volumes and presence of gross residual disease to be important in predicting outcomes. High-grade (grade ≥3) toxicities were rare in both the acute (8%) and late (6%) settings., Conclusion: For spinal chordomas, PBS-PT remains a highly effective and safe method for delivery of dose-escalated adjuvant radiation therapy. The presence of metallic surgical stabilization prognosticates for worsened outcomes. Further investigation is warranted to characterize ideal treatment volumes and effect of surgical stabilization on therapy for these challenging tumors., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: Over the last four decades, Ocular Proton Therapy has been successfully used to treat patients affected by intraocular lesions. For this, treatment geometry verification is routinely performed using radiographic images to align a configuration of fiducial radiopaque markers implanted on the sclera outer surface. This paper describes the clinical application of an alternative approach based on optical eye tracking for three-dimensional noninvasive and automatic eye localization. An experimental protocol was designed to validate the optical-based eye referencing against both radiographic imaging system and the clinically used EYEPLAN treatment planning system., Methods: The eye tracking system (ETS) was installed in the OPTIS 2 treatment room at PSI to acquire eye motions during the treatment of nine patients. The pupil position and the cornea curvature center were localized by segmenting the pupil contour and corneal light reflections on the images acquired by a pair of calibrated optical cameras. After calibration of the ETS, a direct comparison of radiopaque markers position, and consequentially eye position and orientation, provided by the ETS, radiographs and EYEPLAN was performed., Results: Nineteen out of thirty total monitored fractions were excluded from the study due to poor visibility of corneal reflection, resulting in a success rate of acquisition of 37%. For these data, overall median agreement between ETS-based and x-ray-based markers position assessment were 0.29 mm and 0.94° for translations and rotations, respectively. Small discrepancies were also measured in the eye center estimates of the ETS and EYEPLAN. Conversely, variations in measured eye orientation were higher, with interquartile range (IQR) between 4.39° and 7.58°. Nonetheless, dosimetric evaluation of the consequence of ETS uncertainties showed that the target volume would still be covered by more than 95% of the dose in all cases., Conclusion: An ETS was successfully installed in a clinical ocular proton therapy treatment room and used to monitor eye position and orientation in a clinical scenario. First results show the potential of such a system as an eye localization device. However, the low success rate prevents straightforward clinical application and needs further improvements aimed at increasing corneal reflection visibility., (© 2018 American Association of Physicists in Medicine.)

In recent years there has been increasing interest in the more extensive application of proton therapy in a clinical and preferably hospital-based environment. However, broader adoption of proton therapy has been hindered by the costs of treatment, which are still much higher than those in advanced photon therapy. This article presents an overview of on-going technical developments, which have a reduction of the capital investment or operational costs either as a major goal or as a potential outcome. Developments in instrumentation for proton therapy, such as gantries and accelerators, as well as facility layout and efficiency in treatment logistics will be discussed in this context. Some of these developments are indeed expected to reduce the costs. The examples will show, however, that a dramatic cost reduction of proton therapy is not expected in the near future. Although current developments will certainly contribute to a gradual decrease of the treatment costs in the coming years, many steps will still have to be made to achieve a much lower cost per treatment., (Copyright © 2018. Published by Elsevier Inc.)

The lateral fall-off is crucial for sparing organs at risk in proton therapy. It is therefore of high importance to minimize the penumbra for pencil beam scanning (PBS). Three optimisation approaches are investigated: edge-collimated uniformly weighted spots (collimation), pencil beam optimisation of uncollimated pencil beams (edge-enhancement) and the optimisation of edge collimated pencil beams (collimated edge-enhancement). To deliver energies below 70 MeV, these strategies are evaluated in combination with the following pre-absorber methods: field specific fixed thickness pre-absorption (fixed), range specific, fixed thickness pre-absorption (automatic) and range specific, variable thickness pre-absorption (variable). All techniques are evaluated by Monte Carlo simulated square fields in a water tank. For a typical air gap of 10 cm, without pre-absorber collimation reduces the penumbra only for water equivalent ranges between 4-11 cm by up to 2.2 mm. The sharpest lateral fall-off is achieved through collimated edge-enhancement, which lowers the penumbra down to 2.8 mm. When using a pre-absorber, the sharpest fall-offs are obtained when combining collimated edge-enhancement with a variable pre-absorber. For edge-enhancement and large air gaps, it is crucial to minimize the amount of material in the beam. For small air gaps however, the superior phase space of higher energetic beams can be employed when more material is used. In conclusion, collimated edge-enhancement combined with the variable pre-absorber is the recommended setting to minimize the lateral penumbra for PBS. Without collimator, it would be favourable to use a variable pre-absorber for large air gaps and an automatic pre-absorber for small air gaps.

