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Arc proton therapy (ArcPT) is an emerging modality in cancer treatments. It delivers the proton beams following a sequence of irradiation angles while the gantry is continuously rotating around the patient. Compared to conventional proton treatments (intensity modulated proton therapy, IMPT), the number of beams is significantly increased bringing new degrees of freedom that leads to potentially better cancer care. However, the optimization of such treatment plans becomes more complex and several alternative statements of the problem can be considered and compared in order to solve the ArcPT problem. Three such problem statements, distinct in their mathematical formulation and properties, are investigated and applied to solving the ArcPT optimization problem. They make use of (i) fast iterative shrinkage-thresholding algorithm (FISTA), (ii) local search (LS) and (iii) mixed-integer programming (MIP). The treatment plans obtained with those methods are compared among them, but also with IMPT and an existing state-of-the-art method: Spot-Scanning Proton Arc (SPArc). MIP stands out at low scale problems both in terms of dose quality and time delivery efficiency. FISTA shows high dose quality but experiences difficulty to optimize the energy sequence while LS is mostly the antagonist. This detailed study describes independent approaches to solve the ArcPT problem and depending on the clinical case, one should be cautiously picked rather than the other. This paper gives the first formal definition of the problem at stake, as well as a first reference benchmark. Finally, empirical conclusions are drawn, based on realistic assumptions., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: A relative biological effectiveness (RBE) of 1.1 is used for proton therapy though clinical evidence of varying RBE was raised. Clinical studies on RBE variability have been conducted for decades for carbon radiation, which could advance the understanding of the clinical proton RBE given an ion-independent RBE model. In this work, such a model, linear and simple, using the beam quantity Q = Z 2 /E (Z = ion charge, E = kinetic energy per nucleon) was tested and compared to the commonly used, proton-specific and linear energy transfer (LET) based Wedenberg RBE model., Material and Methods: The Wedenberg and Q models, both predicting RBE max and RBE min (i.e., RBE at vanishing and very high dose, respectively), are compared in terms of ion-dependence and prediction power. An experimental in-vitro data ensemble covering 115 publications for various ions was used as dataset., Results: The model parameter of the Q model was observed to be similar for different ions (in contrast to LET). The Q model was trained without any prior knowledge of proton data. For proton RBE, the differences between experimental data and corresponding predictions of the Wedenberg or the Q model were highly comparable., Conclusions: A simple linear RBE model using Q instead of LET was proposed and tested to be able to predict proton RBE using model parameter trained based on only RBE data of other particles in a clinical proton energy range for a large in-vitro dataset. Adding (pre)clinical knowledge from carbon ion therapy may, therefore, reduce the dominating biological uncertainty in proton RBE modelling. This would translate in reduced RBE related uncertainty in proton therapy treatment planning., 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 © 2022 Elsevier B.V. All rights reserved.)

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

Purpose: We propose a method that potentially improves the outcome of mutual-information-based automatic image registration by using the contrast enhancement filter (CEF)., Methods: Seventy-six pairs of two-dimensional X-ray images and digitally reconstructed radiographs for 20 head and neck and nine lung cancer patients were analyzed retrospectively. Automatic image registration was performed using the mutual-information-based algorithm in VeriSuite®. Images were preprocessed using the CEF in VeriSuite®. The correction vector for translation and rotation error was calculated and manual image registration was compared with automatic image registration, with and without CEF. In addition, the normalized mutual information (NMI) distribution between two-dimensional images was compared, with and without CEF., Results: In the correction vector comparison between manual and automatic image registration, the average differences in translation error were < 1 mm in most cases in the head and neck region. The average differences in rotation error were 0.71 and 0.16 degrees without and with CEF, respectively, in the head and neck region; they were 2.67 and 1.64 degrees, respectively, in the chest region. When used with oblique projection, the average rotation error was 0.39 degrees with CEF. CEF improved the NMI by 17.9 % in head and neck images and 18.2 % in chest images., Conclusions: CEF preprocessing improved the NMI and registration accuracy of mutual-information-based automatic image registration on the medical images. The proposed method achieved accuracy equivalent to that achieved by experienced therapists and it will significantly contribute to the standardization of image registration quality., 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 © 2022 Associazione Italiana di Fisica Medica e Sanitaria. Published by Elsevier Ltd. All rights reserved.)

