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Objective. Oxygen depletion is generally believed to play an important role in the FLASH effect-a differential reduction of the radiosensitivity of healthy tissues, relative to that of the tumour under ultra-high dose-rate (UHDR) irradiation conditions. In proton therapy (PT) with pencil-beam scanning (PBS), the deposition of dose, and, hence, the degree of (radiolytic) oxygen depletion varies both spatially and temporally. Therefore, the resulting oxygen concentration and the healthy-tissue sparing effect through radiation-induced hypoxia varies both spatially and temporally as well. Approach. We propose and numerically solve a physical oxygen diffusion model to study these effects and their dependence on tissue parameters and the scan pattern in pencil-beam delivery. Since current clinical FLASH PT (FLASH-PT) is based on 250 MeV shoot-through (transmission) beams, for which dose and dose rate (DR) hardly vary with depth compared to the variation transverse to the beam axis, we focus on the two-dimensional case. We numerically integrate the model to obtain the oxygen concentration in each voxel as a function of time and extract voxel-based and spatially and temporarily integrated metrics for oxygen (FLASH) enhanced dose. Furthermore, we evaluate the impact on oxygen enhancement of standard pencil-beam delivery patterns and patterns that were optimised on dose-rate. Our model can contribute to the identification of tissue properties and pencil-beam delivery parameters that are critical for FLASH-PT and it may be used for the optimisation of FLASH-PT treatment plans and their delivery. Main results. (i) the diffusive properties of oxygen are critical for the steady state concentration and therefore the FLASH effect, even more so in two dimensions when compared to one dimension. (ii) The FLASH effect through oxygen depletion depends primarily on dose and less on other parameters. (iii) At a fixed fraction dose there is a slight dependence on DR. (iv) Scan patterns optimised on DR slightly increase the oxygen induced FLASH effect. Significance. To our best knowledge, this is the first study assessing the impact of scan-pattern optimization (SPO) in FLASH-PT with PBS on a biological FLASH model. While the observed impact of SPO is relatively small, a larger effect is expected for larger target volumes. A better understanding of the FLASH effect and the role of oxygen (depletion) therein is essential for the further development of FLASH-PT with PBS, and SPO., (Creative Commons Attribution license.)

Objective . In head-and-neck cancer intensity modulated proton therapy, adaptive radiotherapy is currently restricted to offline re-planning, mitigating the effect of slow changes in patient anatomies. Daily online adaptations can potentially improve dosimetry. Here, a new, fully automated online re-optimization strategy is presented. In a retrospective study, this online re-optimization approach was compared to our trigger-based offline re-planning (offline TB re-planning) schedule, including extensive robustness analyses. Approach . The online re-optimization method employs automated multi-criterial re-optimization, using robust optimization with 1 mm setup-robustness settings (in contrast to 3 mm for offline TB re-planning). Hard planning constraints and spot addition are used to enforce adequate target coverage, avoid prohibitively large maximum doses and minimize organ-at-risk doses. For 67 repeat-CTs from 15 patients, fraction doses of the two strategies were compared for the CTVs and organs-at-risk. Per repeat-CT, 10.000 fractions with different setup and range robustness settings were simulated using polynomial chaos expansion for fast and accurate dose calculations. Main results . For 14/67 repeat-CTs, offline TB re-planning resulted in <50% probability of D 98% ≥ 95% of the prescribed dose ( D pres ) in one or both CTVs, which never happened with online re-optimization. With offline TB re-planning, eight repeat-CTs had zero probability of obtaining D 98% ≥ 95% D pres for CTV 7000 , while the minimum probability with online re-optimization was 81%. Risks of xerostomia and dysphagia grade ≥ II were reduced by 3.5 ± 1.7 and 3.9 ± 2.8 percentage point [mean ± SD] ( p < 10 -5 for both). In online re-optimization, adjustment of spot configuration followed by spot-intensity re-optimization took 3.4 min on average. Significance . The fast online re-optimization strategy always prevented substantial losses of target coverage caused by day-to-day anatomical variations, as opposed to the clinical trigger-based offline re-planning schedule. On top of this, online re-optimization could be performed with smaller setup robustness settings, contributing to improved organs-at-risk sparing., (Creative Commons Attribution license.)

Objective. Determining and verifying the number of monitor units is crucial to achieving the desired dose distribution in radiotherapy and maintaining treatment efficacy. However, current commercial treatment planning system(s) dedicated to ocular passive eyelines in proton therapy do not provide the number of monitor units for patient-specific plan delivery. Performing specific pre-treatment field measurements, which is time and resource consuming, is usually gold-standard practice. This proof-of-concept study reports on the development of a multi-institutional-based generalized model for monitor units determination in proton therapy for eye melanoma treatments. Approach. To cope with the small number of patients being treated in proton centers, three European institutes participated in this study. Measurements data were collected to address output factor differences across the institutes, especially as function of field size, spread-out Bragg peak modulation width, residual range, and air gap. A generic model for monitor units prediction using a large number of 3748 patients and broad diversity in tumor patterns, was evaluated using six popular machine learning algorithms: (i) decision tree; (ii) random forest, (iii) extra trees, (iv) K-nearest neighbors, (v) gradient boosting, and (vi) the support vector regression. Features used as inputs into each machine learning pipeline were: Spread-out Bragg peak width, range, air gap, fraction and calibration doses. Performance measure was scored using the mean absolute error, which was the difference between predicted and real monitor units, as collected from institutional gold-standard methods. Main results. Predictions across algorithms were accurate within 3% uncertainty for up to 85.2% of the plans and within 10% uncertainty for up to 98.6% of the plans with the extra trees algorithm. Significance. A proof-of-concept of using machine learning-based generic monitor units determination in ocular proton therapy has been demonstrated. This could trigger the development of an independent monitor units calculation tool for clinical use., (Creative Commons Attribution license.)

Background: The first clinical trials to assess the feasibility of FLASH radiotherapy in humans have started (FAST-01, FAST-02) and more trials are foreseen. To increase comparability between trials it is important to assure treatment quality and therefore establish a standard for machine quality assurance (QA). Currently, the AAPM TG-224 report is considered as the standard on machine QA for proton therapy, however, it was not intended to be used for ultra-high dose rate (UHDR) proton beams, which have gained interest due to the observation of the FLASH effect., Purpose: The aim of this study is to find consensus on practical guidelines on machine QA for UHDR proton beams in transmission mode in terms of which QA is required, how they should be done, which detectors are suitable for UHDR machine QA, and what tolerance limits should be applied., Methods: A risk assessment to determine the gaps in the current standard for machine QA was performed by an international group of medical physicists. Based on that, practical guidelines on how to perform machine QA for UHDR proton beams were proposed., Results: The risk assessment clearly identified the need for additional guidance on temporal dosimetry, addressing dose rate (constancy), dose spillage, and scanning speed. In addition, several minor changes from AAPM TG-224 were identified; define required dose rate levels, the use of clinically relevant dose levels, and the use of adapted beam settings to minimize activation of detector and phantom materials or to avoid saturation effects of specific detectors. The final report was created based on discussions and consensus., Conclusions: Consensus was reached on what QA is required for UHDR scanning proton beams in transmission mode for isochronous cyclotron-based systems and how they should be performed. However, the group discussions also showed that there is a lack of high temporal resolution detectors and sufficient QA data to set appropriate limits for some of the proposed QA procedures., (© 2023 The Authors. Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

