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Purpose: Radiation-induced lymphopenia is a common immune toxicity that adversely impacts treatment outcomes. We report here our approach to translate a deep-learning (DL) model developed to predict severe lymphopenia risk among esophageal cancer into a strategy for incorporating the immune system as an organ-at-risk (iOAR) to mitigate the risk. Materials and Methods: We conducted "virtual clinical trials" utilizing retrospective data for 10 intensity-modulated radiation therapy (IMRT) and 10 passively-scattered proton therapy (PSPT) esophageal cancer patients. For each patient, additional treatment plans of the modality other than the original were created employing standard-of-care (SOC) dose constraints. Predicted values of absolute lymphocyte count (ALC) nadir for all plans were estimated using a previously-developed DL model. The model also yielded the relative magnitudes of contributions of iOARs dosimetric factors to ALC nadir, which were used to compute iOARs dose-volume constraints, which were incorporated into optimization criteria to produce "IMRT-enhanced" and "intensity-modulated proton therapy (IMPT)-enhanced" plans. Results: Model-predicted ALC nadir for the original IMRT (IMRT-SOC) and PSPT plans agreed well with actual values. IMPT-SOC showed greater immune sparing vs IMRT and PSPT. The average mean body doses were 13.10 Gy vs 7.62 Gy for IMRT-SOC vs IMPT-SOC for patients treated with IMRT-SOC; and 8.08 Gy vs 6.68 Gy for PSPT vs IMPT-SOC for patients treated with PSPT. For IMRT patients, the average predicted ALC nadir of IMRT-SOC, IMRT-enhanced, IMPT-SOC, and IMPT-enhanced was 281, 327, 351, and 392 cells/µL, respectively. For PSPT patients, the average predicted ALC nadir of PSPT, IMPT-SOC, and IMPT-enhanced was 258, 316, and 350 cells/µL, respectively. Enhanced plans achieved higher predicted ALC nadir, with an average improvement of 40.8 cells/µL (20.6%). Conclusion: The proposed DL model-guided strategy to incorporate the immune system as iOAR in IMRT and IMPT optimization has the potential for radiation-induced lymphopenia mitigation. A prospective clinical trial is planned.

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Introduction and Objective It is unclear if the length of the time interval to initiation of adjuvant radiation therapy (RT) after endoscopic endonasal surgery affects reconstruction outcomes. In this study we present our experience with adjuvant RT after endoscopic endonasal procedures, to determine if the time to RT after surgery impacts post-RT reconstruction complication rates. Methods A retrospective cohort study of 164 patients who underwent endoscopic endonasal surgery between 1998 and 2021 was conducted. Using Cox proportional hazard ratios (HRs), we evaluated several variables and the complications that occurred during the 1-year period after starting RT. Results Seventy-eight (47.5%) and eighty-six patients (52.5%) received RT before and after the sixth postoperative week, respectively. The overall post-RT complication rates were 28%, most of these were severe infections ( n = 20, 12.2%) and delayed CSF leak ( n = 4, 2.5%). There was no significant difference in the post-RT complications between the patients who received postoperative RT before or after the sixth operative week (HR: 1.13; 95% confidence interval: 0.63-2.02; p = 0.675 ). Univariate analysis demonstrated negative impact associated with smoking history ( p = 0.015 ), the use of neoadjuvant chemotherapy ( p = 0.0001 ), and the use of photon therapy ( p = 0.012 ); and we found a positive impact with the use of multilayer reconstruction techniques (overall, p = 0.041 ; with fat, p = 0.038 ; and/or fascia graft, p = 0.035 ). After a multivariate analysis only, smoking history was an independent risk factor for post-RT complications ( p = 0.012 ). Conclusion Delaying RT for more than 6 weeks after endoscopic endonasal surgery does not provide a significant benefit for reconstruction outcomes. However, special attention may be warranted in patients with smoking history who have received neoadjuvant chemotherapy, or in patients who will receive photon-based RT after surgery as these groups were found to have increased complication rates post-RT.