To exploit the full potential of proton therapy, accurate and on-line methods to verify the patient positioning and the proton range during the treatment are desirable. Here we propose and validate an innovative technique for determining patient misalignment uncertainties through the use of a small number of low dose, carefully selected proton pencil beams ('range probes') (RP) with sufficient energy that their residual Bragg peak (BP) position and shape can be measured on exit. Since any change of the patient orientation in relation to these beams will result in changes of the density heterogeneities through which they pass, our hypothesis is that patient misalignments can be deduced from measured changes in Bragg curve (BC) shape and range. As such, a simple and robust methodology has been developed that estimates average proton range and range dilution of the detected residual BC, in order to locate range probe positions with optimal prediction power for detecting misalignments. The validation of this RP based approach has been split into two phases. First we retrospectively investigate its potential to detect translational patient misalignments under real clinical conditions. Second, we test it for determining rotational errors of an anthropomorphic phantom that was systematically rotated using an in-house developed high precision motion stage. Simulations of RPs in these two scenarios show that this approach could potentially predict translational errors to lower than1.5 mm and rotational errors to smaller than 1° using only three or five RPs positions respectively.

Line scanning represents a faster and potentially more flexible form of pencil beam scanning than conventional step-and-shoot irradiations. It seeks to minimize dead times in beam delivery whilst preserving the possibility of modulating the dose at any point in the target volume. Our second generation proton gantry features irradiations in line scanning mode, but it still lacks a dedicated monitoring and validation system that guarantees patient safety throughout the irradiation. We report on its design and implementation in this paper. In line scanning, we steer the proton beam continuously along straight lines while adapting the speed and/or current frequently to modulate the delivered dose. We intend to prevent delivery errors that could be clinically relevant through a two-stage system: safety level 1 monitors the beam current and position every 10 μs. We demonstrate that direct readings from ionization chambers in the gantry nozzle and Hall probes in the scanner magnets provide required information on current and position, respectively. Interlocks will be raised when measured signals exceed their predefined tolerance bands. Even in case of an erroneous delivery, safety level 1 restricts hot and cold spots of the physically delivered fraction dose to  ±[Formula: see text] (±[Formula: see text] of [Formula: see text] biologically). In safety level 2-an additional, partly redundant validation step-we compare the integral line profile measured with a strip monitor in the nozzle to a forward-calculated prediction. The comparison is performed between two line applications to detect amplifying inaccuracies in speed and current modulation. This level can be regarded as an online quality assurance of the machine. Both safety levels use devices and functionalities already installed along the beamline. Hence, the presented monitoring and validation system preserves full compatibility of discrete and continuous delivery mode on a single gantry, with the possibility of switching between modes during the application of a single field.

Motion-induced range changes and incorrectly placed dose spots strongly affect the quality of pencil-beam-scanned (PBS) proton therapy, especially in thoracic tumour sites, where density changes are large. Thus motion-mitigation techniques are necessary, which must be validated in a realistic patient-like geometry. We report on the development and characterisation of a dynamic, anthropomorphic, thorax phantom that can realistically mimic thoracic motions and anatomical features for verifications of proton and photon 4D treatments. The presented phantom is of an average thorax size, and consists of inflatable, deformable lungs surrounded by a skeleton and skin. A mobile 'tumour' is embedded in the lungs in which dosimetry devices (such as radiochromic films) can be inserted. Motion of the tumour and deformation of the thorax is controlled via a custom made pump system driving air into and out of the lungs. Comprehensive commissioning tests have been performed to evaluate the mechanical performance of the phantom, its visibility on CT and MR imaging and its feasibility for dosimetric validation of 4D proton treatments. The phantom performed well on both regular and irregular pre-programmed breathing curves, reaching peak-to-peak amplitudes in the tumour of  <20 mm. Some hysteresis in the inflation versus deflation phases was seen. All materials were clearly visualised in CT scans, and all, except the bone and lung components, were MRI visible. Radiochromic film measurements in the phantom showed that imaging for repositioning was required (as for a patient treatment). Dosimetry was feasible with Gamma Index agreements (4%/4 mm) between film dose and planned dose  >90% in the central planes of the target. The results of this study demonstrate that this anthropomorphic thorax phantom is suitable for imaging and dosimetric studies in a thoracic geometry closely-matched to lung cancer patients under realistic motion conditions.