Background and Purpose: In the Netherlands, head-and-neck cancer (HNC) patients are referred for proton therapy (PT) through model-based selection (MBS). However, treatment errors may compromise adequate CTV dose. Our aims are: (i) to derive probabilistic plan evaluation metrics on the CTV consistent with clinical metrics; (ii) to evaluate plan consistency between photon (VMAT) and proton (IMPT) planning in terms of CTV dose iso-effectiveness and (iii) to assess the robustness of the OAR doses and of the risk toxicities involved in the MBS., Materials and Methods: Sixty HNC plans (30 IMPT/30 VMAT) were included. A robustness evaluation with 100,000 treatment scenarios per plan was performed using Polynomial Chaos Expansion (PCE). PCE was applied to determine scenario distributions of clinically relevant dosimetric parameters, which were compared between the 2 modalities. Finally, PCE-based probabilistic dose parameters were derived and compared to clinical PTV-based photon and voxel-wise proton evaluation metrics., Results: Probabilistic dose to near-minimum volume v = 99.8% for the CTV correlated best with clinical PTV-D 98% and VWmin-D 98%,CTV doses for VMAT and IMPT respectively. IMPT showed slightly higher nominal CTV doses, with an average increase of 0.8 GyRBE in the median of the D 99.8%,CTV distribution. Most patients qualified for IMPT through the dysphagia grade II model, for which an average NTCP gain of 10.5 percentages points (%-point) was found. For all complications, uncertainties resulted in moderate NTCP spreads lower than 3 p.p. on average for both modalities., Conclusion: Despite the differences between photon and proton planning, the comparison between PTV-based VMAT and robust IMPT is consistent. Treatment errors had a moderate impact on NTCPs, showing that the nominal plans are a good estimator to qualify patients for PT., 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 . The Dutch proton robustness evaluation protocol prescribes the dose of the clinical target volume (CTV) to the voxel-wise minimum (VWmin) dose of 28 scenarios. This results in a consistent but conservative near-minimum CTV dose (D 98%,CTV ). In this study, we analyzed (i) the correlation between VWmin/voxel-wise maximum (VWmax) metrics and actually delivered dose to the CTV and organs at risk (OARs) under the impact of treatment errors, and (ii) the performance of the protocol before and after its calibration with adequate prescription-dose levels. Approach . Twenty-one neuro-oncological patients were included. Polynomial chaos expansion was applied to perform a probabilistic robustness evaluation using 100,000 complete fractionated treatments per patient. Patient-specific scenario distributions of clinically relevant dosimetric parameters for the CTV and OARs were determined and compared to clinical VWmin and VWmax dose metrics for different scenario subsets used in the robustness evaluation protocol. Main results . The inclusion of more geometrical scenarios leads to a significant increase of the conservativism of the protocol in terms of clinical VWmin and VWmax values for the CTV and OARs. The protocol could be calibrated using VWmin dose evaluation levels of 93.0%-92.3%, depending on the scenario subset selected. Despite this calibration of the protocol, robustness recipes for proton therapy showed remaining differences and an increased sensitivity to geometrical random errors compared to photon-based margin recipes. Significance . The Dutch proton robustness evaluation protocol, combined with the photon-based margin recipe, could be calibrated with a VWmin evaluation dose level of 92.5%. However, it shows limitations in predicting robustness in dose, especially for the near-maximum dose metrics to OARs. Consistent robustness recipes could improve proton treatment planning to calibrate residual differences from photon-based assumptions., (Creative Commons Attribution license.)