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Background and purpose: Magnetic resonance imaging (MRI)-only workflow is used in photon radiotherapy (RT) today, but not yet for protons. To bring MRI-only proton RT into clinical use, proton dose calculation on MRI-derived synthetic CT (sCT) must be validated. We evaluated proton dose calculation accuracy of prostate cancer proton plans using a commercially available sCT generator already validated for photon planning. Materials and methods: The retrospective planning study included 10 prostate cancer patients who underwent MRI and planning CT (pCT) before RT. sCT were generated from the MRI with MRI Planner v2.3, and compared to pCT using structural mean absolute error (MAE). The pCT was used to create one-arc volumetric modulated arc therapy (VMAT) photon plan and two-field intensity modulated proton therapy (IMPT) proton plan. Each plan was recalculated on the sCT and compared to pCT doses. Dose volume histogram parameters, gamma analyses and range differences were evaluated. Results: Median MAE for the body contour was 71 HU. Dose differences between pCT and sCT were small and similar for VMAT and IMPT plans. Median (range) gamma pass rates were lower for IMPT plans with 95.8 (89.3-98.7) % compared to VMAT plans with 99.4 (91.2-99.6) %. The proton range difference was 1.0 (interquartile range -0.1 - 0.2) mm deeper for sCT compared to the reference. Conclusion: MRI-only IMPT planning for prostate cancer seems feasible in a clinical setting for the evaluated beam arrangement and sCT generator. More patients and evaluation of other beam arrangements are needed for a more general conclusion.

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BACKGROUND: Pencil Beam Scanning proton therapy has many advantages from a therapeutic point of view, but raises technical constraints in terms of treatment verification. The treatment relies on a large number of planned pencil beams (PB) (up to thousands), whose delivery is divided in several low-intensity pulses delivered a high frequency (1 kHz in this study). PURPOSE: The purpose of this study was to develop a three-dimensional quality assurance system allowing to verify all the PBs' characteristics (position, energy, intensity in terms of delivered monitor unit-MU) of patient treatment plans on a pulse-by-pulse or a PB-by-PB basis. METHODS: A system named SCICOPRO has been developed. It is based on a 10 × 10 × 10 cm3 scintillator cube and a fast camera, synchronized with beam delivery, recording two views (direct and using a mirror) of the scintillation distribution generated by the pulses. A specific calibration and analysis process allowed to extract the characteristics of all the pulses delivered during the treatment, and consequently of all the PBs. The system uncertainties, defined here as average value + standard deviation, were characterized with a customized irradiation plan at different PB intensities (0.02, 0.1, and 1 MU) and with two patient's treatment plans of three beams each. The system's ability to detect potential treatment delivery problems, such as positioning errors of the treatment table in this work (1° rotations and a 2 mm translation), was assessed by calculating the confidence intervals (CI) for the different characteristics and evaluating the proportion of PBs within these intervals. RESULTS: The performances of SCICOPRO were evaluated on a pulse-by-pulse basis. They showed a very good signal-to-noise ratio for all the pulse intensities (between 2 × 10-3 MU and 150 × 10-3 MU) allowing uncertainties smaller than 580 µm for the position, 180 keV for the energy and 3% for the intensity on patients treatment plans. The position and energy uncertainties were found to be little dependent from the pulse intensities whereas the intensity uncertainty depends on the pulses number and intensity distribution. Finally, treatment plans evaluations showed that 98% of the PBs were within the CIs with a nominal positioning against 83% or less with the table positioning errors, thus proving the ability of SCICOPRO to detect this kind of errors. CONCLUSION: The high acquisition rate and the very high sensitivity of the system developed in this work allowed to record pulses of intensities as low as 2 × 10-3 MU. SCICOPRO was thus able to measure all the characteristics of the spots of a treatment (position, energy, intensity) in a single measurement, making it possible to verify their compliance with the treatment plan. SCICOPRO thus proved to be a fast and accurate tool that would be useful for patient-specific quality assurance (PSQA) on a pulse-by-pulse or PB-by-PB verification basis.

