Search

This position paper, led by the NRG Oncology Particle Therapy Work Group, focuses on the concept of relative biologic effect (RBE) in clinical proton therapy (PT), with the goal of providing recommendations for the next-generation clinical trials with PT on the best practice of investigating and using RBE, which could deviate from the current standard proton RBE value of 1.1 relative to photons. In part 1, current clinical utilization and practice are reviewed, giving the context and history of RBE. Evidence for variation in RBE is presented along with the concept of linear energy transfer (LET). The intertwined nature of tumor radiobiology, normal tissue constraints, and treatment planning with LET and RBE considerations is then reviewed. Part 2 summarizes current and past clinical data and then suggests the next steps to explore and employ tools for improved dynamic models for RBE. In part 3, approaches and methods for the next generation of prospective clinical trials are explored, with the goal of optimizing RBE to be both more reflective of clinical reality and also deployable in trials to allow clinical validation and interpatient comparisons. These concepts provide the foundation for personalized biologic treatments reviewed in part 4. Finally, we conclude with a summary including short- and long-term scientific focus points for clinical PT. The practicalities and capacity to use RBE in treatment planning are reviewed and considered with more biological data in hand. The intermediate step of LET optimization is summarized and proposed as a potential bridge to the ultimate goal of case-specific RBE planning that can be achieved as a hypothesis-generating tool in near-term proton trials., (Published by Elsevier Inc.)

Background: Minibeam represents a preclinical spatially fractionated radiotherapy modality with great translational potential. The advantage lies in its high therapeutic index (compared to GRID and LATTICE) and ability to treat at greater depth (compared to microbeam). Proton minibeam radiotherapy (pMBRT) is a synergy of proton and minibeam. While the single-gantry proton facility has gained popularity due to its affordability and compact design, it often has limited beam time available for research purposes. Conversely, given the current requirement of pMBRT on specific minibeam hardware collimators, necessitates a reproducible and fast setup to minimize pMBRT treatment time and streamline the switching time between pMBRT and conventional treatment for clinically translation., Purpose: The contribution of this work is the development and characterization of the first pMBRT system tailored for single-gantry proton facility. The system allows for efficient and reproducible plug-and-play setup, achievable within minutes., Methods: The single room pMBRT system is constructed based on IBA ProteusONE proton machine. The end of nozzle is attached with beam modifying accessories though an accessory drawer. A small snout is attached to the accessory drawer and used to hold apertures and range shifters. The minibeam aperture consists of two components: a fitting ring and an aperture body. Three minibeam apertures were manufactured. The first-generation apertures underwent qualitatively analysis with film, and the second generation aperture underwent more comprehensive quantitative measurement. The reproducibility of the setup is accessed, and the film measurements are performed to characterize the pMBRT system in cross validation with Monte Carlo (MC) simulations., Results: We presented initial results of large field pMBRT aperture and the film measurements indicates the effect of source-to-isocenter distance = 930 cm in Y proton scanning direction. Consistent with TOPAS MC simulation, the dose uniformity of pMBRT field <2 cm is demonstrated to be better than 2%, rendering its suitability for pre-clinical studies. Subsequently, we developed the second generation of aperture with five slits and characterized the aperture with film dosimetry studies and compared the results to the benchmark MC. Comprehensive film measurements were also performed to evaluate the effect of divergence, air gap and gantry-angle dependency and repeatability and revealing a consistent performance within 5%. Furthermore, the 2D gamma analysis indicated a passing rate exceeding 99% using 3% dose difference and 0.2 mm distance agreement criteria. We also establish the peak valley dose ratio and the depth dose profile measurements, and the results are within 10% from MC simulation., Conclusions: We have developed the first pMBRT system tailored for a single-gantry proton facility, which has demonstrated accuracy in benchmark with MC simulations, and allows for efficient plug-and-play setup, emphasizing efficiency., (© 2024 American Association of Physicists in Medicine.)

Proton-to-photon comparative treatment planning is a current requirement of Australian Government funding for patients to receive proton beam therapy (PBT) overseas, and a future requirement for Medicare funding of PBT in Australia. Because of the fundamental differences in treatment plan creation and evaluation between PBT and conventional radiation therapy with x-rays (XRT), there is the potential for a lack of consistency in the process of comparing PBT and XRT treatment plans. This may have an impact on patient eligibility assessment for PBT. The objective of these guidelines is to provide a practical reference document for centres performing proton-to-photon comparative planning and thereby facilitate national uniformity., (© 2023 The Authors. Journal of Medical Imaging and Radiation Oncology published by John Wiley & Sons Australia, Ltd on behalf of Royal Australian and New Zealand College of Radiologists.)

Background: While the Bragg peak proton beam (BP) is capable of superior target conformity and organs-at-risk sparing than the transmission proton beam (TB), its efficacy in FLASH-RT is hindered by both a slow energy switching process and the beam current. A universal range shifter (URS) can pull back the high-energy proton beam while preserving the beam current. Meanwhile, a superconducting gantry with large momentum acceptance (LMA-SC gantry) enables fast energy switching., Purpose: This study explores the feasibility of multiple-energy BP FLASH-RT on the LMA-SC gantry., Method and Materials: A simultaneous dose and spot map optimization algorithm was developed for BP FLASH-RT treatment planning to improve the dose delivery efficiency. The URS was designed to be 0-27 cm thick, with 1 cm per step. BP plans using the URS were optimized using single-field optimization (SFO) and multiple-field optimization (MFO) for ten prostate cancer patients and ten lung cancer patients. The plan delivery parameters, dose, and dose rate metrics of BP plans were compared to those of TB plans using the parameters of the LMA-SC gantry., Results: Compared to TB plans, BP plans significantly reduced MUs by 42.7% (P < 0.001) with SFO and 33.3% (P < 0.001) with MFO for prostate cases. For lung cases, the reduction in MUs was 56.8% (P < 0.001) with SFO and 36.4% (P < 0.001) with MFO. BP plans also outperformed TB plans by reducing mean normal tissue doses. BP-SFO plans achieved a reduction of 56.7% (P < 0.001) for prostate cases and 57.7% (P < 0.001) for lung cases, while BP-MFO plans achieved a reduction of 54.2% (P < 0.001) for the prostate case and 40.0% (P < 0.001) for lung cases. For both TB and BP plans, normal tissues in prostate and lung cases received 100.0% FLASH dose rate coverage (>40 Gy/s)., Conclusions: By utilizing the URS and the LMA-SC gantry, it is possible to perform multiple-energy BP FLASH-RT, resulting in better normal tissue sparing, as compared to TB plans., (© 2024 American Association of Physicists in Medicine.)

Purpose: To develop an online graphic processing unit (GPU)-accelerated Monte Carlo-based adaptive radiation therapy (ART) workflow for pencil beam scanning (PBS) proton therapy to address interfraction anatomical changes in patients treated with PBS., Methods and Materials: A four-step workflow was developed using our in-house developed GPU-accelerated Monte Carlo-based treatment planning system to implement online Monte Carlo-based ART for PBS. The first step conducts diffeomorphic demon-based deformable image registration (DIR) to propagate contours on the initial planning CT (pCT) to the verification CT (vCT) to form a new structure set. The second step performs forward dose calculation of the initial plan on the vCT with the propagated contours after manual approval (possible modifications involved). The third step triggers a reoptimization of the plan depending on whether the verification dose meets the clinical requirements or not. A robust evaluation will be done for both the verification plan in the second step and the reopotimized plan in the third step. The fourth step involves a two-stage (before and after delivery) patient-specific quality assurance (PSQA) of the reoptimized plan. The before-delivery PSQA is to compare the plan dose to the dose calculated using an independent fast open-source Monte Carlo code, MCsquare. The after-delivery PSQA is to compare the plan dose to the dose recalculated using the log file (spot MU, spot position, and spot energy) collected during the delivery. Jaccard index (JI), dice similarity coefficients (DSCs), and Hausdorff distance (HD) were used to assess the quality of the propagated contours in the first step. A commercial plan evaluation software, ClearCheck™, was integrated into the workflow to carry out efficient plan evaluation. 3D Gamma analysis was used during the fourth step to ensure the accuracy of the plan dose from reoptimization. Three patients with three different disease sites were chosen to evaluate the feasibility of the online ART workflow for PBS., Results: For all three patients, the propagated contours were found to have good volume conformance [JI (lowest-highest: 0.833-0.983) and DSC (0.909-0.992)] but suboptimal boundary coincidence [HD (2.37-20.76 mm)] for organs-at-risk. The verification dose evaluated by ClearCheck™ showed significant degradation of the target coverage due to the interfractional anatomical changes. Reoptimization on the vCT resulted in great improvement of the plan quality to a clinically acceptable level. 3D Gamma analyses of PSQA confirmed the accuracy of the plan dose before delivery (mean Gamma index = 98.74% with a threshold of 2%/2 mm/10%), and after delivery based on the log files (mean Gamma index = 99.05% with a threshold of 2%/2 mm/10%). The average time cost for the complete execution of the workflow was around 858 s, excluding the time for manual intervention., Conclusion: The proposed online ART workflow for PBS was demonstrated to be efficient and effective by generating a reoptimized plan that significantly improved the plan quality., (© 2022 American Association of Physicists in Medicine.)