Purpose: FLASH dose rates >40 Gy/s are readily available in proton therapy (PT) with cyclotron-accelerated beams and pencil-beam scanning (PBS). The PBS delivery pattern will affect the local dose rate, as quantified by the PBS dose rate (PBS-DR), and therefore needs to be accounted for in FLASH-PT with PBS, but it is not yet clear how. Our aim was to optimize patient-specific scan patterns for stereotactic FLASH-PT of early-stage lung cancer and lung metastases, maximizing the volume irradiated with PBS-DR >40 Gy/s of the organs at risk voxels irradiated to >8 Gy (FLASH coverage)., Methods and Materials: Plans to 54 Gy/3 fractions with 3 equiangular coplanar 244 MeV proton shoot-through transmission beams for 20 patients were optimized with in-house developed software. Planning target volume-based planning with a 5 mm margin was used. Planning target volume ranged from 4.4 to 84 cc. Scan-pattern optimization was performed with a Genetic Algorithm, run in parallel for 20 independent populations (islands). Mapped crossover, inversion, swap, and shift operators were applied to achieve (local) optimality on each island, with migration between them for global optimality. The cost function was chosen to maximize the FLASH coverage per beam at >8 Gy, >40 Gy/s, and 40 nA beam current. The optimized patterns were evaluated on FLASH coverage, PBS-DR distribution, and population PBS-DR-volume histograms, compared with standard line-by-line scanning. Robustness against beam current variation was investigated., Results: The optimized patterns have a snowflake-like structure, combined with outward swirling for larger targets. A population median FLASH coverage of 29.0% was obtained for optimized patterns compared with 6.9% for standard patterns, illustrating a significant increase in FLASH coverage for optimized patterns. For beam current variations of 5 nA, FLASH coverage varied between -6.1%-point and 2.2%-point for optimized patterns., Conclusions: Significant improvements on the PBS-DR and, hence, on FLASH coverage and potential healthy-tissue sparing are obtained by sequential scan-pattern optimization. The optimizer is flexible and may be further fine-tuned, based on the exact conditions for FLASH., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: In intensity modulated proton therapy (IMPT), the impact of setup errors and anatomical changes is commonly mitigated by robust optimization with population-based setup robustness (SR) settings and offline replanning. In this study we propose and evaluate an alternative approach based on daily plan selection from patient-specific pre-treatment established plan libraries (PLs). Clinical implementation of the PL strategy would be rather straightforward compared to daily online re-planning., Materials and Methods: For 15 head-and-neck cancer patients, the planning CT was used to generate a PL with 5 plans, robustly optimized for increasing SR: 0, 1, 2, 3, 5 mm, and 3% range robustness. Repeat CTs (rCTs) and realistic setup and range uncertainty distributions were used for simulation of treatment courses for the PL approach, treatments with fixed SR (fSR 3 ) and a trigger-based offline adaptive schedule for 3 mm SR (fSR 3 OfA). Daily plan selection in the PL approach was based only on recomputed dose to the CTV on the rCT., Results: Compared to using fSR 3 and fSR 3 OfA, the risk of xerostomia grade ≥ II & III and dysphagia ≥ grade III were significantly reduced with the PL. For 6/15 patients the risk of xerostomia and/or dysphagia ≥ grade II could be reduced by > 2% by using PL. For the other patients, adherence to target coverage constraints was often improved. fSR 3 OfA resulted in significantly improved coverage compared to PL for selected patients., Conclusion: The proposed PL approach resulted in overall reduced NTCPs compared to fSR 3 and fSR 3 OfA at limited cost in target coverage., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose and Objective: Besides a dose-rate threshold of 40-100 Gy/s, the FLASH effect may require a dose > 3.5-7 Gy. Even in hypofractioned treatments, with all beams delivered in each fraction (ABEF), most healthy tissue is irradiated to a lower fraction dose. This can be circumvented by single-beam-per-fraction (SBPF) delivery, with a loss of healthy tissue sparing by fractionation. We investigated the trade-off between FLASH and loss of fractionation in SBPF stereotactic proton therapy of lung cancer and determined break-even FLASH-enhancement ratios (FERs)., Materials and Methods: Treatment plans for 12 patients were generated. GTV delineations were available and a 5 mm GTV-PTV margin was applied. Equiangular arrangements of 3, 5, 7, and 9 244 MeV proton transmission beams were used. To facilitate SBPF, the number of fractions was equal to the number of beams. Iso-effective fractionation schedules with a single field uniform dose prescription were used: D 95%,PTV  = 100%D pres per beam. All plans were evaluated in terms of dose to lung and conformity of dose to target of FLASH-enhanced biologically equivalent dose (EQD2)., Results: Compared to ABEF, SBPF resulted in a median increase of EQD2 mean to healthy lung of 56%, 58%, 55% and 54% in plans with 3, 5, 7 and 9 fractions respectively and of 236%, 78%, 50% and 41% in V 100% EQD2 , quantifying conformity. This can be compensated for by FERs of at least 1.28, 1.32, 1.30 and 1.23 respectively for EQD2 mean and 1.29, 1.18, 1.28 and 1.15 for V 100%,EQD2 ., Conclusion: A FLASH effect outweighing the loss of fractionation in SBPF may be achieved in stereotactic lung treatments. The trade-off with fractionation depends on the conditions under which the FLASH effect occurs. Better understanding of the underlying biology and the impact of delivery conditions is needed., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: To investigate the potential clinical benefit of a two-beam arrangement technique using three-dimensional (3D) imaging of uveal melanoma (UM) patients treated with proton therapy and a dedicated eyeline., Material/methods: Retrospective CT-based treatment plans of 39 UM patients performed using a single beam (SB) were compared to plans with two beams (TB) optimized for better trade-offs in organs-at-risk sparing. The RBE-weighted prescribed dose was 60 Gy (D RBE, GTV  = 60 Gy) in four fractions, assuming an RBE of 1.1. Dosimetric findings were analyzed for three patient groups based on tumor-optic nerve distance and UM staging (group GrA: ≤3 mm, T1 T2 UM; GrB: ≤3 mm, T3 UM; GrC: >3 mm, T1 T2 T3 UM). Finally, two schedules were compared on biologically effective dose (BED): both beams being delivered either the same day (TB), or on alternate days (TBalter)., Results: All strategies resulted in dosimetrically acceptable plans. A dose reduction to the anterior structures was achieved in 23/39 cases with the two-beam plans. D 25% was significantly lowered compared to SB plans by 12.4 and 15.4 Gy RBE-weighted median dose in GrA and GrB, respectively. D 2% was reduced by 18.6 and 6.0 Gy RBE-weighted median dose in GrA and GrB, respectively. A cost to the optic nerve was observed with a median difference up to 3.8 Gy RBE-weighted dose in GrB. BED differences were statistically significant for all considered parameters in favor of two beams delivered the same day., Conclusion: A two-beam strategy appears beneficial for posterior tumors abutting the optic nerve. This strategy might have a positive impact on the risk of ocular complications., Competing Interests: Conflict of interest This research was co-funded by the research program PROTONS4Vision (Grant NWO 14654), which is financed by the Netherlands Organization for Scientific Research (NWO), Technology Foundation STW, the Top consortium for Knowledge & Innovation (TKI-HTSM), and Varian Medical Systems Particle Therapy GmbH & Co. KG, Troisdorf, Germany., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Due to its specific physical characteristics, proton irradiation is especially suited for irradiation of chordomas and chondrosarcoma in the axial skeleton. Robust plan optimization renders the proton beam therapy more predictable upon individual setup errors. Reported experience with the planning and delivery of robustly optimized plans in chordoma and chondrosarcoma of the mobile spine and sacrum, is limited. In this study, we report on the clinical use of robustly optimized, intensity modulated proton beam therapy in these patients., Methods: We retrospectively reviewed patient, treatment and acute toxicity data of all patients with chordoma and chondrosarcoma of the mobile spine and sacrum, treated between 1 April 2019 and 1 April 2020 at our institute. Anatomy changes during treatment were evaluated by weekly cone-beam CTs (CBCT), supplemented by scheduled control-CTs or ad-hoc control-CTs. Acute toxicity was scored weekly during treatment and at 3 months after therapy according to CTCAE 4.0., Results: 17 chordoma and 3 chondrosarcoma patients were included. Coverage of the high dose clinical target volume was 99.8% (range 56.1-100%) in the nominal and 80.9% (range 14.3-99.6%) in the voxel-wise minimum dose distribution. Treatment plan adaptation was needed in 5 out of 22 (22.7%) plans. Reasons for plan adaptation were either reduced tumor coverage or increased dose to the OAR., Conclusions: Robustly optimized intensity modulated proton beam therapy for chordoma and chondrosarcoma of the mobile spine is feasible. Plan adaptations due to anatomical changes were required in approximately 23 percent of treatment courses., Competing Interests: Conflict of interest statement None of the authors on this manuscript have any conflict of interest to declare., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Breathing interplay effects in Intensity Modulated Proton Therapy (IMPT) arise from the interaction between target motion and the scanning beam. Assessing the detrimental effect of interplay and the clinical robustness of several mitigation techniques requires statistical evaluation procedures that take into account the variability of breathing during dose delivery. In this study, we present such a statistical method to model intra-fraction respiratory motion based on breathing signals and assess clinical relevant aspects related to the practical evaluation of interplay in IMPT such as how to model irregular breathing, how small breathing changes affect the final dose distribution, and what is the statistical power (number of different scenarios) required for trustworthy quantification of interplay effects. First, two data-driven methodologies to generate artificial patient-specific breathing signals are compared: a simple sinusoidal model, and a precise probabilistic deep learning model generating very realistic samples of patient breathing. Second, we investigate the highly fluctuating relationship between interplay doses and breathing parameters, showing that small changes in breathing period result in large local variations in the dose. Our results indicate that using a limited number of samples to calculate interplay statistics introduces a bigger error than using simple sinusoidal models based on patient parameters or disregarding breathing hysteresis during the evaluation. We illustrate the power of the presented statistical method by analyzing interplay robustness of 4DCT and Internal Target Volume (ITV) treatment plans for a 8 lung cancer patients, showing that, unlike 4DCT plans, even 33 fraction ITV plans systematically fail to fulfill robustness requirements., (Creative Commons Attribution license.)