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Background and aims: Proton therapy (PRT) for Head Neck Cancer (HNC), in view of the Bragg peak, spares critical structures like oral mucosa better than IMRT. In PRT, mouth-bites, besides immobilising and separating mucosal surfaces, may also negate the end-of-range effect. We retrospectively analysed the details and dosimetric impact of mouth-bites in PRT for HNC. Materials and methods: The data of consecutive HNC patients treated with IMPT from May 2020 to August 2022 were studied retrospectively. Details of the mouth-bite used, compliance and resultant mucosal separation were noted. Further analysis, restricted to previously unirradiated patients, comprised volumetric dosimetric data pertaining to the mouth-bite and distal mucosal surfaces. High LET zones, corresponding to 6-12 keV/micron, for mouth-bite doses above 30 Gy, were recalculated from existing plans. Results: A mouth-bite was used in 69 of 80 consecutively treated patients, ranging from 8 to 42 mm in thickness, and 12 to 52 mm in the resultant mucosal sparing. In 42 patients in whom the mouth-bite V 32 Gy was > 0, median Dmean, absolute V32, V39, V50 and V60 GyE (Gray Equivalent) of the mouth bite was 35.65 GyE (Range: 2.65 - 60 GyE), 10 cc (Range: 0.1 - 32 cc), 7.6 cc (Range: 0.1 - 30.8 cc), 5.7 cc (Range: 0.2 - 29.2 cc) and 1.45 cc (Range: 0.2 - 18.1 cc) respectively, all significantly more than the spared adjacent mucosal surface. In absence of a mouth-bite, the spared mucosa would have at least partially received the high dose received by the mouth-bite. High LET zones were noted in 12 of 48 mouth-bites. Conclusion: In PRT for HNC, mouth-bites play a vital role in improving the sparing of mucosa outside the target.

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Proton therapy (PT) is an advancing radiotherapy modality increasingly integrated into clinical settings, transitioning from research facilities to hospital environments. A critical aspect of the commissioning of a proton pencil beam scanning delivery system is the acquisition of experimental beam data for accurate beam modelling within the treatment planning system (TPS). These guidelines describe in detail the acquisition of proton pencil beam modelling data. First, it outlines the intrinsic characteristics of a proton pencil beam-energy distribution, angular-spatial distribution and particle number. Then, it lists the input data typically requested by TPSs. Finally, it describes in detail the set of experimental measurements recommended for the acquisition of proton pencil beam modelling data-integrated depth-dose curves, spot maps in air, and reference dosimetry. The rigorous characterization of these beam parameters is essential for ensuring the safe and precise delivery of proton therapy treatments.

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Background and purpose: Despite the superior dose conformity of proton therapy, the dose distribution is sensitive to daily anatomical changes, which can affect treatment accuracy. This study evaluated the dose recalculation accuracy of two synthetic computed tomography (sCT) generation algorithms in a commercial treatment planning system. Materials and methods: The evaluation was conducted for head-and-neck, thorax-and-abdomen, and pelvis sites treated with proton therapy. Thirty patients with two cone-beam computed tomography (CBCT) scans each were selected. The sCT images were generated from CBCT scans using two algorithms, Corrected CBCT (corrCBCT) and Virtual CT (vCT). Dose recalculations were performed based on these images for comparison with "ground truth" deformed CTs. Results: The choice of algorithm influenced dose recalculation accuracy, particularly in high dose regions. For head-and-neck cases, the corrCBCT method showed closer agreement with the "ground truth", while for thorax-and-abdomen and pelvis cases, the vCT algorithm yielded better results (mean percentage dose discrepancy of 0.6 %, 1.3 % and 0.5 % for the three sites, respectively, in the high dose region). Head-and-neck and pelvis cases exhibited excellent agreement in high dose regions (2 %/2 mm gamma passing rate >98 %), while thorax-and-abdomen cases exhibited the largest differences, suggesting caution in sCT algorithm usage for this site. Significant systematic differences were observed in the clinical target volume and organ-at-risk doses in head-and-neck and pelvis cases, highlighting the importance of using the correct algorithm. Conclusions: This study provided treatment site-specific recommendations for sCT algorithm selection in proton therapy. The findings offered insights for proton beam centers implementing adaptive radiotherapy workflows.