Background: Deformable image registration (DIR)-based dose accumulation (DDA) is regularly used in adaptive radiotherapy research. However, the applicability and reliability of DDA for direct clinical usage are still being debated. One primary concern is the validity of DDA, particularly for scenarios with substantial anatomical changes, for which energy-conservation problems were observed in conceptual studies., Purpose: We present and validate an energy-conservation (EC)-based DDA validation workflow and further investigate its usefulness for actual patient data, specifically for lung cancer cases., Methods: For five non-small cell lung cancer (NSCLC) patients, DDA based on five selective DIR methods were calculated for five different treatment plans, which include one intensity-modulated photon therapy (IMRT), two intensity-modulated proton therapy (IMPT), and two combined proton-photon therapy (CPPT) plans. All plans were optimized on the planning CT (planCT) acquired in deep inspiration breath-hold (DIBH) and were re-optimized on the repeated DIBH CTs of three later fractions. The resulting fractional doses were warped back to the planCT using each DIR. An EC-based validation of the accumulation process was implemented and applied to all DDA results. Correlations between relative organ mass/volume variations and the extent of EC violation were then studied using Bayesian linear regression (BLR)., Results: For most OARs, EC violation within 10% is observed. However, for the PTVs and GTVs with substantial regression, severe overestimation of the fractional energy was found regardless of treatment type and applied DIR method. BLR results show that EC violation is linearly correlated to the relative mass variation (R^2 > 0.95) and volume variation (R^2 > 0.60)., Conclusion: DDA results should be used with caution in regions with high mass/volume variation for intensity-based DIRs. EC-based validation is a useful approach to provide patient-specific quality assurance of the validity of DDA in radiotherapy., (© 2023 The Authors. Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

Background: Quality assurance (QA) is a prerequisite for safe and accurate pencil-beam proton therapy. Conventional measurement-based patient-specific QA (pQA) can only verify limited aspects of patient treatment and is labor-intensive. Thus, a better method is needed to ensure the integrity of the treatment plan., Purpose: Line scanning, which involves continuous and rapid delivery of pencil beams, is a state-of-the-art proton therapy technique. Machine performance in delivering scanning protons is dependent on the complexity of the beam modulations. Moreover, it contributes to patient treatment accuracy. A Monte Carlo (MC) simulation-based QA method that reflects the uncertainty related to the machine during scanning beam delivery was developed and verified for clinical applications to pQA., Methods: Herein, a tool for particle simulation (TOPAS) for nozzle modeling was used, and the code was commissioned against the measurements. To acquire the beam delivery uncertainty for each plan, patient plans were delivered. Furthermore, log files recorded every 60 μs by the monitors downstream of the nozzle were exported from the treatment control system. The spot positions and monitor unit (MU) counts in the log files were converted to dipole magnet strengths and number of particles, respectively, and entered into the TOPAS. For the 68 clinical cases, MC simulations were performed in a solid water phantom, and two-dimensional (2D) absolute dose distributions at 20-mm depth were measured using an ionization chamber array (Octavius 1500, PTW, Freiburg, Germany). Consequently, the MC-simulated 2D dose distributions were compared with the measured data, and the dose distributions in the pre-treatment QA plan created with RayStation (RaySearch Laboratories, Stockholm, Sweden). Absolute dose comparisons were made using gamma analysis with 3%/3 mm and 2%/2 mm criteria for 47 clinical cases without considering daily machine output variation in the MC simulation and 21 cases with daily output variation, respectively. All cases were analyzed with 90% or 95% of passing rate thresholds., Results: For 47 clinical cases not considering daily output variations, the absolute gamma passing rates compared with the pre-treatment QA plan were 99.71% and 96.97%, and the standard deviations (SD) were 0.70% and 3.78% with the 3%/3 mm or 2%/2 mm criteria, respectively. Compared with the measurements, the passing rate of 2%/2 mm gamma criterion was 96.76% with 3.99% of SD. For the 21 clinical cases compared with pre-treatment QA plan data and measurements considering daily output variations, the 2%/2 mm absolute gamma analysis result was 98.52% with 1.43% of SD and 97.67% with 2.72% of SD, respectively. With a 95% passing rate threshold of 2%/2 mm criterion, the false-positive and false-negative were 21.8% and 8.3% for without and with considering output variation, respectively. With a 90% threshold, the false-positive and false-negative reduced to 11.4% and 0% for without and with considering output variation, respectively., Conclusions: A log-file-based MC simulation method for patient QA of line-scanning proton therapy was successfully developed. The proposed method exhibited clinically acceptable accuracy, thereby exhibiting a potential to replace the measurement-based dosimetry QA method with a 90% gamma passing rate threshold when applying the 2%/2 mm criterion., (© 2023 American Association of Physicists in Medicine.)

Background: In cancer care, determining the most beneficial treatment technique is a key decision affecting the patient's survival and quality of life. Patient selection for proton therapy (PT) over conventional radiotherapy (XT) currently entails comparing manually generated treatment plans, which requires time and expertise., Purpose: We developed an automatic and fast tool, AI-PROTIPP (Artificial Intelligence Predictive Radiation Oncology Treatment Indication to Photons/Protons), that assesses quantitatively the benefits of each therapeutic option. Our method uses deep learning (DL) models to directly predict the dose distributions for a given patient for both XT and PT. By using models that estimate the Normal Tissue Complication Probability (NTCP), namely the likelihood of side effects to occur for a specific patient, AI-PROTIPP can propose a treatment selection quickly and automatically., Methods: A database of 60 patients presenting oropharyngeal cancer, obtained from the Cliniques Universitaires Saint Luc in Belgium, was used in this study. For every patient, a PT plan and an XT plan were generated. The dose distributions were used to train the two dose DL prediction models (one for each modality). The model is based on U-Net architecture, a type of convolutional neural network currently considered as the state of the art for dose prediction models. A NTCP protocol used in the Dutch model-based approach, including grades II and III xerostomia and grades II and III dysphagia, was later applied in order to perform automatic treatment selection for each patient. The networks were trained using a nested cross-validation approach with 11-folds. We set aside three patients in an outer set and each fold consists of 47 patients in training, five in validation and five for testing. This method allowed us to assess our method on 55 patients (five patients per test times the number of folds)., Results: The treatment selection based on the DL-predicted doses reached an accuracy of 87.4% for the threshold parameters set by the Health Council of the Netherlands. The selected treatment is directly linked with these threshold parameters as they express the minimal gain brought by the PT treatment for a patient to be indicated to PT. To validate the performance of AI-PROTIPP in other conditions, we modulated these thresholds, and the accuracy was above 81% for all the considered cases. The difference in average cumulative NTCP per patient of predicted and clinical dose distributions is very similar (less than 1% difference)., Conclusions: AI-PROTIPP shows that using DL dose prediction in combination with NTCP models to select PT for patients is feasible and can help to save time by avoiding the generation of treatment plans only used for the comparison. Moreover, DL models are transferable, allowing, in the future, experience to be shared with centers that would not have PT planning expertise., (© 2023 American Association of Physicists in Medicine.)

Introduction: The Australian Bragg Centre for Proton Therapy and Research (ABCPTR) will be Australia's first proton beam therapy (PBT) facility. A model was developed to predict associated public hospital care requirements for patients during PBT, to facilitate resource planning for pediatric, adolescent and young adult (AYA), and adult public hospitals in South Australia., Methods: National incidence rates for specific cancer indications were obtained from the Australian Childhood Cancer Registry, Australian Institute of Health and Welfare and published data. Australian Bureau of Statistics national population projections were used to estimate new cases in 2025 and beyond. Radiation oncologists and pediatric oncologists from the Central Adelaide Local and Women's and Children's Health Network, along with international colleagues, provided guidance on chemotherapy utilization and inpatient admission estimates., Results: It was estimated 180 patients (40.4%) within the adult population (≥25 years) and 265 patients (59.6%) within the pediatric/AYA population (<25 years) would be eligible for PBT in 2025. There was no indication adult cancers would require concurrent outpatient/inpatient chemotherapy, in contrast with pediatric and AYA patients (59.5% and 62.8% outpatient and 18.9% and 41.9% inpatient, respectively). It was estimated 53% and 29% of pediatric and AYA patients could require inpatient admission for toxicity related to disease, concurrent chemotherapy or PBT., Conclusion: Associated public hospital care requirements related to the delivery of a national PBT service were estimated. This has particular implications for planning of the new Women's and Children's hospital, co-located with the ABCPTR. True data accuracy will be determined on future data generation and analysis., (© 2022 John Wiley & Sons Australia, Ltd.)

The relative biological effectiveness is a mathematical quantity first defined in the 1950s. This has resulted in more than 4,000 scientific papers published to date. Yet defining the correct value of the RBE to use in clinical practice remains a challenge. A scientific analysis in the radiation research literature can provide an understanding of how this mathematical quantity has evolved. The purpose of this study is to investigate documents published since 1950 using bibliometric indicators and network visualization. This analysis seeks to provide an assessment of global research activities, key themes, and RBE research within the radiation-related field. It strives to highlight top-performing authors, organizations, and nations that have made major contributions to this research domain, as well as their interactions. The Scopus Collection was searched for articles and reviews pertaining to RBE in radiation research from 1950 through 2023. Scopus and Bibiometrix analytic tools were used to investigate the most productive countries, researchers, collaboration networks, journals, along with the citation analysis of references and keywords. A total of 4,632 documents were retrieved produced by authors originating from 71 countries. Publication trends could be separated in 20-year groupings beginning with slow accrual from 1950 to 1970, an early rise from 1970-1990, followed by a sharp increase in the years 1990s-2010s that matches the development of charged particle therapy in clinics worldwide and opened discussion on the true value of the RBE in proton beam therapy. Since the 2010s, a steady 200 papers, on average, have been published per year. The United States produced the most publications overall (N = 1,378) and Radiation Research was the most likely journal to have published articles related to the RBE (606 publications during this period). J. Debus was the most prolific author (112 contributions, with 2,900 citations). The RBE has captured the research interest of over 7,000 authors in the past decade alone. This study supports that notion that the growth of the body of evidence surrounding the RBE, which started 75 years ago, is far from reaching its end. Applications to medicine have continuously dominated the field, with physics competing with Biochemistry, Genetics and Molecular Biology for second place over the decades. Future research can be predicted to continue. [ABSTRACT FROM AUTHOR]