Background and Purpose: Scenario-based robust optimization and evaluation are commonly used in proton therapy (PT) with pencil beam scanning (PBS) to ensure adequate dose to the clinical target volume (CTV). However, a statistically accurate assessment of the clinical application of this approach is lacking. In this study, we assess target dose in a clinical cohort of neuro-oncological patients, planned according to the DUPROTON robustness evaluation consensus, using polynomial chaos expansion (PCE)., Materials and Methods: A cohort of the first 27 neuro-oncological patients treated at HollandPTC was used, including realistic error distributions derived from geometrical and stopping-power prediction (SPP) errors. After validating the model, PCE-based robustness evaluations were performed by simulating 100.000 complete fractionated treatments per patient to obtain accurate statistics on clinically relevant dosimetric parameters and population-dose histograms., Results: Treatment plans that were robust according to clinical protocol and treatment plansin which robustness was sacrificed are easily identified. For robust treatment plans on average, a CTV dose of 3 percentage points (p.p.) more than prescribed was realized (range +2.7 p.p. to +3.5 p.p.) for 98% of the sampled fractionated treatments. For the entire patient cohort on average, a CTV dose of 0.1 p.p. less than prescribed was achieved (range -2.4 p.p. to +0.5 p.p.). For the 6 treatment plans in which robustness was clinically sacrificed, normalized CTV doses of 0.98, 0.94(7) 1 , 0.94, 0.91, 0.90 and 0.89 were realized. The first of these was clinically borderline non-robust., Conclusion: The clinical robustness evaluation protocol is safe in terms of CTV dose as all plans that fulfilled the clinical robustness criteria were also robust in the PCE evaluation. Moreover, for plans that were non-robust in the PCE-based evaluation, CTV dose was also lower than prescribed in the clinical evaluation., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: Eye-dedicated proton therapy (PT) facilities are used to treat malignant intraocular lesions, especially uveal melanoma (UM). The first commercial ocular PT beamline from Varian was installed in the Netherlands. In this work, the conceptual design of the new eyeline is presented. In addition, a comprehensive comparison against five PT centers with dedicated ocular beamlines is performed, and the clinical impact of the identified differences is analyzed., Material/methods: The HollandPTC eyeline was characterized. Four centers in Europe and one in the United States joined the study. All centers use a cyclotron for proton beam generation and an eye-dedicated nozzle. Differences among the chosen ocular beamlines were in the design of the nozzle, nominal energy, and energy spectrum. The following parameters were collected for all centers: technical characteristics and a set of distal, proximal, and lateral region measurements. The measurements were performed with detectors available in-house at each institution. The institutions followed the International Atomic Energy Agency (IAEA) Technical Report Series (TRS)-398 Code of Practice for absolute dose measurement, and the IAEA TRS-398 Code of Practice, its modified version or International Commission on Radiation Units and Measurements Report No. 78 for spread-out Bragg peak normalization. Energy spreads of the pristine Bragg peaks were obtained with Monte Carlo simulations using Geant4. Seven tumor-specific case scenarios were simulated to evaluate the clinical impact among centers: small, medium, and large UM, located either anteriorly, at the equator, or posteriorly within the eye. Differences in the depth dose distributions were calculated., Results: A pristine Bragg peak of HollandPTC eyeline corresponded to the constant energy of 75 MeV (maximal range 3.97 g/cm 2 in water) with an energy spread of 1.10 MeV. The pristine Bragg peaks for the five participating centers varied from 62.50 to 104.50 MeV with an energy spread variation between 0.10 and 0.70 MeV. Differences in the average distal fall-offs and lateral penumbrae (LPs) (over the complete set of clinically available beam modulations) among all centers were up to 0.25 g/cm 2 , and 0.80 mm, respectively. Average distal fall-offs of the HollandPTC eyeline were 0.20 g/cm 2 , and LPs were between 1.50 and 2.15 mm from proximal to distal regions, respectively. Treatment time, around 60 s, was comparable among all centers. The virtual source-to-axis distance of 120 cm at HollandPTC was shorter than for the five participating centers (range: 165-350 cm). Simulated depth dose distributions demonstrated the impact of the different beamline characteristics among institutions. The largest difference was observed for a small UM located at the posterior pole, where a proximal dose between two extreme centers was up to 20%., Conclusions: HollandPTC eyeline specifications are in accordance with five other ocular PT beamlines. Similar clinical concepts can be applied to expect the same high local tumor control. Dosimetrical properties among the six institutions induce most likely differences in ocular radiation-related toxicities. This interinstitutional comparison could support further research on ocular post-PT complications. Finally, the findings reported in this study could be used to define dosimetrical guidelines for ocular PT to unify the concepts among institutions., (© 2021 The Authors. Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