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BACKGROUND: In head and neck (H&N) cancer treatment, a conventional setup error (SE) of 3mm is often used in robust optimization (cRO3mm). However, cRO3mm may lead to excessive radiation doses to organs at risk (OARs) and does not purposefully compensate for interfractional anatomy variations. PURPOSE: This study introduces a method using predicted images from an anatomical model and a reduced 1mm SE uncertainty for robust optimization (aRO1mm), aiming to decrease the dose to OARs without affecting the coverage of the clinical target volume (CTV). METHODS: This retrospective study involved 10 nasopharynx radiotherapy patients. Validation CT scans (vCT) from treatment weeks 1 to 6 were analyzed. A predictive anatomical model, designed to capture the average anatomical changes over time, provided predicted CT images for weeks 1, 3, and 5. We compared three optimization scenarios: (1) aRO1mm, using three predicted images with 1mm setup shift and 3% range uncertainty, (2) cRO3mm, with a robust 3mm setup shift and 3% range uncertainty, and (3) cRO1mm, a robust 1mm setup shift and 3% range uncertainty. The accumulated dose to CTVs and serial organs was evaluated under these uncertainties, while parallel OARs were assessed using the accumulated nominal dose (without errors). RESULTS: The accumulated volume receiving 94% of the prescribed dose (V94) for CTVs in cRO3mm exceeded 98%, meeting the clinical goal. For high-risk CTV, the minimum V94 was 96.44% in aRO1mm and 94.05% in cRO1mm. For low-risk CTV, these values were 97.68% in aRO1mm and 97.15% in cRO1mm. When comparing aRO1mm to cRO3mm on OARs, aRO1mm reduced normal tissue complication probability (NTCP) for grade ≥ $\ge$ 2 xerostomia and dysphagia by averages of 3.67% and 1.54%, respectively. CONCLUSION: aRO1mm lowers the radiation dose to OARs compared to the traditional approach, while maintaining adequate dose coverage on the target area. This method offers an improved strategy for managing uncertainties in radiation therapy planning for H&N cancer, enhancing treatment effectiveness.

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OBJECTIVE: 12N, having a half-life of 11 milliseconds, is a very promising positron emitter to provide near real-time feedback in proton therapy. There is currently no framework for comparing and validating positron emission imaging of 12N. This work describes the development and validation of a Monte Carlo framework to calculate the images of 12N, as well as long-lived isotopes, originating from activation by protons. Approach: The available dual-panel Biograph mCT PET scanner was modeled in GATE and validated by comparing the simulated sensitivity map with the measured one. The distributions of 12N and long-lived isotopes were calculated by RayStation and used as the input of GATE simulations. The RayStation/GATE combination was verified using proton beam irradiations of homogeneous phantoms. A 120 MeV pulsed pencil beam with 108 protons per pulse was used. Two-dimensional images were created from the GATE output and compared with the images based on the measurements and the 1D longitudinal projection of the full 2D image was used to calculate the 12N activity range. Main results: The simulated sensitivity in the center of the FoV (5.44%) agrees well with the measured one (5.41%). The simulated and measured 2D sensitivity maps agree in good detail. The relative difference between the measured and simulated positron activity range for both 12N and long-lived isotopes is less than 1%. The broadening of the 12N images relative to those of the longer-lived isotopes can be understood in terms of the large positron range of 12N. Significance: We developed and validated a Monte Carlo framework based on RayStation/GATE to support the in-beam PET method for quality assurance of proton therapy. The novel inclusion of the very short-lived isotope 12N makes the framework useful for developing near real-time verification. This represents a significant step towards translating 12N real-time in vivo verification to the clinic. .