Proton therapy, especially in the form of pencil beam scanning (PBS), allows for the delivery of highly conformal dose distributions for complex tumor geometries. However, due to scattering of protons inside the patient, lateral dose gradients cannot be arbitrarily steep, which is of importance in cases with organs at risk (OARs) in close proximity to, or overlapping with, planning target volumes (PTVs). In the PBS approach, physical pencil beams are planned using a regular grid orthogonal to the beam direction. In this work, we propose an alternative to this commonly used approach where pencil beams are placed on an irregular grid along concentric paths based on the target contour. Contour driven pencil beam placement is expected to improve dose confirmation by allowing the optimizer to best enhance the penumbra of irregularly shaped targets using edge enhancement. Its effectiveness has been shown to improve dose confirmation to the target volume and reduce doses to OARs in head-and-neck planning studies. Furthermore, the deliverability of such plans, as well as the dosimetric improvements over conventional grid-based plans, have been confirmed in first phantom based verifications.

Purpose: A detailed analysis of 2728 intensity modulated proton therapy (IMPT) fields that were clinically delivered to patients between 2007 and 2013 at Paul Scherrer Institute (PSI) was performed. The aim of this study was to analyze the results of patient specific dosimetric verifications and to assess possible correlation between the quality assurance (QA) results and specific field metrics., Methods: Dosimetric verifications were performed for every IMPT field prior to patient treatment. For every field, a steering file was generated containing all the treatment unit information necessary for treatment delivery: beam energy, beam angle, dose, size of air gap, nuclear interaction (NI) correction factor, number of range shifter plates, number of Bragg peaks (BPs) with their position and weight. This information was extracted and correlated to the results of dosimetric verification of each field which was a measurement of two orthogonal profiles using an orthogonal ionization chamber array in a movable water column., Results: The data analysis has shown more than 94% of all verified plans were within defined clinical tolerances. The differences between measured and calculated dose depend critically on the number of BPs, total thickness of all range shifter plates inserted in the beam path, and maximal range. An increase of the dose difference was observed with smaller number of BPs (i.e., smaller tumor) and smaller ranges (i.e., superficial tumors). The results of the verification do not depend, however, on the prescribed dose, NI correction, or the size of the air gap. There is no dependency of the transversal and longitudinal spot position precision on the beam angle. The value of NI correction depends on the number of spots and number of range shifter plates., Conclusions: The presented study has shown that the verification method used at Centre for Proton Therapy at Paul Scherrer Institute is accurate and reproducible for performing patient specific QA. The results confirmed that the dose discrepancy is dependent on the size and location of the tumor.