The article introduces the Good Clinical Proton Practice (GCPP) initiative to enhance proton therapy standards, addressing challenges faced by smaller or newly established proton centers. GCPP aims to provide guidelines, technical documentation, and white papers to ensure high-quality treatment for all patients. Key features include consistent quality standards, standardized operating procedures, and the involvement of medical physics experts, with a focus on distribution of resources, sharing knowledge, and engagement with the community. The initiative seeks to promote standardized, high-quality proton therapy to maximize its potential in cancer treatment. [Extracted from the article]

Simple Summary: Proton therapy is a potentially attractive option to treat oropharyngeal cancers due to better dose distribution. We aimed to synthesize the quality of life (QOL) and patient-reported outcomes (PROs) following treatment. We found that studies frequently demonstrated the advantages of proton therapy compared to photon therapy in terms of QOL and PROs; however, biases due to the non-randomized nature of the studies may require confirmation in phase III randomized controlled trials. Background: Complex anatomy surrounding the oropharynx makes proton therapy (PT), especially intensity-modulated PT (IMPT), a potentially attractive option due to its ability to reduce the volume of irradiated healthy tissues. Dosimetric improvement may not translate to clinically relevant benefits. As outcome data are emerging, we aimed to evaluate the evidence of the quality of life (QOL) and patient-reported outcomes (PROs) following PT for oropharyngeal carcinoma (OC). Materials and Methods: We searched PubMed and Scopus electronic databases (date: 15 February 2023) to identify original studies on QOL and PROs following PT for OC. We employed a fluid strategy in the search strategy by tracking citations of the initially selected studies. Reports were extracted for information on demographics, main results, and clinical and dose factor correlates. Quality assessment was performed using the NIH's Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies. The PRISMA guidelines were followed in the preparation of this report. Results: Seven reports were selected, including one from a recently published paper captured from citation tracking. Five compared PT and photon-based therapy, although none were randomized controlled trials. Most endpoints with significant differences favored PT, including xerostomia, cough, need for nutritional supplements, dysgeusia, food taste, appetite, and general symptoms. However, some endpoints favored photon-based therapy (sexual symptoms) or showed no significant difference (e.g., fatigue, pain, sleep, mouth sores). The PROs and QOL improve following PT but do not appear to return to baseline. Conclusion: Evidence suggests that PT causes less QOL and PRO deterioration than photon-based therapy. Biases due to the non-randomized study design remain obstacles to a firm conclusion. Whether or not PT is cost-effective should be the subject of further investigation. [ABSTRACT FROM AUTHOR]