The management of base of skull (BS) chordomas is a neurosurgical conundrum owing to their close proximity to the critical neurovascular structures. Surgical resection is the gold standard treatment followed by adjuvant radiotherapy which includes photon therapy, proton beam therapy (PBT), gamma knife radiosurgery, etc. PBT has become an unparalleled therapeutic modality in the management of BS chordomas. The aim of this systematic review was to assess the outcomes in BS chordoma patients who received PBT as a primary or adjuvant therapy. PubMed and Cochrane databases were screened till May 2022. Following the PRISMA guidelines, studies were reviewed thoroughly, and the data of the included study was extracted. Statistical analysis was performed using the SAS 9.4 with P value < .05 considered as significant. Sixteen studies with 752 patients were included. The majority of the patients were adults (> 18 years) with a male:female ratio of 1.2. The most common clinical features were cranial nerve (3rd, 6th, or 12th) palsy and hearing impairment. Ninety-five percent of the patients underwent surgical resection before PBT. The mean PBT dose received was 74.02 cGe (cobalt gray equivalent). Eighty percent of the patients showed a positive response to the therapy defined in terms of tumor regression. Five-year local control (LC), overall survival (OS), and progression-free survival (PFS) were calculated as 76.6%, 79.6%, and 89%, respectively. Statistical analysis revealed none of the factors had any significant association with 5-year LC. PBT is a growing therapeutic technique that has revolutionized the treatment of BS chordomas., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: A high proportion of pediatric patients with brain tumors (BTs) are known to experience a decline in neurocognitive function after treatment. We prospectively examined neuropsychological functioning of patients with BTs of varying tumor types at different time points before, during, and after proton beam therapy., Materials and Methods: A total of 98 patients with posterior fossa tumors (PFTs; n = 33), germ cell tumors (GCTs; n = 52), and other supratentorial tumors (STTs; n = 13) underwent baseline neuropsychological assessments and 57 patients underwent follow-up assessments., Results: All groups displayed significantly lower performance intelligence quotient (PIQ) and processing speed (PS) scores than the normative means at baseline. The PFT group exhibited significantly lower scores for full-scale IQ, PIQ, PS, attention, and executive function. The GCT group displayed full-scale IQ scores within the normal range, but a significantly high proportion had memory deficits. In the STT group, all functions except for the PIQ and PS were intact. Longitudinal evaluations demonstrated stable global IQ scores over time in all groups. In the PFT group, verbal comprehension, attention, and PS improved over time. However, in the GCT group, verbal IQ scores declined significantly and psychological problems worsened over time, which were correlated with poorer neurocognitive function at 3-5 years after treatment. In the STT group, no significant changes were observed., Conclusion: Because patients with BTs exhibit various types of neurocognitive deficit before radiotherapy, early cognitive treatment tailored to the tumor type maybe beneficial. Interventions for psychological problems and memory function may be necessary, especially for patients with GCT., (© 2021 Wiley Periodicals LLC.)

Purpose: The accurate knowledge of the effective point of measurement (P eff ) is particularly important for measurements in proximity to high dose gradients such as in the distal fall-off of particle beams. For plane-parallel ionization chambers (ICs), P eff is well known and located at the center of the inner surface of the entrance window. For cylindrical ICs, P eff is shifted from the chamber's center toward the beam source. According to IAEA TRS-398, this shift can be calculated as 0.75·r cyl for light ions with r cyl being the radius of the cavity. For proton beams and in absence of a dose gradient, no shift is recommended. We have experimentally determined P eff for the 0.125 cc Semiflex IC in both proton and carbon ion beams., Methods: The first method consisted of simultaneous irradiation of a plane-parallel IC and the Semiflex in a 4-cm wide spread-out Bragg peak. In the second method, a single-energy beam was used, and both ICs were positioned successively at the same measurement depths. For both approaches, the shift of the distal edge of the depth ionization distributions recorded by the two chambers at different reference points was used to calculate P eff of the Semiflex. Both methods were applied in carbon ion beams, and only the latter was applied in proton beams., Results: Both methods yielded a similar P eff for carbon ions, 0.88·r cyl , and 0.84·r cyl , which results in a difference of only 0.1 mm. The difference to the recommended value of 0.75·r cyl is 0.4 and 0.3 mm, respectively, which is larger than the positioning uncertainty. In the proton beam, a P eff of 0.92·r cyl was obtained., Conclusions: The P eff for the 0.125 cc Semiflex IC is shifted further from the cavity center as recommended by IAEA TRS-398 for light ions, with the shift for proton beams being even larger than for carbon ion beams., (© 2021 The Authors. Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

Background: Currently, no available tool easily and effectively measures both the frequency, intensity and distress of symptoms among patients receiving radiotherapy. A core symptom set (fatigue, insomnia, pain, appetite loss, cognitive problems, anxiety, nausea, depression, constipation, diarrhoea and skin reaction) has been identified and assessed across oncology research to better understand the pattern of symptoms and treatment side effects., Aim: The aim was to develop a tool measuring the multiple-symptom experience in patients undergoing radiotherapy and evaluate its psychometric properties (validity, reliability and responsiveness)., Design: This study has a prospective, longitudinal and quantitative design., Methods: We developed a patient-reported outcome questionnaire, the Radiotherapy-Related Symptoms Assessment Scale to assess the frequency, intensity and distress associated with symptoms. Patients (n = 175) with brain tumours undergoing proton beam therapy completed the Radiotherapy-Related Symptoms Assessment Scale and the health-related quality of life questionnaire (EORTC QLQ-C30) during treatment. We assessed the validity, reliability and responsiveness of the Radiotherapy-Related Symptoms Assessment Scale and evaluated the validity against QLQ-C30., Results: There were significant questionnaire-questionnaire correlations regarding selected items, primarily fatigue, insomnia and pain, indicating satisfactory criterion-related validity. The Radiotherapy-Related Symptoms Assessment Scale had fair to good retest reliability., Conclusion: The Radiotherapy-Related Symptoms Assessment Scale is a valid instrument for assessing symptom intensity and distress in patients with brain tumour undergoing PBT, with psychometric properties within the expected range. The Radiotherapy-Related Symptoms Assessment Scale provides nurses with substantial information on symptom experience but requires little effort from the patient. Additional studies are required to further assess the psychometric properties in patients with different cancer diagnoses receiving conventional radiotherapy., (© 2020 The Authors. Scandinavian Journal of Caring Sciences published by John Wiley & Sons Ltd on behalf of Nordic College of Caring Science.)

Purpose: In vivo range and dose verification based on proton-induced acoustics (protoacoustics) is potentially a useful tool for proton therapy. Built upon our previous study with two-dimensional reconstruction, the time reversal (TR) method was extended to three-dimensional (3D) and evaluated at two treatment sites (head and liver) through simulation, with the emphasis on a number of aspects such as increased spatial coverage, computational workload, and signal interference among slices., Methods: Two mono-energetic pencil beams were modeled in each site. The k-Wave toolbox was used to investigate the propagation and TR reconstruction of acoustic waves. The performance was quantitatively assessed based on mean square error (MSE) for dose verification and Bragg peak localization error (Δ BP ) for range verification, with regard to five parameters: number of sensors, sampling duration, sampling timestep, spill time, and noise level., Results: The respective impacts of five parameters are examined. Under the optimum setting, the achievable Δ BP can be limited within 1 voxel (voxel size: 3 × 3 × 3 mm 3 ) and the achievable MSE can be limited below 0.02, for the head case (56 sensors) and the liver case (204 sensors), respectively., Conclusions: The feasibility of range and dose verification utilizing the 3D TR method is demonstrated, as the very first step. In spite of several challenges unique to the 3D case (spatial coverage, computational workload, and signal interference among slices, etc.), promising performance is found and can be further improved through optimizing the deployment of sensors. The proposed approach may find potential use in several applications: beam diagnostics, in vivo dosimetry, and treatment monitoring., (© 2021 American Association of Physicists in Medicine.)

Purpose: To compare the dosimetric impact of all major commercial vendors' metal artifact reduction (MAR) algorithms to one another, as well as to a novel in-house technique (AMPP) using an anthropomorphic head phantom., Materials and Methods: The phantom was an Alderson phantom, modified to allow for artifact-filled and baseline (no artifacts) computed tomography (CT) scans using teeth capsules made with metal amalgams or bone-equivalent materials. It also included a cylindrical insert that was accessible from the bottom of the neck and designed to introduce soft tissue features into the phantom that were used in the analysis. The phantom was scanned with the metal teeth in place using each respective vendor's MAR algorithm: OMAR (Philips), iMAR (Siemens), SEMAR (Canon), and SmartMAR (GE); the AMPP algorithm was designed in-house. Uncorrected and baseline (bone-equivalent teeth) image sets were also acquired using a Siemens scanner. Proton spot scanning treatment plans were designed on the baseline image set for five targets in the phantom. Once optimized, the proton beams were copied onto the different artifact-corrected image sets, with no reoptimization of the beams' parameters, to evaluate dose distribution differences in the different MAR-corrected and -uncorrected image sets. Dose distribution differences were evaluated by comparing dose-volume histogram (DVH) metrics, including planning target volume D95 and clinical target volume D99 coverages, V100, D0.03cc, and heterogeneity indexes, along with a qualitative and water equivalent thickness (WET) analysis., Results: Uncorrected CT metal artifacts and commercial MAR algorithms negatively impacted the proton dose distributions of all five target shapes and locations in an inconsistent manner, sometimes overdosing by as much as 11.1% (D0.03) or underdosing by as much as 11.7% (V100) the planning target volumes. The AMPP-corrected images, however, provided dose distributions that consistently agreed with the baseline dose distribution. The dosimetry results also suggest that the commercial MAR algorithms' performances varied more with target location and less with target shape. Once relocated further from the metal, the target showed dose distributions that agreed more with the baseline for all commercial solutions, improving the overdosing by as much as 6%, implying inadequate HU correction from commercial MAR algorithms. In comparison to the baseline, HU profile shapes were considerably altered by commercial algorithms and reference values showed differences that represent stopping power percentage differences of 2.7-10%. The AMPP algorithm plans showed the smallest WET differences with the baseline (0.06 cm on average), while the commercial image sets created differences that ranged from 0.11 to 0.54 cm., Conclusions: Computed tomography metal artifacts negatively impacted proton dose distributions on all five targets analyzed. The commercial MAR solutions performed inconsistently throughout all targets compared to the metal-free baseline. A lack of CTV coverage and an increased number of hotspots were observed throughout all commercial solutions. Dose distribution errors were related to the proximity to the artifacts, demonstrating the inability of commercial techniques to adequately correct severe artifacts. In contrast, AMPP consistently showed dose distributions that best matched the baseline, likely because it makes use of accurate HU information, as opposed to interpolated data like commercial algorithms., (© 2020 American Association of Physicists in Medicine.)