Background and Purpose: Patient selection for intensity modulated proton therapy (IMPT), using comparative photon therapy planning, is workload-intensive and time-consuming. Pre-selection aims at avoidance of manual IMPT planning for patients that are in the end ineligible. We investigated the use of machine learning together with automated IMPT treatment planning for pre-selection of head and neck cancer patients, and validated the methodology for the Dutch model based selection (MBS) approach., Materials & Methods: For forty-five head and neck patients with a previous MBS, an IMPT plan was generated with non-clinical, fully-automated planning. Dosimetric differences of these plans with the corresponding previously generated photon plans, and the outcomes of the former MBS, were used to train a Gaussian naïve Bayes classifier for MBS outcome prediction. During training, strong emphasis was placed on avoiding misclassification of IMPT eligible patients (i.e. false negatives)., Results: Pre-selection with the classifier resulted in 0 false negatives, 12 (27%) true negatives, 27 (60%) true positives, and only 6 (13%) false positive predictions. Using this pre-selection, the number of formal selection procedures with involved manual IMPT planning that resulted in a negative outcome could be reduced by 67%., Conclusion: With pre-selection, using machine learning and automated treatment planning, the percentage of patients with unnecessary manual IMPT planning for MBS could be drastically reduced, thereby saving costs, labor and time. With the developed approach, larger patient populations can be screened, and likely bias in pre-selection of patients can be mitigated by assisting the physician during patient pre-selection., 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 © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Purpose: A method was recently developed for online-adaptive intensity modulated proton therapy (IMPT) in patients with cervical cancer. The advantage of this approach, relying on the use of tight margins, is challenged by the intrafraction target motion. The purpose of this study was to evaluate the dosimetric effect of intrafraction motion on the target owing to changes in bladder filling in patients with cervical cancer treated with online-adaptive IMPT., Methods and Materials: In 10 patients selected to have large uterus motion induced by bladder filling, the intrafraction anatomic changes were simulated for several prefraction durations for online (automated) contouring and planning. For each scenario, the coverage of the primary target was evaluated with margins of 2.5 and 5 mm., Results: Using a 5- mm planning target volume margin, median accumulated D98% was greater than 42.75 Gy RBE1.1 (95% of the prescribed dose) in the case of a prefraction duration of 5 and 10 minutes. For a prefraction duration of 15 minutes, this parameter deteriorated to 42.6 Gy RBE1.1 . When margins were reduced to 2.5 mm, only a 5-minute duration resulted in median target D98% above 42.75 Gy RBE1.1 . In addition, smaller bladders were found to be associated with larger dose degradations compared with larger bladders., Conclusions: This study indicates that intrafraction anatomic changes can have a substantial dosimetric effect on target coverage in an online-adaptive IMPT scenario for patients subject to large uterus motion. A margin of 5 mm was sufficient to compensate for the intrafraction motion due to bladder filling for up to 10 minutes of prefraction time. However, compensation for the uncertainties that were disregarded in this study, by using margins or robust optimization, is also required. Furthermore, a large bladder volume restrains intrafraction target motion and is recommended for treating patients in this scenario. Assuming that online-adaptive IMPT remains beneficial as long as narrow margins are used (5 mm or below), this study demonstrates its feasibility with regard to intrafraction motion., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background/purpose: Intensity-modulated proton therapy (IMPT) is highly sensitive to anatomical variations which can cause inadequate target coverage during treatment. Available mitigation techniques include robust treatment planning and online-adaptive IMPT. This study compares a robust planning strategy to two online-adaptive IMPT strategies to determine the benefit of online adaptation., Materials/methods: We derived the robustness settings and safety margins needed to yield adequate target coverage (V 95% ≥98%) for >90% of 11 patients in a prostate cancer cohort (88 repeat CTs). For each patient, we also adapted a non-robust prior plan using a simple restoration and a full adaptation method. The restoration uses energy-adaptation followed by a fast spot-intensity re-optimization. The full adaptation uses energy-adaptation followed by the addition of new spots and a range-robust spot-intensity optimization. Dose was prescribed as 55 Gy(RBE) to the low-dose target (lymph nodes and seminal vesicles) with a boost to 74 Gy(RBE) to the high-dose target (prostate). Daily patient set-up was simulated using implanted intra-prostatic markers., Results: Margins of 4 and 8 mm around the high- and low-dose target regions, a 6 mm setup error and a 3% range error were found to obtain adequate target coverage for all repeat CTs of 10/11 patients (94.3% of all 88 repeat CTs). Both online-adaptive strategies yielded V 95% ≥98% and better OAR sparing in 11/11 patients. Median OAR improvements up to 11%-point and 16%-point were observed when moving from robust planning to respectively restoration and full adaption., Conclusion: Both full plan adaptation and simple dose restoration can increase OAR sparing besides better conforming to the target criteria compared to robust treatment planning., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Purpose: Radiotherapy of skull-base meningiomas is challenging due to the close proximity of multiple sensitive organs at risk (OARs). This study systematically compared intensity modulated proton therapy (IMPT), non-coplanar volumetric modulated arc therapy (VMAT) and intensity modulated radiotherapy (IMRT) based on automated treatment planning. Differences in OARs sparing, with specific focus on the hippocampi, and low-dose delivery were quantified., Materials and Methods: Twenty patients, target diameter >3 cm, were included. Automated plan generation was used to calculate a VMAT plan with three non-coplanar arcs, an IMRT plan with nine non-coplanar beams with optimized gantry and couch angles, and an IMPT plan with three patient-specific selected non-coplanar beams. A prescription dose of 50.4 GyRBE in 28 fractions was used. The same set of constraints and prioritized objectives was used. All plans were rescaled to the same target coverage. Repeated measures ANOVA was used to assess the statistical significance of differences in OAR dose parameters between planning techniques., Results: Compared to VMAT and IMRT, IMPT significantly improved dose conformity to the target volume. Consequently, large dose reductions in OARs were observed. With respect to VMAT, the mean dose and D 40% in the bilateral hippocampus were on average reduced by 48% and 74%, respectively (p ≤ 0.005). With IMPT, the mean dose in the normal brain and volumes receiving 20-30 Gy were up to 47% lower (p ≤ 0.01). When comparing IMPT and IMRT, even larger dose differences in those OARs were observed., Conclusion: For skull-base meningiomas IMPT allows for a considerable dose reduction in the hippocampi, normal brain and other OARs compared to both non-coplanar VMAT and IMRT, which may lead to a clinically relevant reduction of late neurocognitive side effects., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background and Purpose: A planning target volume (PTV) in photon treatments aims to ensure that the clinical target volume (CTV) receives adequate dose despite treatment uncertainties. The underlying static dose cloud approximation (the assumption that the dose distribution is invariant to errors) is problematic in intensity modulated proton treatments where range errors should be taken into account as well. The purpose of this work is to introduce a robustness evaluation method that is applicable to photon and proton treatments and is consistent with (historic) PTV-based treatment plan evaluations., Materials and Methods: The limitation of the static dose cloud approximation was solved in a multi-scenario simulation by explicitly calculating doses for various treatment scenarios that describe possible errors in the treatment course. Setup errors were the same as the CTV-PTV margin and the underlying theory of 3D probability density distributions was extended to 4D to include range errors, maintaining a 90% confidence level. Scenario dose distributions were reduced to voxel-wise minimum and maximum dose distributions; the first to evaluate CTV coverage and the second for hot spots. Acceptance criteria for CTV D98 and D2 were calibrated against PTV-based criteria from historic photon treatment plans., Results: CTV D98 in worst case scenario dose and voxel-wise minimum dose showed a very strong correlation with scenario average D98 (R 2  > 0.99). The voxel-wise minimum dose visualised CTV dose conformity and coverage in 3D in agreement with PTV-based evaluation in photon therapy. Criteria for CTV D98 and D2 of the voxel-wise minimum and maximum dose showed very strong correlations to PTV D98 and D2 (R 2  > 0.99) and on average needed corrections of -0.9% and +2.3%, respectively., Conclusions: A practical approach to robustness evaluation was provided and clinically implemented for PTV-less photon and proton treatment planning, consistent with PTV evaluations but without its static dose cloud approximation., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Intensity-modulated proton therapy is sensitive to inter-fraction variations, including density changes along the pencil-beam paths and variations in organ-shape and location. Large day-to-day variations are seen for cervical cancer patients. The purpose of this study was to develop and evaluate a novel method for online selection of a plan from a patient-specific library of prior plans for different anatomies, and adapt it for the daily anatomy. Material and methods: The patient-specific library of prior plans accounting for altered target geometries was generated using a pretreatment established target motion model. Each fraction, the best fitting prior plan was selected. This prior plan was adapted using (1) a restoration of spot-positions (Bragg peaks) by adapting the energies to the new water equivalent path lengths; and (2) a spot addition to fully cover the target of the day, followed by a fast optimization of the spot-weights with the reference point method (RPM) to obtain a Pareto-optimal plan for the daily anatomy. Spot addition and spot-weight optimization could be repeated iteratively. The patient cohort consisted of six patients with in total 23 repeat-CT scans, with a prescribed dose of 45 Gy(RBE) to the primary tumor and the nodal CTV. Using a 1-plan-library (one prior plan based on all motion in the motion model) was compared to choosing from a 2-plan-library (two prior plans based on part of the motion). Results: Applying the prior-plan adaptation method with one iteration of adding spots resulted in clinically acceptable target coverage ( V 95 % ≥ 95 % and V 107 % ≤ 2 % ) for 37/46 plans using the 1-plan-library and 41/46 plans for the 2-plan-library. When adding spots twice, the 2-plan-library approach could obtain acceptable coverage for all scans, while the 1-plan-library approach showed V 107 % > 2 % for 3/46 plans. Similar OAR results were obtained. Conclusion: The automated prior-plan adaptation method can successfully adapt for the large day-to-day variations observed in cervical cancer patients.

Purpose: To develop and validate a robust and accurate registration pipeline for automatic contour propagation for online adaptive Intensity-Modulated Proton Therapy (IMPT) of prostate cancer using elastix software and deep learning., Methods: A three-dimensional (3D) Convolutional Neural Network was trained for automatic bladder segmentation of the computed tomography (CT) scans. The automatic bladder segmentation alongside the computed tomography (CT) scan is jointly optimized to add explicit knowledge about the underlying anatomy to the registration algorithm. We included three datasets from different institutes and CT manufacturers. The first was used for training and testing the ConvNet, where the second and the third were used for evaluation of the proposed pipeline. The system performance was quantified geometrically using the dice similarity coefficient (DSC), the mean surface distance (MSD), and the 95% Hausdorff distance (HD). The propagated contours were validated clinically through generating the associated IMPT plans and compare it with the IMPT plans based on the manual delineations. Propagated contours were considered clinically acceptable if their treatment plans met the dosimetric coverage constraints on the manual contours., Results: The bladder segmentation network achieved a DSC of 88% and 82% on the test datasets. The proposed registration pipeline achieved a MSD of 1.29 ± 0.39, 1.48 ± 1.16, and 1.49 ± 0.44 mm for the prostate, seminal vesicles, and lymph nodes, respectively, on the second dataset and a MSD of 2.31 ± 1.92 and 1.76 ± 1.39 mm for the prostate and seminal vesicles on the third dataset. The automatically propagated contours met the dose coverage constraints in 86%, 91%, and 99% of the cases for the prostate, seminal vesicles, and lymph nodes, respectively. A Conservative Success Rate (CSR) of 80% was obtained, compared to 65% when only using intensity-based registration., Conclusion: The proposed registration pipeline obtained highly promising results for generating treatment plans adapted to the daily anatomy. With 80% of the automatically generated treatment plans directly usable without manual correction, a substantial improvement in system robustness was reached compared to a previous approach. The proposed method therefore facilitates more precise proton therapy of prostate cancer, potentially leading to fewer treatment-related adverse side effects., (© 2019 The Authors. Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.)