Introduction: The aim was to evaluate and compare the dosimetric effect and robustness towards day-to-day anatomical and setup variations in the delivered dose for photon and proton treatments of sinonasal cancer (SNC) patients., Materials and Methods: Photon (VMAT) and proton (IMPT) plans were optimized retrospectively for 24 SNC patients. Synthetic CTs (synCT) were obtained by deforming the planning CT (pCT) to the anatomy of every daily cone-beam CT. Both VMAT and IMPT plans were recalculated on the synCTs. The recalculated daily dose was accumulated over the whole treatment on the pCT. Target coverage and dose to organs and risk (OARs) were evaluated for all patients for the nominal, daily and accumulated dose distribution., Results: In general, dose to OARs farther away from the target, including brain, chiasm and contralateral optic nerve, was lower for proton plans than photon plans. Whereas, OARs in proximity of the target received a lower dose for photon plans. For proton plans, the target coverage (volume of CTV receiving 95% of prescribed dose), V95%, fell below 99% for 9/24 patients in one or more fractions. For photon plans, 4/24 patients had one or more fractions where V95% fell below 99%. For accumulated doses, V95% was below 99% only in two cases, but above 98% for all patients., Conclusion: Photon and proton treatment have different strengths regarding OAR sparing. The robustness was high for both treatment modalities. Patient selection for either proton or photon radiation therapy of SNC patients should be based on a case-by-case comparison., 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 © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Purpose: Plan complexity and robustness are two essential aspects of treatment plan quality but there is a great variability in their management in clinical practice. This study reports the results of the 2020 ESTRO survey on plan complexity and robustness to identify needs and guide future discussions and consensus., Methods: A survey was distributed online to ESTRO members. Plan complexity was defined as the modulation of machine parameters and increased uncertainty in dose calculation and delivery. Robustness was defined as a dose distribution's sensitivity towards errors stemming from treatment uncertainties, patient setup, or anatomical changes., Results: A total of 126 radiotherapy centres from 33 countries participated, 95 of them (75%) from Europe and Central Asia. The majority controlled and evaluated plan complexity using monitor units (56 centres) and aperture shapes (38 centres). To control robustness, 98 (97% of question responses) photon and 5 (50%) proton centres used PTV margins for plan optimization while 75 (94%) and 5 (50%), respectively, used margins for plan evaluation. Seventeen (21%) photon and 8 (80%) proton centres used robust optimisation, while 10 (13%) and 8 (80%), respectively, used robust evaluation. Primary uncertainties considered were patient setup (photons and protons) and range calculation uncertainties (protons). Participants expressed the need for improved commercial tools to control and evaluate plan complexity and robustness., Conclusion: Clinical implementation of methods to control and evaluate plan complexity and robustness is very heterogeneous. Better tools are needed to manage complexity and robustness in treatment planning systems. International guidelines may promote harmonization., 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 © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: This paper focused on the design and optimization of ridge filter-based intensity-modulated proton therapy (IMPT), and its potential applications for FLASH. Differing from the standard pencil beam scanning (PBS) mode, no energy/layer switching is required and total treatment time can be shortened., Methods: Unique dose-influence matrices were generated as a proton beam traverses through slabs of different thicknesses (i.e., modulation by different layers). To establish the references for comparison, conventional IMPT plans (single field) were created using a large-scale nonlinear solver. The spot weights from the reference IMPT plans were used as inputs for optimizing the design of ridge filters. Two designs were evaluated: model A (static) and model B (dynamic). The ridge filter designs were first verified (by GEANT4 simulation) in a water phantom and then in an H&N case. A direct comparison was made between the GEANT4 simulation results of two models and their respective references, with regard to plan quality, dose-averaged dose rate, and total treatment time., Results: In both the water phantom and the H&N case, two models are able to modulate dose distributions with high conformity, showing no significant difference relative to the reference plans. Dose rate-volume histograms suggest that in order to achieve a dose rate of 40 Gy/s over 90% PTV, the beam intensity needs to be 2.5 × 10 11 protons/s for both models. For a fraction dose of 10 Gy, the total treatment time (including both irradiation time and dead time) can be shortened by a factor of 4.9 (model A) and 6.5 (model B), relative to the reference plans., Conclusion: Two proposed designs (both static and dynamic) can be used for PBS-IMPT requiring no layer switching. They are promising candidates for FLASH-IMPT capable of reducing treatment time and achieving high dose rates while maintaining dose conformity simultaneously., (© 2022 American Association of Physicists in Medicine.)

Purpose: To demonstrate predictive anatomical modelling for improving the clinical workflow of adaptive intensity-modulated proton therapy (IMPT) for head and neck cancer., Methods: 10 radiotherapy patients with nasopharyngeal cancer were included in this retrospective study. Each patient had a planning CT, weekly verification CTs during radiotherapy and predicted weekly CTs from our anatomical model. Predicted CTs were used to create predicted adaptive plans in advance with the aim of maintaining clinically acceptable dosimetry. Adaption was triggered when the increase in mean dose (D mean ) to the parotid glands exceeded 3 Gy(RBE). We compared the accumulated dose of two adaptive IMPT strategies: 1) Predicted plan adaption: One adaptive plan per patient was optimised on a predicted CT triggered by replan criteria. 2) Standard replan: One adaptive plan was created reactively in response to the triggering weekly CT., Results: Statistical analysis demonstrates that the accumulated dose differences between two adaptive strategies are not significant (p > 0.05) for CTVs and OARs. We observed no meaningful differences in D 95 between the accumulated dose and the planned dose for the CTVs, with mean differences to the high-risk CTV of -1.20 %, -1.23 % and -1.25 % for no adaption, standard and predicted plan adaption, respectively. The accumulated parotid D mean using predicted plan adaption is within 3 Gy(RBE) of the planned dose and 0.31 Gy(RBE) lower than the standard replan approach on average., Conclusion: Prediction-based replanning could potentially enable adaptive therapy to be delivered without treatment gaps or sub-optimal fractions, as can occur during a standard replanning strategy, though the benefit of using predicted plan adaption over the standard replan was not shown to be statistically significant with respect to accumulated dose in this study. Nonetheless, a predictive replan approach can offer advantages in improving clinical workflow efficiency., 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 © 2022 Elsevier B.V. All rights reserved.)