Introduction: Australia's first proton beam therapy (PBT) service, The Australian Bragg Centre for Proton Therapy and Research, is scheduled to open in the near future providing PBT for patients closer to home. Patients currently access Commonwealth funding for PBT via the Medicare Medical Treatment Overseas Program (MTOP). Proton versus photon treatment planning is a pre-requisite for the MTOP application. The Royal Adelaide Hospital (RAH) Department of Radiation Oncology has been providing this since 2016. We aim to provide a descriptive overview of our proton versus photon treatment planning process, presenting a summary of the comparative planning results and the treatment pathways selected for the patients referred., Methods: All patients referred to the RAH for comparative planning between January 2016 and December 2018 were included in the analysis. Comparative plans were generated for each case using Pinnacle or Eclipse treatment planning systems. The planning techniques used and plan quality metrics were reported., Results: Forty three patients were referred for comparative planning. The age range was 1-63 years, with the majority (72%) being paediatric patients (age ≤18 years). Of the 19 cases that have been submitted to MTOP, 16 have been accepted and 3 denied. Two of the accepted cases chose not to travel abroad for PBT. The other 14 cases have received PBT overseas., Conclusions: The RAH has provided an important service to demonstrate the dosimetric difference between PBT and photon therapy for Australian patients, an important step in supporting the funding of patients for treatment overseas., (© 2020 The Royal Australian and New Zealand College of Radiologists.)

Purpose: To evaluate the quantitative imaging performance of a spectral photon-counting computed tomography (SPCCT) scanner for radiotherapy applications. An experimental comparison of the quantitative performance of a Siemens dual-energy CT (DECT) and a MARS SPCCT scanner is performed to estimate physical properties relevant to radiotherapy of human substitute materials and contrast agent solutions. In human substitute materials, the accuracy of quantities relevant to photon therapy, proton therapy, and Monte-Carlo simulations, such as the electron density, proton stopping power, and elemental composition is evaluated. For contrast agent solutions, the accuracy of the contrast agent concentrations and the virtual non-contrast (VNC) electron density is evaluated., Methods: Human tissue substitute phantoms (Gammex 467 and 472) as well as diluted solutions of contrast agents (iodine and gadolinium based) are scanned with two commercial systems: a Siemens dual-source CT (SOMATOM Definition Flash, Siemens Healthineers, Forchheim, Germany) and a MARS spectral photon-counting micro-CT (MARS V5.2, MARS Bioimaging Ltd., Christchurch, New Zealand). Material decomposition is performed in a maximum a posteriori framework with an optimized material basis tailored to characterize either human substitute materials or contrast agents in the context of experimental multi-energy CT data., Results: The root-mean-square error (RMSE) of the electron density calculated over all Gammex inserts is reduced from 1.09 to 0.89% when going from DECT to SPCCT. For the proton stopping power, the RMSE is reduced from 1.92 to 0.89%. Elemental mass fractions of hydrogen, carbon, nitrogen, oxygen, and calcium are more accurately estimated with the MARS scanner. The RMSE on the iodine-based contrast agents concentration is reduced from 0.27 to 0.12 mg/mL with SPCCT, and the VNC electron density from 0.40 to 0.22%., Conclusion: In the present phantom study, a MARS photon-counting scanner provides superior accuracy compared to a Siemens SOMATOM Definition Flash DECT scanner to quantify physical parameters relevant to radiotherapy. This work experimentally demonstrates the benefits of using more energies to characterize human tissue equivalent materials. This highlights the potential of SPCCT for particle therapy, where more accurate tissue characterization is needed, as well as for Monte-Carlo based planning, which requires accurate elemental mass fractions., (© 2020 American Association of Physicists in Medicine.)

Purpose: To commission an open source Monte Carlo (MC) dose engine, "MCsquare" for a synchrotron-based proton machine, integrate it into our in-house C++-based I/O user interface and our web-based software platform, expand its functionalities, and improve calculation efficiency for intensity-modulated proton therapy (IMPT)., Methods: We commissioned MCsquare using a double Gaussian beam model based on in-air lateral profiles, integrated depth dose of 97 beam energies, and measurements of various spread-out Bragg peaks (SOBPs). Then we integrated MCsquare into our C++-based dose calculation code and web-based second check platform "DOSeCHECK." We validated the commissioned MCsquare based on 12 different patient geometries and compared the dose calculation with a well-benchmarked GPU-accelerated MC (gMC) dose engine. We further improved the MCsquare efficiency by employing the computed tomography (CT) resampling approach. We also expanded its functionality by adding a linear energy transfer (LET)-related model-dependent biological dose calculation., Results: Differences between MCsquare calculations and SOBP measurements were <2.5% (<1.5% for ~85% of measurements) in water. The dose distributions calculated using MCsquare agreed well with the results calculated using gMC in patient geometries. The average 3D gamma analysis (2%/2 mm) passing rates comparing MCsquare and gMC calculations in the 12 patient geometries were 98.0 ± 1.0%. The computation time to calculate one IMPT plan in patients' geometries using an inexpensive CPU workstation (Intel Xeon E5-2680 2.50 GHz) was 2.3 ± 1.8 min after the variable resolution technique was adopted. All calculations except for one craniospinal patient were finished within 3.5 min., Conclusions: MCsquare was successfully commissioned for a synchrotron-based proton beam therapy delivery system and integrated into our web-based second check platform. After adopting CT resampling and implementing LET model-dependent biological dose calculation capabilities, MCsquare will be sufficiently efficient and powerful to achieve Monte Carlo-based and LET-guided robust optimization in IMPT, which will be done in the future studies., (© 2020 American Association of Physicists in Medicine.)

Purpose: Protons and heavy ions are considered to be ideal particles for use in external beam radiotherapy due to the superior properties of the dose distribution. While a photon (x-ray) beam delivers considerable dose to healthy tissues around the tumor, a proton beam that is delivered with sufficient energies has: a low entrance dose (the dose in front of the tumor); a high-dose region within the tumor, known as the Bragg peak; and, no exit dose beyond the tumor. Proton therapy is the next major step in advancing radiotherapy treatment. The purpose of this project was to adapt an existing radioisotope production cyclotron, a General Electric (GE) PETtrace, to enable radiobiological studies using proton beams. During routine use the PETtrace delivers 16.5 MeV protons to target with beam currents in the range of 10-100 µA resulting in dose rates in the order of kGy/s. To achieve the aim of the project the dose rate had to be reduced to the Gy/min range, without attenuating the proton energy below 5 MeV. This paper covers the design, construction and validation of the beam port., Methods: Monte Carlo simulations were performed, using GEANT4, SRIM and PACE4 to design the beam port and optimize its components. Once the beam port was fabricated, validation experiments were performed using EBT3 and HD-V2 Gafchromic™ films, and a Keithley 6485 picoampere meter., Results and Conclusion: The external beam port was successfully modeled, designed and fabricated. By using a 0.25 mm thick gold foil and a brass pin-hole collimator the beam was spread from a narrow full beam diameter of 10 mm to a wide beam with a 5% flatness area in the center of the beam that had a diameter of ~20 mm. In using this system the dose rate was reduced from kGy/s to ~30 Gy/min., (© 2019 American Association of Physicists in Medicine.)

Purpose: To provide an introduction to the special issue containing the proceedings of the workshop on cancer therapy using hadrons (proton, carbon ions or boron neutron capture therapy) that was held in Pavia in October 2023 and organized by CNAO and IAEA. Methods: Papers contained in the issue are briefly summarized. Results: This issue contains a collection of papers from the workshop that provide a great opportunity to learn about the status and progress of this technology. Conclusions: Particle therapy is exponentially growing worldwide. While several clinical trials are now providing convincing evidence of the effectiveness of the treatment in tumor control and reduced toxicity, the technology remains expensive and the cost effectiveness is still under debate. The IAEA-CNAO workshop provided a clear picture of the state of the art and future prospective of this technology. [ABSTRACT FROM AUTHOR]

Introduction: Hadron therapy is today an established modality in cancer radiation therapy that, world-wide, is available in about hundred centres. About 90% of them are devoted to proton therapy and the rest also to carbon ion therapy. Based on the superior ballistic and radiobiological properties of fast ions, this discipline experienced a remarkable growth in the last 30 years. Purpose: This paper reviews the history of hadron therapy starting from the initial work done at Berkeley in the 30's. Methods: Fast neutron therapy is not forgotten but the main accent is on the parallel development of proton and carbon ion therapy. For space reasons pion therapy, to which a lot of efforts have been devoted without success, is not discussed. Results: The activities of the main protagonists in USA, Japan and Europe are shortly presented so that the reader can appreciate the relevance of the contribution given by each of them to the advancement of the field. Conclusions: The review ends in 2005, when the carbon ion centres HIT in Heidelberg and CNAO in Pavia were under construction, with the aim of putting at the disposal of European citizens advanced treatments of radioresistant tumours, which cannot be effectively treated neither with X rays nor with protons. [ABSTRACT FROM AUTHOR]