The aim of this study was to investigate the feasibility of using prompt gamma (PG) ray emission profiles to monitor changes in dose to the planning target volume (PTV) during pencil beam scanning (PBS) proton therapy as a result of day-to-day variation in patient anatomy. For 11 prostate patients, we simulated treatment plan delivery using the patients' daily anatomy as observed in the planning CT and 7-9 control CT scans, including the detected PG profiles resulting from the 5%, 10%, and 20% most intense proton pencil beams. For each patient, we determined the changes in dosimetric parameters for the high- and low-dose PTVs between the simulations performed using the planning CT scan and the different control CT scans and correlated these to changes in the PG emission profiles. Changes in coverage of the high- and low-dose PTV correlated most strongly with the median and mean absolute PG emission profile shifts of the 5% most intense pencil beams, respectively. With a mean Pearson correlation coefficient of  -0.76 (SD: 0.17) for the high-dose PTV and of  -0.60 (SD: 0.51) for the low-dose PTV. We showed, as a proof of principle, that PG emission profiles obtained during PBS proton therapy could be used to detect changes in PTV coverage due to day-to-day anatomical variation.

Proton therapy plans are very sensitive to anatomical changes such as density changes along the pencil-beam paths and changes in organ shape and location. Previously, we developed a restoration method which compensates for density changes along the pencil-beam paths but which is unable to adapt for anatomical changes. This study's purpose is to develop and evaluate an automated method for adaptation of IMPT plans in near real-time to the anatomy of the day. We developed an automated treatment plan adaptation method using (1) a restoration of spot positions (Bragg peaks) by adapting the energies to the new water equivalent path lengths; and (2) a spot addition to fully cover the target of the day, followed by a fast reference point method optimization of the spot weights resulting in a Pareto optimal plan for the daily anatomy. The method was developed and evaluated using 8-10 repeat CT scans of 11 prostate cancer patients, prescribing 55 Gy(RBE) (seminal vesicles and lymph nodes) with a boost to 74 Gy(RBE) (prostate). Applying the automated adaptation method resulted in a clinically acceptable target coverage (V 95% [Formula: see text] 98% and V 107% [Formula: see text] 2%) for 96% of the scans after a single iteration of adding 2500 spots. The other scans obtained target coverages with V 95% [Formula: see text] 98% and 2  <  V 107% [Formula: see text] 5%. When using two spot-addition iterations, all scans obtained clinically acceptable results. Compared to the restoration method the adaptation lowered the mean dose to rectum and bladder with median values of 6.2 Gy(RBE) and 4.7 Gy(RBE) respectively. The largest improvements were obtained for V 45Gy(RBE) for both rectum and bladder, with median differences of 10.3%-point and 10.8%-point respectively, and maximum differences up to 22%-point. The two adaptation steps took on average 7.3 s and 1.7 min respectively. No user interaction was needed, making this fast and fully automated method a first step towards online adaptive proton therapy.

The aim of this study is to develop an anatomical robust optimization method for intensity-modulated proton therapy (IMPT) that accounts for interfraction variations in nasal cavity filling, and to compare it with conventional single-field uniform dose (SFUD) optimization and online plan adaptation. We included CT data of five patients with tumors in the sinonasal region. Using the planning CT, we generated for each patient 25 'synthetic' CTs with varying nasal cavity filling. The robust optimization method available in our treatment planning system 'Erasmus-iCycle' was extended to also account for anatomical uncertainties by including (synthetic) CTs with varying patient anatomy as error scenarios in the inverse optimization. For each patient, we generated treatment plans using anatomical robust optimization and, for benchmarking, using SFUD optimization and online plan adaptation. Clinical target volume (CTV) and organ-at-risk (OAR) doses were assessed by recalculating the treatment plans on the synthetic CTs, evaluating dose distributions individually and accumulated over an entire fractionated 50 Gy RBE treatment, assuming each synthetic CT to correspond to a 2 Gy RBE fraction. Treatment plans were also evaluated using actual repeat CTs. Anatomical robust optimization resulted in adequate CTV doses (V 95%   ⩾  98% and V 107%   ⩽  2%) if at least three synthetic CTs were included in addition to the planning CT. These CTV requirements were also fulfilled for online plan adaptation, but not for the SFUD approach, even when applying a margin of 5 mm. Compared with anatomical robust optimization, OAR dose parameters for the accumulated dose distributions were on average 5.9 Gy RBE (20%) higher when using SFUD optimization and on average 3.6 Gy RBE (18%) lower for online plan adaptation. In conclusion, anatomical robust optimization effectively accounted for changes in nasal cavity filling during IMPT, providing substantially improved CTV and OAR doses compared with conventional SFUD optimization. OAR doses can be further reduced by using online plan adaptation.

Background and Purpose: The impact of treatment accuracy on NTCP-based patient selection for proton therapy is currently unknown. This study investigates this impact for oropharyngeal cancer patients., Materials and Methods: Data of 78 patients was used to automatically generate treatment plans for a simultaneously integrated boost prescribing 70 Gy RBE /54.25 Gy RBE in 35 fractions. IMRT treatment plans were generated with three different margins; intensity modulated proton therapy (IMPT) plans for five different setup and range robustness settings. Four NTCP models were evaluated. Patients were selected for proton therapy if NTCP reduction was ≥10% or ≥5% for grade II or III complications, respectively., Results: The degree of robustness had little impact on patient selection for tube feeding dependence, while the margin had. For other complications the impact of the robustness setting was noticeably higher. For high-precision IMRT (3 mm margin) and high-precision IMPT (3 mm setup/3% range error), most patients were selected for proton therapy based on problems swallowing solid food (51.3%) followed by tube feeding dependence (37.2%), decreased parotid flow (29.5%), and patient-rated xerostomia (7.7%)., Conclusions: Treatment accuracy has a significant impact on the number of patients selected for proton therapy. Therefore, it cannot be ignored in estimating the number of patients for proton therapy., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Proton therapy is becoming increasingly available, so it is important to apply objective and individualized patient selection to identify those who are expected to benefit most from proton therapy compared to conventional intensity modulated radiation therapy (IMRT). Comparative treatment planning using normal tissue complication probability (NTCP) evaluation has recently been proposed. This work investigates the impact of NTCP model and dose uncertainties on model-based patient selection., Material and Methods: We used IMRT and intensity modulated proton therapy (IMPT) treatment plans of 78 oropharyngeal cancer patients, which were generated based on automated treatment planning and evaluated based on three published NTCP models. A reduction in NTCP of more than a certain threshold (e.g. 10% lower NTCP) leads to patient selection for IMPT, referred to as 'nominal' selection. To simulate the effect of uncertainties in NTCP-model coefficients (based on reported confidence intervals) and planned doses on the accuracy of model-based patient selection, the Monte Carlo method was used to sample NTCP-model coefficients and doses from a probability distribution centered at their nominal values. Patient selection accuracy within a certain sample was defined as the fraction of patients which had similar selection in both the 'nominal' and 'sampled' scenario., Results: For all three NTCP models, the median patient selection accuracy was found to be above 70% when only NTCP-model uncertainty was considered. Selection accuracy decreased with increasing uncertainty resulting from differences between planned and delivered dose. In case of excessive dose uncertainty, selection accuracy decreased to 60%., Conclusion: Model and dose uncertainty highly influence the accuracy of model-based patient selection for proton therapy. A reduction of NTCP-model uncertainty is necessary to reach more accurate model-based patient selection.