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BACKGROUND: We conducted a systematic review to evaluate outcomes and toxicities associated with proton therapy in the treatment of adult-type diffuse glioma. METHODS: Following PRISMA guidelines, we searched PubMed for both prospective and retrospective studies on proton therapy for adult diffuse gliomas, including IDH-mutated gliomas WHO grade 2-3 and glioblastomas. Survival and toxicity outcomes were reported separately for these glioma types. RESULTS: Twelve studies from 2013 to 2023 were selected, comprising 3 prospective and 9 retrospective studies. The analysis covered 570 patients with WHO grade 2-3 gliomas and 240 patients with glioblastoma or WHO grade 4 gliomas. Proton therapy was found to be comparable to conventional radiotherapy in terms of survival outcomes. Its main advantage is the ability to minimize radiation exposure to healthy tissues. DISCUSSION: Proton therapy offers comparable survival outcomes to conventional radiotherapy for adult diffuse gliomas and may enhance treatment tolerance, especially regarding neurocognitive function. A major limitation of this review is the predominance of retrospective studies. Future research should ensure rigorous patient selection and adhere to the latest WHO 2021 classification.

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BACKGROUND: The interaction between breathing motion and scanning beams causes interplay effects in spot-scanning proton therapy for lung cancer, resulting in compromised treatment quality. This study investigated the effects and clinical robustness of two types of spot-scanning proton therapy with motion-mitigation techniques for locally advanced non-small cell lung cancer (NSCLC) using a new simulation tool (4DCT-based dose reconstruction). METHODS: Three-field single-field uniform dose (SFUD) and robustly optimized intensity-modulated proton therapy (IMPT) plans combined with gating and re-scanning techniques were created using a VQA treatment planning system for 15 patients with locally advanced NSCLC (70 GyRBE/35 fractions). In addition, gating windows of three or five phases around the end-of-expiration phase and two internal gross tumor volumes (iGTVs) were created, and a re-scanning number of four was used. First, the static dose (SD) was calculated using the end-of-expiration computed tomography (CT) images. The four-dimensional dynamic dose (4DDD) was then calculated using the SD plans, 4D-CT images, and the deformable image registration technique on end-of-expiration CT. The target coverage (V98%, V100%), homogeneity index (HI), and conformation number (CN) for the iGTVs and organ-at-risk (OAR) doses were calculated for the SD and 4DDD groups and statistically compared between the SD, 4DDD, SFUD, and IMPT treatment plans using paired t-test. RESULTS: In the 3- and 5-phase SFUD, statistically significant differences between the SD and 4DDD groups were observed for V100%, HI, and CN. In addition, statistically significant differences were observed for V98%, V100%, and HI in phases 3 and 5 of IMPT. The mean V98% and V100% in both 3-phase plans were within clinical limits (> 95%) when interplay effects were considered; however, V100% decreased to 89.3% and 94.0% for the 5-phase SFUD and IMPT, respectively. Regarding the significant differences in the deterioration rates of the dose volume histogram (DVH) indices, the 3-phase SFUD plans had lower V98% and CN values and higher V100% values than the IMPT plans. In the 5-phase plans, SFUD had higher deterioration rates for V100% and HI than IMPT. CONCLUSIONS: Interplay effects minimally impacted target coverage and OAR doses in SFUD and robustly optimized IMPT with 3-phase gating and re-scanning for locally advanced NSCLC. However, target coverage significantly declined with an increased gating window. Robustly optimized IMPT showed superior resilience to interplay effects, ensuring better target coverage, prescription dose adherence, and homogeneity than SFUD. TRIAL REGISTRATION: None.