Proton detection in solid state NMR is continuously developing and allows one to gain new insights in structural biology. Overall, this progress is a result of the synergy between hardware development, new NMR methodology and new isotope labeling strategies, to name a few factors. Even though current developments are rapid, it is worthwhile to summarize what can currently be achieved employing proton detection in biological solids. We illustrate this by analysing the signal-to-noise ratio (SNR) for spectra obtained for a microcrystalline α-spectrin SH3 domain protein sample by (i) employing different degrees of chemical dilution to replace protons by incorporating deuterons in different sites, by (ii) variation of the magic angle spinning (MAS) frequencies between 20 and 110 kHz, and by (iii) variation of the static magnetic field B 0 . The experimental SNR values are validated with numerical simulations employing up to 9 proton spins. Although in reality a protein would contain far more than 9 protons, in a deuterated environment this is a sufficient number to achieve satisfactory simulations consistent with the experimental data. The key results of this analysis are (i) with current hardware, deuteration is still necessary to record spectra of optimum quality; (ii) 13CH3 isotopomers for methyl groups yield the best SNR when MAS frequencies above 100 kHz are available; and (iii) sensitivity increases with a factor beyond B0 3/2 with the static magnetic field due to a transition of proton-proton dipolar interactions from a strong to a weak coupling limit., 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 © 2022 Elsevier B.V. All rights reserved.)

Normal tissue complication probability (NTCP) models can guide clinical decision making in radiotherapy. In recent years, they have been used for patient selection for proton beam therapy (PBT) for some anatomical tumour sites. This review synthesizes the published evidence regarding the use of NTCP models to predict the toxicity of PBT, for different end points in patients with brain tumours. A search of Medline and Embase using the Patients, Intervention, Comparison, Outcome (PICO) criteria was undertaken. In total, 37 articles were deemed relevant and were reviewed in detail. Nineteen articles on NTCP modelling of toxicity end points were included. Of these, 11 were comparative NTCP studies of PBT versus conventional photon radiotherapy (XRT), which evaluated differences in plan dosimetry and then assumed that XRT-derived literature estimates of NTCP would be applicable to both. Seven papers derived NTCP models based on PBT outcome data, two of which provided model parameters. Among analysed end points, the reduced risk of secondary tumours with PBT as compared with XRT is estimated - through modelling studies - to be considerable and was highlighted by most authors. For other analysed end points, the clinical benefit of PBT mainly depends on tumour location in relation to organs at risk as well as prescription doses. NTCP models can be useful tools for treatment plan comparison. However, most published toxicity data were derived from XRT cohorts; this review has highlighted the need for further studies relating dose-volume parameters to observed toxicity in PBT-treated patients. Specifically, there is a need for PBT-specific NTCP models that can be implemented in the clinical practice. NTCP models built on robust clinical data for the most common radiotherapy toxicities in the brain would potentially redefine the current indications for PBT., (Copyright © 2021 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

While FLASH radiation therapy is inspiring enthusiasm to transform the field, it is neither new nor well understood with respect to the radiobiological mechanisms. As FLASH clinical trials are designed, it will be important to ensure we can deliver dose consistently and safely to every patient. Much like hyperthermia and proton therapy, FLASH is a promising new technology that will be complex to implement in the clinic and similarly will require customized credentialing for multi-institutional clinical trials. There is no doubt that FLASH seems promising, but many technologies that we take for granted in conventional radiation oncology, such as rigorous dosimetry, 3D treatment planning, volumetric image guidance, or motion management, may play a major role in defining how to use, or whether to use, FLASH radiotherapy. Given the extended time frame for patients to experience late effects, we recommend moving deliberately but cautiously forward toward clinical trials. In this paper, we review the state of quality assurance and safety systems in FLASH, identify critical pre-clinical data points that need to be defined, and suggest how lessons learned from previous technological advancements will help us close the gaps and build a successful path to evidence-driven FLASH implementation., (© 2022 The Authors. Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

The editorial discusses the potential of FLASH radiotherapy, which delivers ultra-high dose rates, for cancer treatment with reduced side effects. While promising, questions remain regarding safe clinical translation for curative cancer care, as seen in studies on osteoradionecrosis in animals. The Research Topic includes articles addressing gaps in knowledge and technology for effective clinical translation of FLASH, focusing on dose rates, normal tissue sparing, tumour efficacy, and machine limitations. Despite remaining questions, this research contributes to the efficient clinical translation of FLASH. [Extracted from the article]