In this dosimetric comparison study it was shown that IMPT with robust planning reduces dose to surrounding organs in cervical and endometrial cancer treatment compared with IMRT. Especially for the para-aortic region, clinically relevant dose reductions were obtained for kidneys, spinal cord and bowel, justifying the use of proton therapy for this indication., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Purpose: To quantify the impact of the degree of robustness against setup errors and range errors on organ-at-risk (OAR) dose and normal tissue complication probabilities (NTCPs) in intensity-modulated proton therapy for oropharyngeal cancer patients., Material and Methods: For 20 oropharyngeal cases (10 unilateral and 10 bilateral), robust treatment plans were generated using 'minimax' worst-case optimization. We varied the robustness against setup errors ('setup robustness') from 1 to 7mm and the robustness against range errors ('range robustness') from 1% to 7% (+1mm). We evaluated OAR doses and NTCP-values for xerostomia, dysphagia and larynx edema., Results: Varying the degree of setup robustness was found to have a considerably larger impact than varying the range robustness. Increasing setup robustness from 1mm to 3, 5, and 7mm resulted in average NTCP-values to increase by 1.9, 4.4 and 7.5 percentage point, whereas they increased by only 0.4, 0.8 and 1.2 percentage point when increasing range robustness from 1% to 3%, 5% and 7%. The degree of setup robustness was observed to have a clinically significant impact in bilateral cases in particular., Conclusions: For oropharyngeal cancer patients, minimizing setup errors should be given a higher priority than minimizing range errors., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Purpose: We aimed to derive a "robustness recipe" giving the range robustness (RR) and setup robustness (SR) settings (ie, the error values) that ensure adequate clinical target volume (CTV) coverage in oropharyngeal cancer patients for given gaussian distributions of systematic setup, random setup, and range errors (characterized by standard deviations of Σ, σ, and ρ, respectively) when used in minimax worst-case robust intensity modulated proton therapy (IMPT) optimization., Methods and Materials: For the analysis, contoured computed tomography (CT) scans of 9 unilateral and 9 bilateral patients were used. An IMPT plan was considered robust if, for at least 98% of the simulated fractionated treatments, 98% of the CTV received 95% or more of the prescribed dose. For fast assessment of the CTV coverage for given error distributions (ie, different values of Σ, σ, and ρ), polynomial chaos methods were used. Separate recipes were derived for the unilateral and bilateral cases using one patient from each group, and all 18 patients were included in the validation of the recipes., Results: Treatment plans for bilateral cases are intrinsically more robust than those for unilateral cases. The required RR only depends on the ρ, and SR can be fitted by second-order polynomials in Σ and σ. The formulas for the derived robustness recipes are as follows: Unilateral patients need SR = -0.15Σ(2) + 0.27σ(2) + 1.85Σ - 0.06σ + 1.22 and RR=3% for ρ = 1% and ρ = 2%; bilateral patients need SR = -0.07Σ(2) + 0.19σ(2) + 1.34Σ - 0.07σ + 1.17 and RR=3% and 4% for ρ = 1% and 2%, respectively. For the recipe validation, 2 plans were generated for each of the 18 patients corresponding to Σ = σ = 1.5 mm and ρ = 0% and 2%. Thirty-four plans had adequate CTV coverage in 98% or more of the simulated fractionated treatments; the remaining 2 had adequate coverage in 97.8% and 97.9%., Conclusions: Robustness recipes were derived that can be used in minimax robust optimization of IMPT treatment plans to ensure adequate CTV coverage for oropharyngeal cancer patients., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: To shorten delivery times of intensity modulated proton therapy by reducing the number of energy layers in the treatment plan., Methods and Materials: We have developed an energy layer reduction method, which was implemented into our in-house-developed multicriteria treatment planning system "Erasmus-iCycle." The method consisted of 2 components: (1) minimizing the logarithm of the total spot weight per energy layer; and (2) iteratively excluding low-weighted energy layers. The method was benchmarked by comparing a robust "time-efficient plan" (with energy layer reduction) with a robust "standard clinical plan" (without energy layer reduction) for 5 oropharyngeal cases and 5 prostate cases. Both plans of each patient had equal robust plan quality, because the worst-case dose parameters of the standard clinical plan were used as dose constraints for the time-efficient plan. Worst-case robust optimization was performed, accounting for setup errors of 3 mm and range errors of 3% + 1 mm. We evaluated the number of energy layers and the expected delivery time per fraction, assuming 30 seconds per beam direction, 10 ms per spot, and 400 Giga-protons per minute. The energy switching time was varied from 0.1 to 5 seconds., Results: The number of energy layers was on average reduced by 45% (range, 30%-56%) for the oropharyngeal cases and by 28% (range, 25%-32%) for the prostate cases. When assuming 1, 2, or 5 seconds energy switching time, the average delivery time was shortened from 3.9 to 3.0 minutes (25%), 6.0 to 4.2 minutes (32%), or 12.3 to 7.7 minutes (38%) for the oropharyngeal cases, and from 3.4 to 2.9 minutes (16%), 5.2 to 4.2 minutes (20%), or 10.6 to 8.0 minutes (24%) for the prostate cases., Conclusions: Delivery times of intensity modulated proton therapy can be reduced substantially without compromising robust plan quality. Shorter delivery times are likely to reduce treatment uncertainties and costs., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: Setup, range, and anatomical uncertainties influence the dose delivered with intensity modulated proton therapy (IMPT), but clinical quantification of these errors for oropharyngeal cancer is lacking. We quantified these factors and investigated treatment fidelity, that is, robustness, as influenced by adaptive planning and by applying more beam directions., Methods and Materials: We used an in-house treatment planning system with multicriteria optimization of pencil beam energies, directions, and weights to create treatment plans for 3-, 5-, and 7-beam directions for 10 oropharyngeal cancer patients. The dose prescription was a simultaneously integrated boost scheme, prescribing 66 Gy to primary tumor and positive neck levels (clinical target volume-66 Gy; CTV-66 Gy) and 54 Gy to elective neck levels (CTV-54 Gy). Doses were recalculated in 3700 simulations of setup, range, and anatomical uncertainties. Repeat computed tomography (CT) scans were used to evaluate an adaptive planning strategy using nonrigid registration for dose accumulation., Results: For the recalculated 3-beam plans including all treatment uncertainty sources, only 69% (CTV-66 Gy) and 88% (CTV-54 Gy) of the simulations had a dose received by 98% of the target volume (D98%) >95% of the prescription dose. Doses to organs at risk (OARs) showed considerable spread around planned values. Causes for major deviations were mixed. Adaptive planning based on repeat imaging positively affected dose delivery accuracy: in the presence of the other errors, percentages of treatments with D98% >95% increased to 96% (CTV-66 Gy) and 100% (CTV-54 Gy). Plans with more beam directions were not more robust., Conclusions: For oropharyngeal cancer patients, treatment uncertainties can result in significant differences between planned and delivered IMPT doses. Given the mixed causes for major deviations, we advise repeat diagnostic CT scans during treatment, recalculation of the dose, and if required, adaptive planning to improve adequate IMPT dose delivery., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objective: Our goal was to investigate the performance of an open source deformable image registration package, elastix , for fast and robust contour propagation in the context of online-adaptive intensity-modulated proton therapy (IMPT) for prostate cancer. Methods: A planning and 7–10 repeat CT scans were available of 18 prostate cancer patients. Automatic contour propagation of repeat CT scans was performed using elastix and compared with manual delineations in terms of geometric accuracy and runtime. Dosimetric accuracy was quantified by generating IMPT plans using the propagated contours expanded with a 2 mm (prostate) and 3.5 mm margin (seminal vesicles and lymph nodes) and calculating dosimetric coverage based on the manual delineation. A coverage of V 95% ≥ 98% (at least 98% of the target volumes receive at least 95% of the prescribed dose) was considered clinically acceptable. Results: Contour propagation runtime varied between 3 and 30 s for different registration settings. For the fastest setting, 83 in 93 (89.2%), 73 in 93 (78.5%), and 91 in 93 (97.9%) registrations yielded clinically acceptable dosimetric coverage of the prostate, seminal vesicles, and lymph nodes, respectively. For the prostate, seminal vesicles, and lymph nodes the Dice Similarity Coefficient (DSC) was 0.87 ± 0.05, 0.63 ± 0.18, and 0.89 ± 0.03 and the mean surface distance (MSD) was 1.4 ± 0.5 mm, 2.0 ± 1.2 mm, and 1.5 ± 0.4 mm, respectively. Conclusion: With a dosimetric success rate of 78.5–97.9%, this software may facilitate online adaptive IMPT of prostate cancer using a fast, free and open implementation. [ABSTRACT FROM AUTHOR]