Background and Purpose: Disregarding the increase of relative biological effectiveness (RBE) may raise the risk of acute and late adverse events after proton beam therapy (PBT). This study aims to explore the relationship between variable RBE (above 1.1)-induced normal tissue complication probabilities (NTCP) and patient-specific factors, identify patients at high risk of RBE-induced NTCP increase, and assess risk mitigation by incorporating RBE variability into treatment planning., Materials and Methods: We retrospectively analyzed 105 primary brain tumor patients treated with PBT (RBE = 1.1). We calculated differences in estimated NTCP (ΔNTCP) using a variable RBE-weighted dose (D RBE , Wedenberg model) and a constant RBE-weighted dose (D RBE=1.1 ), across 16 NTCP models. These differences were correlated with patient-specific characteristics. Based on ΔNTCP, patients were classified as high risk (32 %) or low risk (68 %) for adverse events due to RBE-induced NTCP. This classification was compared with alternative classifications based on (a) relevant patient-specific characteristics, (b) D RBE=1.1 , and (c) the difference between D RBE and D RBE=1.1 (ΔD), assessing the balanced accuracy. The potential to reduce RBE-induced NTCP through track-end and linear energy transfer (LET) optimization was evaluated in six example patients., Results: Using a variable RBE instead of a constant one resulted in NTCP increases (up to 32 percentage points). Variable-RBE-induced NTCP increases were strongly negatively correlated with the distance between the clinical target volume (CTV) and the organ at risk (OAR) for most side-effects, and positively correlated with CTV volume for certain side-effects. High increases were associated with (a) specific patient factors, particularly the proximity of the CTV to OARs, (b) D RBE=1.1 , and (c) ΔD, with a balanced accuracy of 0.88, 0.94, and 0.86, respectively. Optimization of track-ends and LET considerably reduced NTCP values, achieving a mean reduction of 31 % for optimized OARs., Conclusion: The risk of variable-RBE-induced NTCP strongly depends on patient-specific factors and the considered side-effect. A small distance between the tumor and OARs notably increases the risk. Integrating biologically-guided objectives into treatment planning can effectively mitigate the risk., Competing Interests: Declaration of competing interest For the present study, the authors received no external financial support, neither for the study design or materials used, nor for the collection, analysis, and interpretation of data, nor for the writing of the publication. OncoRay has a research collaboration with RaySearch Laboratories. Dr. Christian Hahn is employed at RaySearch Laboratories AB. In the past 5 years, Dr. Mechthild Krause received funding for her research projects by Merck KGaA (2014-2018 for preclinical study; 2018-2020 for clinical study), Medipan GmbH (2014-2018). Dr. Mechthild Krause is involved in an ongoing publicly funded (German Federal Ministry of Education and Research) project with the companies Medipan (2019-2022), Attomol GmbH (2019-2022), GA Generic Assays GmbH (2019-2022), Gesellschaft für medizinische und wissenschaftliche genetische Analysen (2019-2022), Lipotype GmbH (2019-2022) and PolyAn GmbH (2019-2022). Dr. Krause confirms that, to the best of their knowledge, none of the above-mentioned funding sources were involved in the preparation of this paper. All other authors have declared no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Fatigue may significantly effect everyday- and working life for radiotherapy patients. Some studies indicate a correlation between radiation dose and irradiated volume of the brain and the presence of fatigue. Our hypothesis was that patient reported outcome measures (PROMs) can improve our understanding of the patients' symptoms following proton beam therapy (PBT) and optimize PBT for future patients., Methods: This study included 167 adult patients (>18 years) who received PBT for malignant brain tumours. Data on dose metrics to intra-cranial structures was obtained from PBT treatment plans. To explore fatigue and health related quality of life (HRQoL); Multidimensional Fatigue Inventory (MFI-20) and EORTC QLQ-C30 was used at 6-, 12-, 24- and 36 months post PBT. The correlation between fatigue and dosimetry was explored using Spearman's signed rank test., Results: No severe fatigue was recorded during the 36 months follow-up. Correlations between higher radiation dose and worsened fatigue scores were generally weak (rho < 0.3). At 12 months post PBT, higher mean dose to the brain, brainstem, hippocampi and pituitary was correlated to worsened MFI Physical Fatigue. Further, Reduced Motivation according to MFI was correlated to higher radiation dose to the brainstem and the pituitary gland. At 36 months follow-up post-PBT, both Reduced Activity and Reduced motivation according to MFI were correlated to higher radiation dose to the brain, brainstem and hippocampi., Conclusion: Proton beam therapy are well tolerated, with similar degree of fatigue pre- and post PBT. Achieving further reduction in mean brain dose appears beneficial., 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 © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background and Purpose: Proton arc therapy and FLASH radiotherapy (FLASH-RT) each offer unique advantages in proton therapy. However, clinical translation of FLASH-RT faces challenges in defining and delivering high dose rates. We propose the use of proton FLASH-arc therapy (PFAT) to leverage the benefits of arc while addressing FLASH delivery concerns by spatially fractionating dose delivery to healthy tissue., Materials and Methods: Treatment plans for an abdominal phantom and a clinical brain case were designed in OpenTPS, using monoenergetic beams within a 360-degree gantry rotation. Beams were optimized to achieve target coverage while maximizing spatial fractionation in non-target regions. The temporal dose delivery to healthy-tissue voxels, or in specified organs-at-risk (OARs), was constrained via selective spot removal in the beamlets matrix. The dose, LET, number of spots per voxel, and voxel-wise average dose rate were calculated for each PFAT plan and compared to a corresponding IMPT scenario., Results: PFAT plans demonstrated comparable dose conformity to IMPT, with LET hotspots shifted towards the target center. The number of spots influencing healthy-tissue voxels was reduced, leading to regions of substantially higher dose rates in many points outside the target. OAR dose-rate optimization in the brain plan resulted in dose rates exceeding 40 Gy/s in the majority of points in the brainstem., Conclusion: The PFAT technique combines the advantages of FLASH and arc therapy, providing improved LET distributions and enhanced biological effect in the target, while achieving high dose rates in healthy tissue, thus reducing healthy tissue damage. This feasibility study demonstrates the capability of PFAT, setting the foundation for further optimization and application in diverse patient cases and complex geometries., 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 © 2024 Elsevier B.V. All rights reserved.)

Background: Data evaluating the impact of intensity-modulated proton therapy (IMPT) on survival among nasopharyngeal carcinoma (NPC) patients are limited. This study aims to elucidate the survival benefits and toxicity profiles of IMPT compared to modern photon therapy, volumetric-modulated arc therapy (VMAT), over an extended follow-up period., Methods: We analyzed data from NPC patients recorded in the Chang Gung Research Database. This analysis focused on individuals who received definitive radiotherapy, either IMPT or VMAT therapy, from 2016 to 2021. Patients with distant metastasis or concurrent other malignancies were excluded. We performed 1:1 matching based on stage, year of diagnosis, and age (± 10 years). Oncological outcomes and toxicities were assessed using Cox proportional hazards modeling. For sensitivity analysis, we employed inverse probability of treatment weighting and additional 1:2 matching., Results: Out of a 1,202 NPC patients' cohort, 276 were selected from a subset of 294 who received IMPT and matched with an equivalent number of patients receiving VMAT. IMPT was associated with improved oncological outcomes after matching, with an adjusted hazard ratio (aHR) of 0.31 (95% CI: 0.15-0.62) for all-cause mortality and an aHR of 0.58 (95% CI: 0.34-0.99) for disease recurrence. Additionally, IMPT was linked to a reduced incidence of feeding tube placement, with an aHR of 0.31 (95% CI: 0.18-0.55). Competing risk and sensitivity analyses corroborated these trends, though the significance for disease recurrence was not consistent., Conclusion: IMPT was associated with significantly better overall survival outcomes and a lower incidence of dysphagia compared to VMAT in NPC patients. Further randomized trials are needed to confirm these findings., 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 © 2024 Elsevier B.V. All rights reserved.)

Backgrounds: Intensity-modulated proton therapy (IMPT) is particularly susceptible to range and setup uncertainties, as well as anatomical changes., Purpose: We present a framework for IMPT planning that employs a deep learning method for dose prediction based on multiple-CT (MCT). The extra CTs are created from cone-beam CT (CBCT) using deformable registration with the primary planning CT (PCT). Our method also includes a dose mimicking algorithm., Methods: The MCT IMPT planning pipeline involves prediction of robust dose from input images using a deep learning model with a U-net architecture. Deliverable plans may then be created by solving a dose mimicking problem with the predictions as reference dose. Model training, dose prediction and plan generation are performed using a dataset of 55 patients with head and neck cancer in this retrospective study. Among them, 38 patients were used as training set, 7 patients were used as validation set, and 10 patients were reserved as test set for final evaluation., Results: We demonstrated that the deliverable plans generated through subsequent MCT dose mimicking exhibited greater robustness than the robust plans produced by the PCT, as well as enhanced dose sparing for organs at risk. MCT plans had lower D 2% (76.1 Gy vs. 82.4 Gy), better homogeneity index (7.7% vs. 16.4%) of CTV1 and better conformity index (70.5% vs. 61.5%) of CTV2 than the robust plans produced by the primary planning CT for all test patients., Conclusions: We demonstrated the feasibility and advantages of incorporating daily CBCT images into MCT optimization. This approach improves plan robustness against anatomical changes and may reduce the need for plan adaptations in head and neck cancer treatments., 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 © 2024. Published by Elsevier B.V.)