Charged particle therapy (proton beam therapy and carbon ion therapy) is a form of radiotherapy which has the unique characteristic of superior depth dose distribution, and has been used for the treatment of hepatocellular carcinoma (HCC) in a limited number of patients, especially in Japan. We undertook a systematic review to define the clinical utility of charged particle therapy for patients with HCC. We searched the MEDLINE database from 1983 to June 2016 to identify clinical studies on charged particle therapy for HCC. Primary outcomes of interest were local control, overall survival, and late radiation morbidities. A total of 13 cohorts from 11 papers were selected from an initial dataset of 78 papers. They included a randomized controlled trial comparing proton beam therapy with transarterial chemoembolization, 9 phase I or II trials and 2 retrospective studies. The reported actuarial local control rates ranged from 71.4-95% at 3 years, and the overall survival rates ranged from 25-42.3% at 5 years. Late severe radiation morbidities were uncommon, and a total of 18 patients with grade ≥3 late adverse events were reported among the 787 patients included in this analysis. Charged particle therapy for HCC was associated with good local control with limited probability of severe morbidities. The cost-effectiveness and the distinctive clinical advantages of charged particle therapies should be clarified in order to become a socially accepted treatment modality for HCC. [ABSTRACT FROM AUTHOR]

Current proton therapy scanning systems always use two independent dipole magnets for spot scanning in proton therapy. However, the space occupied by these two dipole magnets located after the final gantry bending magnets is very large and increases the overall size of the gantry. In order to construct a compact nozzle and decrease the size of the gantry, we decide to design an octupole scanning magnet to replace these two separate dipole magnets. The octupole scanning magnet, which is completely different from traditional octupole magnet, can generate rotating dipole magnetic field with the change of the loaded sinusoidal current phases. In this paper, we have finished the static optimization of an octupole scanning magnet model, including the length and shape of the poles, the diameter of the gap, and the shims on the pole edges, both in Opera two-dimensional (2-D) and 3-D. The corresponding relationship between the size of the gap and the good field region was also studied. The effect of eddy currents on magnetic field stability was also simulated in Opera 3-D. All the simulation results are presented in this paper. [ABSTRACT FROM AUTHOR]

In this paper we propose a solution to the need for a fast particle transport algorithm in Online Adaptive Proton Therapy capable of cheaply, but accurately computing the changes in patient dose metrics as a result of changes in the system parameters. We obtain the proton phase-space density through the product of the numerical solution to the one-dimensional Fokker-Planck equation and the analytical solution to the Fermi-Eyges equation. Moreover, a corresponding adjoint system was derived and solved for the adjoint flux. The proton phase-space density together with the adjoint flux and the metric (chosen as the energy deposited by the beam in a variable region of interest) allowed assessing the accuracy of our algorithm to different perturbation ranges in the system parameters and regions of interest. The algorithm achieved negligible errors ( 1.1 × 10 − 6 % to 3.6 × 10 − 3 % ) for small Hounsfield unit (HU) perturbation ranges (–40 HU to 40 HU) and small to moderate errors (3% to 17%) – in line with the well-known limitation of adjoint approaches – for large perturbation ranges (–400 HU to 400 HU) in the case of most clinical interest where the region of interest surrounds the Bragg peak. Given these results coupled with the capability of further improving the timing performance it can be concluded that our algorithm presents a viable solution for the specific purpose of Online Adaptive Proton Therapy. [ABSTRACT FROM AUTHOR]