Purpose: The safe clinical implementation of pencil beam scanning (PBS) proton therapy for lung tumors is complicated by the delivery uncertainties caused by breathing motion. The purpose of this feasibility study was to investigate whether a voluntary breath-hold technique could limit the delivery uncertainties resulting from interfractional motion., Methods and Materials: Data from 15 patients with peripheral lung tumors previously treated with stereotactic radiation therapy were included in this study. The patients had 1 computed tomographic (CT) scan in voluntary breath-hold acquired before treatment and 3 scans during the treatment course. PBS proton treatment plans with 2 fields (2F) and 3 fields (3F), respectively, were calculated based on the planning CT scan and subsequently recalculated on the 3 repeated CT scans. Recalculated plans were considered robust if the V95% (volume receiving ≥95% of the prescribed dose) of the gross target volume (GTV) was within 5% of what was expected from the planning CT data throughout the simulated treatment., Results: A total of 14/15 simulated treatments for both 2F and 3F met the robustness criteria. Reduced V95% was associated with baseline shifts (2F, P=.056; 3F, P=.008) and tumor size (2F, P=.025; 3F, P=.025). Smaller tumors with large baseline shifts were also at risk for reduced V95% (interaction term baseline/size: 2F, P=.005; 3F, P=.002)., Conclusions: The breath-hold approach is a realistic clinical option for treating lung tumors with PBS proton therapy. Potential risk factors for reduced V95% are small targets in combination with large baseline shifts. On the basis of these results, the baseline shift of the tumor should be monitored (eg, through image guided therapy), and appropriate measures should be taken accordingly. The intrafractional motion needs to be investigated to confirm that the breath-hold approach is robust., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: Four-dimensional computed tomography-magnetic resonance imaging (4DCT-MRI) is an image-processing technique for simulating many 4DCT data sets from a static reference CT and motions extracted from 4DMRI studies performed using either volunteers or patients. In this work, different motion extraction approaches were tested using 6 liver cases, and a detailed comparison between 4DCT-MRI and 4DCT was performed., Methods and Materials: 4DCT-MRI has been generated using 2 approaches. The first approach used motion extracted from 4DMRI as being "most similar" to that of 4DCT from the same patient (subject-specific), and the second approach used the most similar motion obtained from a motion library derived from 4DMRI liver studies of 13 healthy volunteers (population-based). The resulting 4DCT-MRI and 4DCTs were compared using scanned proton 4D dose calculations (4DDC)., Results: Dosimetric analysis showed that 93% ± 8% of points inside the clinical target volume (CTV) agreed between 4DCT and subject-specific 4DCT-MRI (gamma analysis: 3%/3 mm). The population-based approach however showed lower dosimetric agreement with only 79% ± 14% points in the CTV reaching the 3%/3 mm criteria., Conclusions: 4D CT-MRI extends the capabilities of motion modeling for dose calculations by accounting for realistic and variable motion patterns, which can be directly employed in clinical research studies. We have found that the subject-specific liver modeling appears more accurate than the population-based approach. The former is particularly interesting for clinical applications, such as improved target delineation and 4D dose reconstruction for patient-specific QA to allow for inter- and/or intra-fractional plan corrections., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Pencil beam scanning (PBS) proton therapy requires the delivery of many thousand proton beams, each modulated for position, energy and monitor units, to provide a highly conformal patient treatment. The quality of the treatment is dependent on the delivery accuracy of each beam and at each fraction. In this work we describe the use of treatment log files, which are a record of the machine parameters for a given field delivery on a given fraction, to investigate the integrity of treatment delivery compared to the nominal planned dose. The dosimetry-relevant log file parameters are used to reconstruct the 3D dose distribution on the patient anatomy, using a TPS-independent dose calculation system. The analysis was performed for patients treated at Paul Scherrer Institute on Gantry 2, both for individual fields and per series (or plan), and delivery quality was assessed by determining the percentage of voxels in the log file dose distribution within  +/-  1% of the nominal dose. It was seen that, for all series delivered, the mean pass rate is 96.4%. Furthermore, this work establishes a correlation between the delivery quality of a field and the beam position accuracy. This correlation is evident for all delivered fields regardless of individual patient or plan characteristics. We have also detailed further usefulness of log file analysis within our clinical workflow. In summary, we have highlighted that the integrity of PBS treatment delivery is dependent on daily machine performance and is specifically highly correlated with the accuracy of beam position. We believe this information will be useful for driving machine performance improvements in the PBS field.

Pencil beam scanning proton therapy allows the delivery of highly conformal dose distributions by delivering several thousand pencil beams. These beams have to be individually optimised and accurately delivered requiring a significant quality assurance workload. In this work we describe a toolkit for independent dose calculations developed at Paul Scherrer Institut which allows for dose reconstructions at several points in the treatment workflow. Quality assurance based on reconstructed dose distributions was shown to be favourable to pencil beam by pencil beam comparisons for the detection of delivery uncertainties and estimation of their effects. Furthermore the dose reconstructions were shown to have a sensitivity of the order of or higher than the measurements currently employed in the clinical verification procedures. The design of the independent dose calculation tool allows for a high modifiability of the dose calculation parameters (e.g. depth dose profiles, angular spatial distributions) allowing for a safe environment outside of the clinical treatment planning system for investigating the effect of such parameters on the resulting dose distributions and thus distinguishing between different contributions to measured dose deviations. The presented system could potentially reduce the amount of patient-specific quality assurance measurements which currently constitute a bottleneck in the clinical workflow.

We aim to define a site-specific robustness protocol to be used during the clinical plan evaluation process. Plan robustness of 16 skull base IMPT plans to systematic range and random set-up errors have been retrospectively and systematically analysed. This was determined by calculating the error-bar dose distribution (ebDD) for all the plans and by defining some metrics used to define protocols aiding the plan assessment. Additionally, an example of how to clinically use the defined robustness database is given whereby a plan with sub-optimal brainstem robustness was identified. The advantage of using different beam arrangements to improve the plan robustness was analysed. Using the ebDD it was found range errors had a smaller effect on dose distribution than the corresponding set-up error in a single fraction, and that organs at risk were most robust to the range errors, whereas the target was more robust to set-up errors. A database was created to aid planners in terms of plan robustness aims in these volumes. This resulted in the definition of site-specific robustness protocols. The use of robustness constraints allowed for the identification of a specific patient that may have benefited from a treatment of greater individuality. A new beam arrangement showed to be preferential when balancing conformality and robustness for this case. The ebDD and error-bar volume histogram proved effective in analysing plan robustness. The process of retrospective analysis could be used to establish site-specific robustness planning protocols in proton therapy. These protocols allow the planner to determine plans that, although delivering a dosimetrically adequate dose distribution, have resulted in sub-optimal robustness to these uncertainties. For these cases the use of different beam start conditions may improve the plan robustness to set-up and range uncertainties.