Background and Purpose: With proton therapy, the relative biological effectiveness (RBE) accounts for increased DNA damage caused by higher linear energy transfer (LET) compared to photons. However, the LET and hence the RBE varies along the proton range, particularly at the Bragg peak, introducing challenges in proton treatment planning for brain tumors. The aim of this paper is to standardize evaluating and reporting LET and RBE in proton therapy for patients with grade 2 and 3 IDH mutant gliomas among the Dutch proton therapy centers., Materials and Methods: A working group, comprising experts from three Dutch proton therapy centers, conducted nine meetings between 2020 and 2023. A joint literature review supported the standardized evaluation and reporting of LET and RBE. Questionnaires sent out to the three Dutch proton centers in 2020 and 2023 provided input for discussions on clinical practices. Three clinical examples were chosen to illustrate the application of the recommended methodology in treatment planning., Results: Following the literature review, a guideline on evaluation and reporting using the dose averaged LET (LET d ) of primary and secondary protons calculated in water normalized to unit density was established. The McNamara variable RBE model with an α/β value of 2 Gy was selected for reporting., Conclusion: The study presents a harmonization of approaches to evaluating and reporting LET and variable RBE in a guideline for the three Dutch proton therapy centers, providing clarity for future clinical interpretation. Having chosen a single variable RBE model offers practicality, although its accuracy remains a topic of ongoing research., 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 © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Purpose: A risk calculation model was presented in 2021 by Keilty et al. for determining the likelihood of severe hearing impairment (HI) for paediatric patients treated with photon radiation therapy. This study aimed to validate their risk-prediction model for our cohort of paediatric patients treated with proton therapy (PT) for malignancies of the head and neck (H&N) or central nervous system (CNS)., Materials and Methods: This was a single-institution study which extracted data on all patients aged ≤ 18 years treated with PT between Feb 2010 - Feb 2022 for malignancies of the H&N/CNS. The factors required for input into the Keilty model were extracted: age at PT, time since end of PT, mean cochlea dose, and platinum chemotherapy doses. Validation was performed using the statistical software R v 4.3.1, which analysed event discrimination and model calibration., Results: 587 patients met the criteria. Validation of the model demonstrated excellent discriminative ability, with an "optimal" cut-off value of 16% at a specificity and sensitivity of 82%. However, model calibration was less satisfactory, indicating an overestimation of risk of severe hearing loss (HI) by the model as compared to clinically observed events in our cohort, possibly linked to differences in event scoring between the model developers and this study, and short follow-up time in this study., Conclusion: The published (photon-based) model of Keilty et al. was validated in a PT context, demonstrating a high discriminative ability to determine patients at high risk versus low risk for severe HI. However the overall observed risk was lower than model predictions., 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 © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: To evaluate the patient's positioning reproducibility during upright treatment with image-guided adaptive proton therapy (IGAPT) for head and neck cancers., Materials and Methods: 10 head and neck (H&N) patients were treated with gantry-less IGAPT, which includes daily 3D computed tomography (CT) and two 2D kilovoltage radiographs before treatment and weekly 3DCT immediately after irradiation. All procedures were performed in the carbon chair on the 6 degrees of freedom robotic positioner., Results: Prior to treatment we registered shifts in patient positioning using 3D/3D registration at the imaging isocenter: X  = -0.1 ± 3.9 (mean ± standard deviation) mm, Y = -3.7 ± 3.5 mm, Z = 0.5 ± 6.2 mm. The corresponding vector was applied to the robotic positioner to compensate for the registered shifts, after which the patients were moved to the treatment isocenter and the following shifts were obtained there using 2D/3D registration: X  = -0.31 ± 1.37 mm, Y = -0.02 ± 1.33 mm, Z = 0.59 ± 1.55 mm. Finally, the weekly follow-up 3D/3D registration showed X  = -0.2 ± 1.2 mm, Y = -0.0 ± 1.4 mm, Z = 2.3 ± 2.0 mm., Conclusions: A novel image-guided gantry-less PT facility showed reliable results in terms of patient positioning for H&N cases during clinical trials. This fact confirmed the suitability of using gantry-less PT for H&N treatment. A small, systematic shift in the vertical direction was detected in the follow-up 3D/3D registration. The effect of this shift will be investigated in further studies with pre/post treatment 2D/3D registration. The next phase of the clinical trial of this facility is dedicated to the thorax region., 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 © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Purpose: Proton Minibeam Radiation Therapy (pMBRT) is an unconventional radiation technique based on a strong modulation of the dose deposition. Due to its specific pattern, pMBRT involves several dosimetry (peak and valley doses, peak-to-valley dose ratio (PVDR)) and geometrical parameters (beam width, spacing) that can influence the biological response. This study aims at contributing to the efforts to deepen the comprehension of how the various parameters relate to central biological mechanisms, particularly anti-tumor immunity, and how these correlations affect treatment outcomes with the goal to fully unleash the potential of pMBRT. We also evaluated the effects of X-ray MBRT to further elucidate the influence of peak dose and dose heterogeneity., Methods and Materials: An orthotopic rat model of glioblastoma underwent several pMBRT configurations. The impact of different dosimetric parameters on survival and on the modulation of crucial mechanisms for pMBRT, such as immune response, was investigated. The latter was assessed by immunohistochemistry and flow cytometry at 7 days post-irradiation., Results: Survival was improved across the various pMBRT regimens via maintaining a minimum valley dose as well as a higher dose heterogeneity, which is driven by peak dose. While the mean dose did not impact immune infiltration, a higher PVDR promoted a less immunosuppressive microenvironment., Conclusions: Our results suggest that both tumor eradication, and immune infiltration are associated with higher dose heterogeneity. Higher dose heterogeneity was achieved by optimizing the peak dose, as well as maintaining a minimum valley dose. These parameters contributed to direct tumor eradication as well as reduction of immunosuppression, which is a departure from the more immunosuppressive tumor environment found in conventional proton therapy that delivers uniform dose distributions., 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 © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Purpose: This study aims to compare the dosimetric impact of incorporating systematic and random setup uncertainties in the robust optimization of head and neck cancer (HNC) Intensity Modulated Proton Therapy (IMPT) plans., Methods: Bilateral HNC patients (n = 10) previously treated with conventional photon therapy at our institution were included. Both systematic and random setup uncertainties were incorporated into the robust optimization process of IMPT planning. Dosimetric comparisons were made between plans optimized with systematic (IMPT-S) versus random (IMPT-R) setup uncertainties, assessing both the clinical target volume (CTVs) and organs at risk (OARs) across various dosimetric metrics. Both plans applied a fixed range uncertainty of ± 3 % and a maximum setup uncertainty of ± 3 mm., Results: Both IMPT-S and IMPT-R plans achieved similar target coverage, meeting robustness criteria for CTVs. On average, the D 95% voxel-wise min to the high-risk CTV (CTV&#95;HR) was slightly higher in IMPT-S plans by 1.78 ± 0.72 % compared to IMPT-R plans. However, IMPT-R plans provided better OAR sparing, which was evident in both nominal and voxel-wise maximum values. While random setup errors in robust optimization improved OAR sparing, the clinical impact may be minimal where OAR doses are already well below tolerance levels., Conclusion: Both IMPT-S and IMPT-R techniques met the robustness criteria for CTVs in HNC IMPT planning. Incorporating random setup uncertainties in robust optimization improves OAR sparing compared to systematic setup uncertainties. Further research is needed to explore the broader applicability of random setup errors and to integrate random uncertainties in robustness evaluations for a more comprehensive assessment of treatment plans., 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 © 2024 Associazione Italiana di Fisica Medica e Sanitaria. Published by Elsevier Ltd. All rights reserved.)

Objective . Bragg peak measurements play a key role in the beam quality assurance in proton therapy. Used as base data for the treatment planning softwares, the accuracy of the data is crucial when defining the range of the protons in the patient. Approach . In this paper a protocol to reconstruct a Pristine Bragg Peak exploring the direct correlation between the particle flux and the dose deposited by particles is presented. Proton flux measurements at the HollandPTC and FLUKA Monte Carlo simulations are used for this purpose. This new protocol is applicable to plastic scintillator detectors developed for Quality Assurance applications. In order to obtain the Bragg curve using a plastic fiber detector, a PMMA phantom with a decoupled and moveable stepper was designed. The step phantom allows to change the depth of material in front of the fiber detector during irradiations. The Pristine Bragg Peak reconstruction protocol uses the measured flux of particles at each position and multiplies it by the average dose obtained from the Monte Carlo simulation at each position. Main results . The results show that with this protocol it is possible to reconstruct the Bragg Peak with an accuracy of about 470 µ m, which is in accordance with the tolerances set by the AAPM. Significance . It has the advantage to be able to overcome the quenching problem of scintillators in the high ionization density region of the Bragg peak., (© 2024 Institute of Physics and Engineering in Medicine. All rights, including for text and data mining, AI training, and similar technologies, are reserved.)