Background: In preclinical studies, FLASH therapy, in which radiation delivered at ultrahigh dose rates of ≥40 Gy per second, has been shown to cause less injury to normal tissues than radiotherapy delivered at conventional dose rates. This paper describes the protocol for the first-in-human clinical investigation of proton FLASH therapy. Objective: FAST-01 is a prospective, single-center trial designed to assess the workflow feasibility, toxicity, and efficacy of FLASH therapy for the treatment of painful bone metastases in the extremities. Methods: Following informed consent, 10 subjects aged ≥18 years with up to 3 painful bone metastases in the extremities (excluding the feet, hands, and wrists) will be enrolled. A treatment field selected from a predefined library of plans with fixed field sizes (from 7.5 cm Ã-- 7.5 cm up to 7.5 cm Ã-- 20 cm) will be used for treatment. Subjects will receive 8 Gy of radiation in a single fraction-a well-established palliative regimen evaluated in prior investigations using conventional dose rate photon radiotherapy. A FLASH-enabled Varian ProBeam proton therapy unit will be used to deliver treatment to the target volume at a dose rate of ≥40 Gy per second, using the plateau (transmission) portion of the proton beam. After treatment, subjects will be assessed for pain response as well as any adverse effects of FLASH radiation. The primary end points include assessing the workflow feasibility and toxicity of FLASH treatment. The secondary end point is pain response at the treated site(s), as measured by patient-reported pain scores, the use of pain medication, and any flare in bone pain after treatment. The results will be compared to those reported historically for conventional dose rate photon radiotherapy, using the same radiation dose and fractionation. Results: FAST-01 opened to enrollment on November 3, 2020. Initial results are expected to be published in 2022. Conclusions: The results of this investigation will contribute to further developing and optimizing the FLASH-enabled ProBeam proton therapy system workflow. The pain response and toxicity data acquired in our study will provide a greater understanding of FLASH treatment effects on tumor responses and normal tissue toxicities, and they will inform future FLASH trial designs. [ABSTRACT FROM AUTHOR]

Stereotactic radiosurgery and stereotactic body radiation therapy have been increasingly utilized in radiation oncology to treat early stage tumors, metastatic targets, and retreatment of relapsed diseases due to their efficiency, treatment effect, and cost effectiveness over the past two decades. Stereotactic radiosurgery and stereotactic body radiation therapy both demand high specifications for their delivery machines, as they deliver radiation doses with fewer treatment fractions and higher doses per fraction. Manufacturers have either invented specialized technologies solely or customized their existing machines for this purpose. In this paper, we review the major technologies and treatment machines for stereotactic radiosurgery and stereotactic body radiation therapy, describe their main features, and discuss the advantages and disadvantages. [ABSTRACT FROM AUTHOR]

The accurate measurement of the beam range in the frame of quality assurance (QA) is a requirement for clinical use of a proton therapy machine. Conventionally used detectors mostly estimate the range by measuring the depth dose distribution of the protons. In this paper, we use pixel detectors designed for individual particle tracking in the high-radiation environment of the ATLAS experiment at LHC. The detector measures the deposited energy in the sensor for individual protons. Due to the limited dynamic energy range of the readout chip, several ways to measure the proton energy or range are examined. A staircase phantom is placed on the detector to perform an energy calibration relative to the NIST PSTAR stopping power database. In addition, track length measurements are performed using the detector aligned parallel with the beam axis to investigate the Linear Energy Transfer (LET) per pixel along the trajectory of individual protons. In this proof-of-principle study, we show that this radiation hardness detector can successfully be used to determine the initial proton energy for protons impinging on the sensor with an energy below 44 MeV after the range shifters. It becomes clear that an improvement of the energy resolution of the readout chip is required for clinical use. [ABSTRACT FROM AUTHOR]