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BACKGROUND AND OBJECTIVE: Understanding the intricate interactions among leucocyte subpopulations following radiotherapy is crucial for advancing cancer research and immunology. Recently, interest in recent radiotherapy modalities, such as protons, has increased. Herein, we present a framework utilizing Bayesian networks to uncover these complex relationships via an illustrative example of brain irradiation in rodents. METHODS: We utilized data from 96 healthy C57BL/6 adult mice subjected to either X-ray or proton brain irradiation. Leucocyte subpopulations in the blood collected 12 h after the final irradiated fraction were quantified. We employed Bayesian networks to detect causal interplay between physiological parameters, radiation variables and circulating leucocytes. The causal structure was learned via the use of the Bayesian information criterion as a scored criterion. Parameter estimation was performed to quantify the strength of the identified causal relationships. Cross-validation was used to validate our Bayesian network model's performance. RESULTS: In the X-ray model, we discovered previously undisclosed interactions between NK-cells and neutrophils, and between monocytes and T-CD4+ cells. The proton model revealed an interplay involving T-CD4+ cells and neutrophils. Both X-rays and protons led to heightened interactions between T-CD8+ cells and B cells, indicating their significant role in orchestrating immune responses. Additionally, the proton model displayed strengthened interactions between T-CD4+ and T-CD8+ cells, emphasizing a dynamic and coordinated immune response post-irradiation. Cross-validation results demonstrated the robustness of the Bayesian network model in explaining data uncertainty. CONCLUSION: The use of Bayesian networks as tools for causal structure discovery has revealed novel insights into the dynamics of immune responses to radiation exposure.

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BACKGROUND: This study assessed the cost-effectiveness of proton beam therapy (PBT) compared to conventional radiotherapy (CRT) for treating patients with brain tumors in Sweden. METHODS: Data from a longitudinal non-randomized study performed between 2015 and 2020 was used, and included adult patients with brain tumors, followed during treatment and through a one-year follow-up. Clinical and demographic data were sourced from the longitudinal study and linked to Swedish national registers to get information on healthcare resource use. A cost-utility framework was used to evaluate the cost-effectiveness of PBT vs. CRT. Patients in PBT group (n = 310) were matched with patients in CRT group (n = 40) on relevant observables using propensity score matching with replacement. Costs were estimated from a healthcare perspective and included costs related to inpatient and specialized outpatient care, and prescribed medications. The health outcome was quality-adjusted life-years (QALYs), derived from the EORTC-QLQ-C30. Generalized linear models (GLM) and two-part models were used to estimate differences in costs and QALYs. RESULTS: PBT yielded higher total costs, 14,639 US$, than CRT, 13,308 US$, with a difference of 1,372 US$ (95% CI, -4,914-7,659) over a 58 weeks' time horizon. Further, PBT resulted in non-significantly lower QALYs, 0.746 compared to CRT, 0.774, with a difference of -0.049 (95% CI, -0.195-0.097). The probability of PBT being cost-effective was < 30% at any willingness to pay. CONCLUSIONS: These results suggest that PBT cannot be considered a cost-effective treatment for brain tumours, compared to CRT. TRIAL REGISTRATION: Not applicable.

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Radiotherapy is a crucial component in the holistic management of breast cancer, with approximately 60% of individuals diagnosed with breast cancer requiring this treatment. As the survival rate of individuals with breast cancer has significantly increased, there is a growing focus on the long-term well-being of patients. Proton therapy (PT) is a new and rapidly developing radiotherapy method. In comparison with conventional photon therapy, PT offers the benefits of decreased radiation toxicity and increased dosage in the designated region. This can extend patients' lifespan and enhance their overall well-being. The present analysis examines the function of PT in diminishing the harmful effects of radiation in cases of breast cancer, while also providing a brief overview of the future potential and obstacles associated with PT for breast cancer.