Purpose: Increasing concern that brainstem toxicity incidence after proton radiation therapy might be higher than with photons led to a 2014 University of Florida (UF) landmark paper identifying its risk factors and proposing more conservative dose constraints. We evaluated how practice patterns changed among the Pediatric Proton/Photon Consortium Registry (PPCR)., Material and Methods: This prospective multicenter cohort study gathered data from patients under the age of 22 years enrolled on the PPCR, treated between 2002 and 2019 for primary posterior fossa brain tumors. After standardizing brainstem contours, we garnered dosimetry data and correlated those meeting the 2014 proton-specific brainstem constraint guidelines by treatment era, histology, and extent of surgical resection., Results: A total of 467 patients with evaluable proton radiation therapy plans were reviewed. Median age was 7.1 years (range: <1-21.9), 63.0% (n = 296) were men, 76.0% (n = 357) were White, and predominant histology was medulloblastoma (55.0%, n = 256), followed by ependymoma (27.0%, n = 125). Extent of resection was mainly gross total resection (GTR) (67.0%, n = 312), followed by subtotal resection (STR) or biopsy (20.0%, n = 92), and near total resection (NTR) (9.2%, n = 43). The UF brainstem constraint metrics most often exceeded were the goal D 50% of 52.4 gray relative biological equivalents (43.3%, n = 202) and maximal D 50% of 54 gray relative biological equivalents (12.6%, n = 59). The compliance rate increased after the new guidelines (2002-2014: 64.0% vs 2015-2019: 74.6%, P = .02), except for ependymoma (46.3% pre- vs 50.0% post-guidelines, P = .86), presenting lower compliance (48.8%) in comparison to medulloblastoma/ primitive neuroectodermal tumors/pineoblastoma (77.7%), glioma (89.1%), and atypical teratoid/rhabdoid tumors (90.9%) (P < .001). Degree of surgical resection did not affect compliance rates (GTR/NTR 71.0% vs STR/biopsy 72.8%, P = .45), even within the ependymoma subset (GTR/NTR 50.5% vs STR/biopsy 38.1%, P = .82)., Conclusion: Since the publication of the UF guidelines, the pediatric proton community has implemented more conservative brainstem constraints in all patients except those with ependymoma, irrespective of residual disease after surgery. Future work will evaluate if this change in practice is associated with decreased rates of brainstem toxicity., Competing Interests: Disclosures Dora Correia has a leadership role as chair of the EORTC Young and Early-Career Investigator Radiation Oncology Scientific Council not conferring a conflict of interest. Daniel J. Indelicato has an honorarium for committee service at the NCI Central IRB. Nadia N. Laack receives NCI institutional and COG support for the ACCL2031 randomized trial. Stephanie M. Perkins is part of the board of the National Association of Proton Therapy, Proton Collaborative Group, and Mevion Medical Systems, Inc., receiving support and honoraria from the latter. Torunn I. Yock receives in-kind funding for the Pediatric Proton/Photon Consortium Registry (PPCR) from MIM Software, IBA, Protom, and Elekta., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Comprehensive Quality Assurance (QA) protocols are necessary for complex beam delivery systems like Pencil Beam Scanning (PBS) proton therapy. This study focuses on automating the evaluation of beam delivery accuracy using irradiation log files and machine learning (ML) models., Methods: Irradiation log files of 935 clinical treatment fields and routine QA beams were analysed to evaluate spot parameters and Monitor Unit (MU) accuracy. ML models predicted spot size along the X, Y, major, and minor axes. In-house scripts automated log file analysis and spot size predictions. Predicted spot sizes were compared with expected baselines, and the accuracy of spot position, symmetry, and MU for each spot in the beam was evaluated., Results: More than 99.5 % of spot positions were accurate within a 1 mm. The mean and Standard Deviation (SD) of X positional error were -0.021 mm (SD: 0.181 mm), and for Y positional error, they were -0.002 mm (SD: 0.132 mm). ML models accurately predicted spot sizes, with over 95 % of spots demonstrating size variations within 10 % of the baseline. The Root Mean Squared Error (RMSE) of X and Y spot size differences were 0.15 mm and 0.16 mm, respectively. Spot symmetry was within 10 %, and MU accuracy showed 95 % of spots with MU per spot variation less than 2 %., Conclusion: This method can validate the vendor's beam delivery safety interlock system and serve as a quick alternative to patient-specific QA in adaptive treatment, where time is limited, as well as for routine QA spot parameter evaluations., 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 © 2024 Associazione Italiana di Fisica Medica e Sanitaria. Published by Elsevier Ltd. All rights reserved.)

We present a multi-stage and multi-resolution deformable image registration framework for image-guidance at a small animal proton irradiation platform. The framework is based on list-mode proton radiographies acquired at different angles, which are used to deform a 3D treatment planning CT relying on normalized mutual information (NMI) or root mean square error (RMSE) in the projection domain. We utilized a mouse X-ray micro-CT expressed in relative stopping power (RSP), and obtained Monte Carlo simulations of proton images in list-mode for three different treatment sites (brain, head and neck, lung). Rigid transformations and controlled artificial deformation were applied to mimic position misalignments, weight loss and breathing changes. Results were evaluated based on the residual RMSE of RSP in the image domain including the comparison of extracted local features, i.e. between the reference micro-CT and the one transformed taking into account the calculated deformation. The residual RMSE of the RSP showed that the accuracy of the registration framework is promising for compensating rigid (>97% accuracy) and non-rigid (∼95% accuracy) transformations with respect to a conventional 3D-3D registration. Results showed that the registration accuracy is degraded when considering the realistic detector performance and NMI as a metric, whereas the RMSE in projection domain is rather insensitive. This work demonstrates the pre-clinical feasibility of the registration framework on different treatment sites and its use for small animal imaging with a realistic detector. Further computational optimization of the framework is required to enable the use of this tool for online estimation of the deformation., 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 GmbH.. All rights reserved.)

Purpose: To explore the feasibility of a novel intensity-modulated proton arc technique that uses a single-energy beam from the cyclotron. The beam energy is externally modulated at each gantry angle by a tertiary energy modulator (EM). We hypothesize that irradiating in an arc without requiring an energy change from the cyclotron will achieve a faster delivery (main advantage of our technique) while keeping clinically desirable dosimetric results., Methods: In a retrospective cohort of four patients with female pelvis, prostate, lung, and brain cancers, we investigated our volumetric-modulated proton arc therapy (VPAT) technique. Arcs were simulated by sectors of 1°-spaced static beams. Keeping the energy requested from the cyclotron the same for each entire arc was supported by a predesigned EM placed in front of the nozzle. As a feasibility measure, EM thicknesses were calculated. Delivery times and doses to targets and organs at risk (OARs) were compared to those of the clinical plans., Results: VPAT plans were comparable to their clinical counterparts in achieving target dose conformity, being robust to uncertainties, and meeting clinical dose-volume constraints. Cyclotron energies for the four cases were within 159-220 MeV, and energy modulation range was 69-100 MeV, equivalent to 13-19 cm of water-equivalent thickness (WET). Plan delivery times were reduced from > 5 min in our clinical practice to < 3.5 min in VPAT., Conclusion: For the evaluated plans, the novel VPAT approach achieved shorter delivery times without sacrificing robustness, OAR sparing or target coverage. VPAT's EMs had WETs implementable in a clinical setup., 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 © 2024 Associazione Italiana di Fisica Medica e Sanitaria. Published by Elsevier Ltd. All rights reserved.)

Background and Purpose: This study aimed to evaluate the plan quality of our deep learning-based automated treatment planning method for robustly optimized intensity-modulated proton therapy (IMPT) plans in patients with oropharyngeal carcinoma (OPC). The assessment was conducted through a retrospective and prospective study, blindly comparing manual plans with deep learning plans., Materials and Methods: A set of 95 OPC patients was split into training (n = 60), configuration (n = 10), test retrospective study (n = 10), and test prospective study (n = 15). Our deep learning optimization (DLO) method combines IMPT dose prediction using a deep learning model with a robust mimicking optimization algorithm. Dosimetrists manually adjusted the DLO plan for individual patients. In both studies, manual plans and manually adjusted deep learning (mDLO) plans were blindly assessed by a radiation oncologist, a dosimetrist, and a physicist, through visual inspection, clinical goal evaluation, and comparison of normal tissue complication probability values. mDLO plans were completed within an average time of 2.5 h. In comparison, the manual planning process typically took around 2 days., Results: In the retrospective study, in 10/10 (100%) patients, the mDLO plans were preferred, while in the prospective study, 9 out of 15 (60%) mDLO plans were preferred. In 4 out of the remaining 6 cases, the manual and mDLO plans were considered comparable in quality. Differences between manual and mDLO plans were limited., Conclusion: This study showed a high preference for mDLO plans over manual IMPT plans, with 92% of cases considering mDLO plans comparable or superior in quality for OPC patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Prompt gammas imaging (PGI) is a promising method for observing a beam's shape and estimating the range of the beam from outside a subject. However 2-dimensional images of prompt gammas (PGs) during irradiation of protons were still difficult to measure. To achieve PGI, we developed a new gamma camera and imaged PGs while irradiating a phantom by proton beams. We also simultaneously measured prompt X-ray (PX) images with an X-ray camera from opposed direction and compared the images. The developed gamma camera uses a 10 mm thick GAGG block optically coupled to a flat panel photomultiplier tube (FP-PMT), and it is contained in a 20 mm thick tungsten container with a pinhole collimator attached. A poly-methyl-methacrylate (PMMA) block was irradiated by proton beams with total number of the protons similar to the clinical level, and the gamma camera imaged PGs and X-ray camera imaged PXs simultaneously. For all of the tested beams, we could measure the beam shapes of the PGs and the PXs and the ranges could also be estimated from the images. For both PG and PX images, time sequential images and accumulated images could be derived. We confirmed that the PGI using our developed gamma camera, as well as PXI, is promising for beam imaging and range estimation in proton therapy., 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 © 2024 Associazione Italiana di Fisica Medica e Sanitaria. Published by Elsevier Ltd. All rights reserved.)