Simple Summary: Chemoradiation with photon radiotherapy is very effective as a locally advanced cervical cancer (LACC) treatment. However, the majority of women with LACC experience treatment-related toxicity involving the gastrointestinal and urogenital tracts and the immune system. Compared to that of photon therapy, proton therapy substantially reduces undesired dose to the organs around the tumor, leading to a decrease in radiotherapy-related side-effects. At present, few studies on proton therapy in patients with LACC will be conducted. The PROTECT trial aims to evaluate the differences in side effects between photon therapy and proton therapy, both combined with chemotherapy, for LACC. Fifteen patients will be enrolled per treatment group. Information will be collected on the differences in dose to the organs around the tumor, treatment-related side effects, and the impact on the immune system. This information will be used to assess the potential of proton therapy as an innovative treatment for LACC. External beam radiation therapy (EBRT) with concurrent chemotherapy followed by brachytherapy is a very effective treatment for locally advanced cervical cancer (LACC). However, treatment-related toxicity is common and reduces the patient's quality of life (QoL) and ability to complete treatment or undergo adjuvant therapies. Intensity modulated proton therapy (IMPT) enables a significant dose reduction in organs at risk (OAR), when compared to that of standard intensity-modulated radiation therapy (IMRT) or volumetric-modulated arc therapy (VMAT). However, clinical studies evaluating whether IMPT consequently reduces side effects for LACC are lacking. The PROTECT trial is a nonrandomized prospective multicenter phase-II-trial comparing clinical outcomes after IMPT or IMRT/VMAT in LACC. Thirty women aged >18 years with a histological diagnosis of LACC will be included in either the IMPT or IMRT/VMAT group. Treatment includes EBRT (45 Gy in 25 fractions of 1.8 Gy), concurrent five weekly cisplatin (40 mg/m2), and 3D image (MRI)-guided adaptive brachytherapy. The primary endpoint is pelvic bones Dmean and mean bowel V15Gy. Secondary endpoints include dosimetric parameters, oncological outcomes, health-related QoL, immune response, safety, and tolerability. This study provides the first data on the potential of IMPT to reduce OAR dose in clinical practice and improve toxicity and QoL for patients with LACC. [ABSTRACT FROM AUTHOR]

• Despite its consistency in terms of TCP, the Dutch RE protocol lead to substantial inter-patient and inter-center variation in terms of CTV dose. • The Dutch MBS protocol for PT patient selection is robust against treatment errors. • Probabilistic evaluations could aid in the harmonization and consensus of robustness evaluation protocols. • Polynomial Chaos Expansion (PCE) allows for a better comprehension of the robustness of treatment plans and evaluation protocols. In the Netherlands, 2 protocols have been standardized for PT among the 3 proton centers: a robustness evaluation (RE) to ensure adequate CTV dose and a model-based selection (MBS) approach for IMPT patient-selection. This multi-institutional study investigates (i) inter-patient and inter-center variation of target dose from the RE protocol and (ii) the robustness of the MBS protocol against treatment errors for a cohort of head-and-neck cancer (HNC) patients treated in the 3 Dutch proton centers. Clinical treatment plans of 100 HNC patients were evaluated. Polynomial Chaos Expansion (PCE) was used to perform a comprehensive robustness evaluation per plan, enabling the probabilistic evaluation of 100,000 complete fractionated treatments. PCE allowed to derive scenario distributions of clinically relevant dosimetric parameters to assess CTV dose (D 99.8% /D 0.2% , based on a prior photon plan calibration) and tumour control probabilities (TCP) as well as the evaluation of the dose to OARs and normal tissue complication probabilities (NTCP) per center. For the CTV 70.00 , doses from the RE protocol were consistent with the clinical plan evaluation metrics used in the 3 centers. For the CTV 54.25 , D 99.8% were consistent with the clinical plan evaluation metrics at center 1 and 2 while, for center 3, a reduction of 1 GyRBE was found on average. This difference did not impact modelled TCP at center 3. Differences between expected and nominal NTCP were below 0.3 percentage point for most patients. The standardization of the RE and MBS protocol lead to comparable results in terms of TCP and the NTCPs. Still, significant inter-patient and inter-center variation in dosimetric parameters remained due to clinical practice differences at each institution. The MBS approach is a robust protocol to qualify patients for PT. [ABSTRACT FROM AUTHOR]

• Our study is the first overview on hematologic toxicity predictors for cervical cancer. • Bone marrow defined as whole pelvic bone is most associated with hematologic toxicity. • Pelvic bone V10 > 95–75%, V20 > 80–65%, and V40 > 37–28% predict hematologic toxicity. Patients with locally advanced cervical cancer (LACC) treated with chemoradiation often experience hematologic toxicity (HT), as chemoradiation can induce bone marrow (BM) suppression. Studies on the relationship between BM dosimetric parameters and clinically significant HT might provide relevant indices for developing BM sparing (BMS) radiotherapy techniques. This systematic review studied the relationship between BM dose and HT in patients with LACC treated with primary cisplatin-based chemoradiation. A systematic search was conducted in Embase, Medline, and Web of Science. Eligibility criteria were treatment of LACC-patients with cisplatin-based chemoradiation and report of HT or complete blood cell count (CBC). The search identified 1346 papers, which were screened on title and abstract before two reviewers independently evaluated the full-text. 17 articles were included and scored according to a selection of the TRIPOD criteria. The mean TRIPOD score was 12.1 out of 29. Fourteen studies defining BM as the whole pelvic bone contour (PB) detected significant associations with V10 (3/14), V20 (6/14), and V40 (4/11). Recommended cut-off values were V10 > 95–75%, V20 > 80–65%, and V40 > 37–28%. The studies using lower density marrow spaces (PBM) or active bone marrow (ABM) as a proxy for BM only found limited associations with HT. Our study was the first literature review providing an overview of articles evaluating the correlation between BM and HT for patients with LACC undergoing cisplatin-based chemoradiation. There is a scarcity of studies independently validating developed prediction models between BM dose and HT. Future studies may use PB contouring to develop normal tissue complication probability models. [ABSTRACT FROM AUTHOR]