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Background and Purpose: The primary cause of range uncertainty in proton therapy is inaccuracy in estimating the stopping-power ratio from computed tomography. This study examined the impact on dose-volume metrics by reducing range uncertainty in robust optimisation for a diverse patient cohort and determined the level of range uncertainty that resulted in a relevant reduction in doses to organs-at-risk (OARs). Materials and Methods: The effect of reducing range uncertainty on OAR doses was evaluated by robustly optimising six proton plans with varying range uncertainty levels (ranging from 3.5% in the original plan to 1.0%), keeping setup uncertainty fixed. All plans used the initial clinical treatment plan's beam directions and optimisation objectives and were optimised until a clinically acceptable plan was achieved across all setup and range scenarios. The effect of reduced range uncertainty on dose-volume metrics for OARs near the target was evaluated. This study included 30 brain cancer patients, as well as five head-and-neck and five breast cancer patients, investigating the relevance of reducing range uncertainty when different setup uncertainties were used. Results: Lowering range uncertainty slightly reduced the nominal dose to surrounding tissue. For body volume receiving 80% of the prescribed dose, reducing range uncertainty from 3.5% to 2.0% resulted in a median decrease of 4 cm3 for the brain, 17 cm3 for head-and-neck, and 27 cm3 for breast cancer patients. Conclusions: Reducing range uncertainty in robust optimisation showed a reduction in dose to OARs. The clinical relevance depends on the affected organs and the clinical dose constraints.

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Background and purpose: Since patients with primary brain tumor are expected to become long-term survivors, the prevention of long-term treatment-induced side effects is particularly important. This study aimed to explore whether symptom experience and symptom distress change over five years in adults with primary brain tumors treated with proton therapy. An additional aim was to explore whether symptom experience and symptom distress correlate. Materials and methods: The study had a longitudinal observational design. Adult (≥18 years) patients (n = 170) with primary brain tumors treated with proton therapy were followed over five years. Symptom experience and symptom distress were evaluated using the patient-reported Radiotherapy-Related Symptom Assessment Scale. Data from baseline, 1, 12, and 60 months were analyzed using non-parametric tests. Results: Of the 170 patients, the levels of symptoms and symptom distress were low. Fatigue increased at 1 (p=0.005) and 12 months (p=0.025) and was the most frequent symptom from baseline to 60 months' follow-up. Cognitive impairment increased at 12 (p=0.027) and 60 months (p<0.001) and was the most distressing symptom at 60 months' follow-up. There were significant, moderate to strong, correlations at all time points between symptom experience and symptom distress of fatigue, insomnia, pain, dyspnea, cognitive impairment, worry, anxiety, nausea, sadness, constipation, and skin reactions. Conclusion: Symptom experience and symptom distress changed in intensity over time with cognitive impairment as the most distressing symptom at 60 months. Future research should focus on identifying effective interventions aimed at alleviating these symptoms and reducing symptom distress for this vulnerable group of patients.

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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 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%/3mm). 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 minutes [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 minutes [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. .