Simple Summary: Proton therapy allows for more effective organs at risk avoidance than photon radiotherapy, thus reducing both radiation-induced toxicity and second cancer risk. The aim of the present paper is to compare protons and photons outcomes in the context of oropharyngeal and nasopharyngeal cancer and provide an updated comprehensive overview of the most promising new approaches and methodologies for treating head and neck cancer with protons. The growing interest in proton therapy (PT) in recent decades is justified by the evidence that protons dose distribution allows maximal dose release at the tumor depth followed by sharp distal dose fall-off. But, in the holistic management of head and neck cancer (HNC), limiting the potential of PT to a mere dosimetric advantage appears reductive. Indeed, the precise targeting of PT may help evaluate the effectiveness of de-escalation strategies, especially for patients with human papillomavirus associated-oropharyngeal cancer (OPC) and nasopharyngeal cancer (NPC). Furthermore, PT could have potentially greater immunogenic effects than conventional photon therapy, possibly enhancing both the radiotherapy (RT) capability to activate anti-tumor immune response and the effectiveness of immunotherapy drugs. Based on these premises, the aim of the present paper is to conduct a narrative review reporting the safety and efficacy of PT compared to photon RT focusing on NPC and OPC. We also provide a snapshot of ongoing clinical trials comparing PT with photon RT for these two clinical scenarios. Finally, we discuss new insights that may further develop clinical research on PT for HNC. [ABSTRACT FROM AUTHOR]

Background and Purpose: Radiation-induced alopecia (RIA) is one of the most frequent and upsetting cosmetic side effects after radiotherapy (RT) for brain cancer. We report the incidence of RIA in a cohort of brain tumours patients treated with Proton Therapy (PT) and externally validate published NTCP models of grade 2 (G2) RIA for their implementation in clinical practice., Methods: Data for patients treated for brain tumours with scanning beam PT between 2018 and 2022 were extracted. Acute, late and permanent RIA events were evaluated according to CTCAE 5.0. Lyman-Kutcher-Burman (LKB) and multivariable logistic regression (MLR) published models were computed from the relative dose-surface histogram of the scalp. External validity of models was assessed in terms of discrimination and calibration., Results: In the 264 patients analysed, rates of any grade acute (≤90 days after PT completion), late (>90 days) and permanent RIA (persisting for> 12 months) were 61.8 %, 24.7 % and 14.4 %, respectively. In our independent cohort, LKB- and MLR-NTCP showed a good discrimination for G2 RIA (0.71≤ROC-AUC≤0.83) while model calibration was unsatisfactory possibly due to a different outcome evaluation between training and validation cohorts, as well as differences in clinical and treatment related variables between the two groups., Conclusions: Despite the reasonable sensitivity and specificity of the NTCP models for RIA in the validation cohort, our study emphasizes the significance of differences between the cohorts utilized for model development and validation. Specifically, variations in the reporting of clinical outcomes inevitably jeopardize the validation of NTCP models. A standardize and objective RIA scoring system is essential., 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 © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background and Purpose: To investigate the toxicity and survival outcomes of proton and carbon ion radiotherapy for patients with operable early-stage lung cancer who are eligible for lobectomy., Materials and Methods: This multicenter nationwide prospective cohort study included patients with operable early-stage lung cancer. Proton and carbon ion radiotherapy was performed according to the schedule stipulated in the unified treatment policy. Progression-free survival (PFS), overall survival (OS) and treatment-related toxicities were evaluated., Results: A total of 274 patients were enrolled and included in efficacy and safety analyses. The most common tumor type was adenocarcinoma (44 %), while 105 cases (38 %) were not histologically confirmed or diagnosed clinically. Overall, 250 (91 %) of the 274 patients had tumors that were peripherally situated, while 138 (50 %) and 136 (50 %) patients were treated by proton and carbon ion radiotherapy, respectively. The median follow-up time for all censored patients was 42.8 months (IQR 36.7-49.0). Grade 3 or severe treatment-related toxicity was observed in 4 cases (1.5 %). Three-year PFS was 80.5 % (95 % CI: 75.7 %-85.5 %) and OS was 92.5 % (95 % CI: 89.3 %-95.8 %). Pathological confirmation and clinical stage were factors significantly associated with PFS, while tumor location and particle-ion type were not. Meanwhile, clinical stage was significantly associated with OS, but pathological confirmation, tumor location, and particle-ion type were not., Conclusions: Particle therapy for operable early-stage lung cancer resulted in excellent 3-year OS and PFS in each subset. In this disease context, proton and carbon ion beam therapies are feasible alternatives to curative surgery., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that would directly affect the research reported in this paper. Hideyuki Harada received Honoraria from Astrazeneca, Accuray, Chugai pharmaceutical, Takeda pharmaceutical, MSD, Eizai pharmaceutical, Phizer, Brainlab, Hitachi, Novartis, Guerbet Japan, GE Healthcare, Nihon Medi-Physics and Taiho pharmaceutical outside this work. Keita Mori received Honoraria from Chugai Pharmaceutical, Ono Pharmaceutical, Bristol Myers Squibb, Daiichi-Sankyo and Eli Lilly Japan outside this work. Hitoshi Ishikawa received Honoraria from Boston Scientific Corporation and MSD outside this work. Masaki Nakamura received Honoraria from Astrazeneca outside this work. Nobuteru Kubo received Honoraria from Astrazeneca outside this work. Miyako Satouchi received Honoraria from Chugai pharmaceutical, Astrazeneca,Eli Lilly Japan, Ono pharmaceutical, Bristol-Myers Squibb, MSD, Merck Janssen Pharmaceutical, Amgen, Taiho pharmaceutical, Pfizer, Daiichi-Sankyo, Eisai, Takeda pharmaceutical, Novartis, GlaxoSmithKline Consumer Healthcare Japan and Bayer pharmaceutical and research funding from GlaxoSmithKline, AstraZeneca, MSD, Janssen, Amgen, Taiho pharmaceutical, Ono pharmaceutical, Bristol Myers Squibb, Pfizer, Daiichi-Sankyo, and Eisai outside this work. Yoshiyuki Shioyama received Honoraria from Astrazeneca outside this work., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background and Purpose: As no guidelines for pencil beam scanning (PBS) proton therapy (PT) of paediatric posterior fossa (PF) tumours exist to date, this study investigated planning techniques across European PT centres, with special considerations for brainstem and spinal cord sparing., Materials and Methods: A survey and a treatment planning comparison were initiated across nineteen European PBS-PT centres treating paediatric patients. The survey assessed all aspects of the treatment chain, including but not limited to delineations, dose constraints and treatment planning. Each centre planned two PF tumour cases for focal irradiation, according to their own clinical practice but based on common delineations. The prescription dose was 54 Gy(RBE) for Case 1 and 59.4 Gy(RBE) for Case 2. For both cases, planning strategies and relevant dose metrics were compared., Results: Seventeen (89 %) centres answered the survey, and sixteen (80 %) participated in the treatment planning comparison. In the survey, thirteen (68 %) centres reported using the European Particle Therapy Network definition for brainstem delineation. In the treatment planning study, while most centres used three beam directions, their configurations varied widely across centres. Large variations were also seen in brainstem doses, with a brainstem near maximum dose (D2%) ranging from 52.7 Gy(RBE) to 55.7 Gy(RBE) (Case 1), and from 56.8 Gy(RBE) to 60.9 Gy(RBE) (Case 2)., Conclusion: This study assessed the European PBS-PT planning of paediatric PF tumours. Agreement was achieved in e.g. delineation-practice, while wider variations were observed in planning approach and consequently dose to organs at risk. Collaboration between centres is still ongoing, striving towards common guidelines., 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 © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Purpose: In this study, we assessed the robustness of intensity modulated proton therapy (IMPT) in esophageal cancer for anatomical variations during treatment., Methods: The first sixty esophageal cancer patients, treated clinically with chemoradiotherapy were included. The treatment planning strategy was based on an internal target volume (ITV) approach, where the ITV was created from the clinical target volumes (CTVs) delineated on all phases of a 4DCT. For optimization, a 3 mm isotropic margin was added to the ITV, combined with robust optimization using 5 mm setup and 3 % range uncertainty. Each patient received weekly repeat CTs (reCTs). Robust plan re-evaluation on all reCTs, and a robust dose summation was performed. To assess the factors influencing ITV coverage, a multivariate linear regression analysis was performed. Additionally, clinical adaptations were evaluated., Results: The target coverage was adequate (ITV V94%>98 % on the robust voxel-wise minimum dose) on most reCTs (91 %), and on the summed dose in 92 % of patients. Significant predictors for ITV coverage in the multivariate analysis were diaphragm baseline shift and water equivalent depth (WED) of the ITV in the beam direction. Underdosage of the ITV mainly occurred in week 1 and 4, leading to treatment adaptation of eight patients, all on the first reCT., Conclusion: Our IMPT treatment of esophageal cancer is robust for anatomical variations. Adaptation appears to be most effective in the first week of treatment. Diaphragm baseline shifts and WED are predictive factors for ITV underdosage, and should be incorporated in an adaptation protocol., 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 © 2024 Elsevier B.V. All rights reserved.)

Introduction: Sacrococcygeal chordomas have high recurrence rates and are challenging to treat., Methods: In this phase II prospective, randomized, stratified trial, the safety and feasibility of hypofractionated ion radiation therapy were investigated. The primary focus was monitored through the incidence of Grade 3-5 NCI-CTC-AE toxicity. Secondary endpoints included local progression-free (LPFS) and overall survival (OS)., Results: The study enrolled 82 patients with primary (87 %) and recurrent (13 %) inoperable or incompletely resected sacral chordomas from January 2013 to July 2022, divided equally into proton therapy (Arm A) and carbon ion beam therapy (Arm B) groups, each receiving a total dose of 64 Gy (RBE) in 16 fractions, 5-6 fractions per week. Overall 74 % of patients received no previous surgery and 66 % of tumors were confirmed by a brachyury staining. The mean and median Gross Tumor Volume at the time of treatment (GTV) was 407 ml and 185 ml, respectively. The median follow-up of the surviving patients was 44.7 months, and the 2-year and 4-year OS rates were 96 % and 81 %, respectively. Factors such as smaller GTV and younger age trended towards better OS. The LPFS after 2-year and 4-year was 84 % and 70 %, respectively. Male gender emerged as a significant predictor of LPFS. There was no significant difference between the treatment groups. We observed five grade 4 wound healing disorders (6 %)., Conclusion: The initial response rates were promising; however local control was not sustained. More comparative research on fractionation schemes is essential to refine treatment approaches for inoperable sacral chordoma., 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 © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)