The presented work has two goals. First, to demonstrate the feasibility of accurately characterizing a proton radiation field at treatment head exit for Monte Carlo dose calculation of active scanning patient treatments. Second, to show that this characterization can be done based on measured depth dose curves and spot size alone, without consideration of the exact treatment head delivery system. This is demonstrated through calibration of a Monte Carlo code to the specific beam lines of two institutions, Massachusetts General Hospital (MGH) and Paul Scherrer Institute (PSI). Comparison of simulations modeling the full treatment head at MGH to ones employing a parameterized phase space of protons at treatment head exit reveals the adequacy of the method for patient simulations. The secondary particle production in the treatment head is typically below 0.2% of primary fluence, except for low-energy electrons (<0.6 MeV for 230 MeV protons), whose contribution to skin dose is negligible. However, there is significant difference between the two methods in the low-dose penumbra, making full treatment head simulations necessary to study out-of-field effects such as secondary cancer induction. To calibrate the Monte Carlo code to measurements in a water phantom, we use an analytical Bragg peak model to extract the range-dependent energy spread at the two institutions, as this quantity is usually not available through measurements. Comparison of the measured with the simulated depth dose curves demonstrates agreement within 0.5 mm over the entire energy range. Subsequently, we simulate three patient treatments with varying anatomical complexity (liver, head and neck and lung) to give an example how this approach can be employed to investigate site-specific discrepancies between treatment planning system and Monte Carlo simulations.

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: Base of skull meningioma can be treated with both intensity modulated radiation therapy (IMRT) and spot scanned proton therapy (PT). One of the main benefits of PT is better sparing of organs at risk, but due to the physical and dosimetric characteristics of protons, spot scanned PT can be more sensitive to the uncertainties encountered in the treatment process compared with photon treatment. Therefore, robustness analysis should be part of a comprehensive comparison between these two treatment methods in order to quantify and understand the sensitivity of the treatment techniques to uncertainties. The aim of this work was to benchmark a spot scanning treatment planning system for planning of base of skull meningioma and to compare the created plans and analyze their robustness to setup errors against the IMRT technique., Methods: Plans were produced for three base of skull meningioma cases: IMRT planned with a commercial TPS [Monaco (Elekta AB, Sweden)]; single field uniform dose (SFUD) spot scanning PT produced with an in-house TPS (PSI-plan); and SFUD spot scanning PT plan created with a commercial TPS [XiO (Elekta AB, Sweden)]. A tool for evaluating robustness to random setup errors was created and, for each plan, both a dosimetric evaluation and a robustness analysis to setup errors were performed., Results: It was possible to create clinically acceptable treatment plans for spot scanning proton therapy of meningioma with a commercially available TPS. However, since each treatment planning system uses different methods, this comparison showed different dosimetric results as well as different sensitivities to setup uncertainties. The results confirmed the necessity of an analysis tool for assessing plan robustness to provide a fair comparison of photon and proton plans., Conclusions: Robustness analysis is a critical part of plan evaluation when comparing IMRT plans with spot scanned proton therapy plans.

Mitigation of organ motion in active, scanning proton therapy is a challenge. One of the easiest methods to implement is re-scanning, where a treatment plan is applied several times with accordingly smaller weights. As a consequence, motion effects are averaged out. For discrete spot scanning, a major drawback of this method is the treatment time, which increases linearly with the number of re-scans. Continuous line scanning, on the other hand, eliminates the dead time between the positioning of each beam, and in this work, continuous line scanning has been investigated experimentally from the point of view of dose, penumbral width and its effectiveness for re-scanning. As shown by measurements in a homogeneous phantom, dose distributions delivered by continuous line scanning were comparable with those of discrete spot scanning for both geometric and realistic targets, with only a modest degradation of lateral penumbra in the direction of scanning. In addition, delivered dose levels have also been found to agree well between discrete and line scanning. With continuous line scanning, however, more re-scans could be applied without the artefacts seen in discrete spot scanning, with motions of up to 1 cm peak-to-peak amplitude being mitigated by 10 re-scans. For larger motion, in the interest of reducing the volume of irradiated normal tissue re-scanning should be combined with other motion mitigation techniques such as gating or breath-hold.