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Background and purpose: Intensity modulated proton therapy (IMPT) enables generation of conformal dose plans with organ at risk (OAR) sparing potential. However, pelvic IMPT robustness is challenged by inter-fraction motion caused by constant anatomical variations. In this study, the dosimetric impact of inter-fraction motion on target coverage and dose to OAR was quantified in the prospective phase II study ReRad-II on dose-escalated proton reirradiation for locally recurrent rectal cancer (LRRC). Materials and methods: The inter-fraction motion robustness was assessed for the initial twelve patients enrolled in the ReRad-II study. Patients with resectable LRRC were assessed for neoadjuvant IMPT (55 Gy(RBE)/44Fx) and unresectable recurrences for definitive IMPT (57.5-65 Gy(RBE)/ 46-52Fx). Target coverage and dose to OAR were assessed for robustly optimised three-field IMPT, on 12 plan computerized tomography (CT) scans (pCT) - and 47 repetitive control CT scans (cCTs) during the treatment. The target coverage and doses to OAR were re-calculated on each cCT and the mean dose ratio (pCT/cCT-ratio) and target coverage (V95%) was evaluated. Results: The target coverage was robust with a mean dose pCT/cCT-ratio of 1.00 (+/-1%). The V95% target coverage for every cCT were above the accepted worst-case scenario in the robust evaluation. Considerable variation in bladder-, bowel bag-, and bowel loop volume was observed. The OAR with the largest variation in ratio was the bladder (pCT/cCT-ratio: 1.3 (range: 0.5-4.7). Conclusions: IMPT for dose-escalated reirradiation of LRRC provided anatomically robust target coverage despite OAR changes. Inter-fraction motion resulted in OAR doses varying within clinically acceptable range.

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OBJECTIVE: The aim of this study was to evaluate the feasibility and plan quality of spot-scanning proton arc therapy (SPArc) using a synchrotron-accelerator-based proton therapy system compared to intensity-modulated proton therapy (IMPT). APPROACH: Five representative disease sites, including head and neck, lung, liver, brain chordoma, and prostate cancers, were retrospectively selected. Both IMPT and SPArc plans are generated with the HITACHI ProBEAT PBS system's minimum MU constraints and physics beam model. The SPArc plans are generated with 2.5° sampling frequency. The static delivery time was simulated based on the previously published synchrotron delivery sequence model, and the dynamic delivery time was simulated using a proton arc gantry mechanical model integrated with the synchrotron delivery sequence. Both dosimetric plan quality and delivery efficiency are evaluated. MAIN RESULTS: A superior plan quality is reached compared with the IMPT plans generated for the same disease site. However, a relatively prolonged static and dynamic delivery time post new challenge, as static time increased by 49.22% and dynamic time 59.10% on average. SIGNIFICANCE: This study presents the first simulation results of delivering the SPArc plans using a synchrotron-accelerated proton therapy system. The result shows its feasibility and limitations, which could guide future development.

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Purpose/objectives: The indications, techniques, and extent to which proton beam therapy (PBT) is employed for breast cancer are unknown. We seek to determine PBT utilization for breast cancer. Materials/methods: The Particle Therapy Co-Operative Group (PTCOG) Breast Subcommittee developed an IRB-approved 29-question survey and sent it to breast cancer radiation oncologists at all active PBT centers worldwide in June 2023. Descriptive statistics were used to summarize responses, and comparisons by continent were performed using Fisher's exact tests. Results: Of 79 surveys distributed, 28 recipients submitted responses (35 % response rate) representing fifteen U.S., 8 European, and 5 Asian centers (continent response rate 50 %, 38 %, and 18 %, respectively). Overall, 93 % reported treating breast cancer patients with PBT; 13 (50 %) have treated ≥100 breast cancer patients at their center since opening. Most (89 %) have pencil beam scanning technology. Nearly half (46 %) use moderate hypofractionation (15-20 fractions) for regional nodal irradiation and 42 % conventional fractionation (25-30 fractions). More European centers prefer hypofractionation (88 %) vs. Asian (50 %) and U.S. (21 %) centers (p = 0.003). Common patient selection methods were practitioner determination/patient preference (n = 16) and comparative plan evaluation (n = 15). U.S. centers reported the most experience with breast PBT, with 71 % having treated ≥100 breast cancer patients vs. 38 % in Europe and none in Asia (p = 0.001). Of respondent centers, 39 % enrolled ≥75 % of breast PBT patients on a research study. Conclusion: Utilization, patient selection methods, and dose-fractionation approaches for breast cancer PBT vary worldwide. These survey data serve as a benchmark from which successor surveys can provide insight on practice pattern evolution.