Aims: Proton therapy is a radiation technique that yields less dose in normal tissues than photon therapy. In the Netherlands, proton therapy is reimbursed if the reduced dose to normal tissues is predicted to translate into a prespecified reduction in toxicity, based on nationally approved validated models. The aim of this paper is to present the development of a national indication protocol for proton therapy (NIPP) for model-based selection of breast cancer patients and to report on first clinical experiences., Materials and Methods: A national proton therapy working group for breast cancer (PWG-BC) screened the literature for prognostic models able to estimate the individual risk of specific radiation-induced side-effects. After critical appraisal and selection of suitable models, a NIPP for breast cancer was written and subjected to comments by all stakeholders. The approved NIPP was subsequently introduced to select breast cancer patients who would benefit most from proton therapy., Results: The model of Darby et al. (N Engl J Med 2013; 368:987-82) was the only model fulfilling the criteria prespecified by the PWG-BC. The model estimates the relative risk of an acute coronary event (ACE) based on the mean heart dose. The absolute lifetime risk of ACE <80 years was calculated by applying this model to the Dutch absolute incidence of ACE for female and male patients, between 40 and 70 years at breast cancer radiotherapy, with/without cardiovascular risk factors. The NIPP was approved for reimbursement in January 2019. Based on a threshold value of a 2% absolute lower risk on ACE for proton therapy compared with photons, 268 breast cancer patients have been treated in the Netherlands with proton therapy between February 2019 and January 2021., Conclusion: The NIPP includes a model that allows the estimation of the absolute risk on ACE <80 years based on mean heart dose. In the first 2 years, 268 breast cancer patients have been treated with proton therapy in The Netherlands., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: To comprehensively describe the treatment of mediastinal lymphoma by pencil beam scanning (PBS) proton therapy., Methods: Fourteen patients underwent PBS proton treatment in a supine position in deep inspiration breath-hold (DIBH). Three DIBH computed tomography (CT) scans were acquired for each patient to delineate the Internal Target Volume (ITV). Intensity-modulated proton therapy (IMPT) was planned by min-max robust optimization on the ITV, with a 6 mm setup and 3.5% range uncertainties. Robustness analysis was performed and dose coverage was visually inspected on the corresponding voxel-wise minimum map. Layer repainting was set equal to 5 to compensate for cardiac motion. Intra-fraction reproducibility during treatment was assessed by repeated daily DIBH X-ray imaging. Finally, an additional CT was acquired at half treatment to estimate the impact of inter-fraction dosimetric reproducibility., Results: IMPT guaranteed robust mediastinal target coverage and organs-at-risk sparing. However, visual voxel-wise robustness evaluation showed that in five patients a second optimization with focused objectives in the cost-function was necessary to achieve a robust coverage of the target regions at the interface between lungs and soft tissue. In six patients, repainting was not used due to excessive treatment time length and poor patient compliance. Intra-fraction average reproducibility was within 1 mm/1degree. On repeated CT scans, inter-fraction setup errors and/or anatomical changes showed minimal dosimetric differences in CTV coverage., Conclusion: IMPT in DIBH is effective and reproducible to treat mediastinal lymphomas. Caution is recommended to guarantee robust dose delivery to high-risk regions at the interface between lungs and soft tissue., 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 © 2022 Elsevier B.V. All rights reserved.)

Treatment of ocular tumors on dedicated scattering-based proton therapy systems is standard afforded due to sharp lateral and distal penumbras. However, most newer proton therapy centers provide pencil beam scanning treatments. In this paper, we present a pencil beam scanning (PBS)-based ocular treatment solution. The design, commissioning, and validation of an applicator mount for a conventional PBS snout to allow for ocular treatments are given. In contrast to scattering techniques, PBS-based ocular therapy allows for inverse planning, providing planners with additional flexibility to shape the radiation field, potentially sparing healthy tissues. PBS enables the use of commercial Monte Carlo algorithms resulting in accurate dose calculations in the presence of heterogeneities and fiducials. The validation consisted of small field dosimetry measurements of point doses, depth doses, and lateral profiles relevant to ocular therapy. A comparison of beam properties achieved through the applicator against published literature is presented. We successfully showed the feasibility of PBS-based ocular treatments., (© 2022. The Author(s).)

Purpose: Treatment-related toxicity after irradiation of brain tumours has been underreported in the literature. Furthermore, there is considerable heterogeneity on how and when toxicity is evaluated. The aim of this European Particle Network (EPTN) collaborative project is to develop recommendations for uniform follow-up and toxicity scoring of adult brain tumour patients treated with radiotherapy., Methods: A Delphi method-based consensus was reached among 24 international radiation-oncology experts in the field of neuro-oncology concerning the toxicity endpoints, evaluation methods and time points., Results: In this paper, we present a basic framework for consistent toxicity scoring and follow-up, using multiple levels of recommendation. Level I includes all recommendations that are considered minimum of care, whereas level II and III are optional evaluations in the advanced clinical or research setting, respectively. Per outcome domain, the clinical endpoints and evaluation methods per level are listed. Where relevant, the organ at risk threshold doses for recommended referral to specific organ specialists are defined., Conclusion: These consensus-based recommendations for follow-up will enable the collection of uniform toxicity data of brain tumour patients treated with radiotherapy. With adoptation of this standard, collaboration will be facilitated and we can further propel the research field of radiation-induced toxicities relevant for these patients. An online tool to implement this guideline in clinical practice is provided at www.cancerdata.org., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objective. In intensity modulated particle therapy (IMPT), the adoption of spatially and temporally heterogeneous dose distributions allows to decouple the fractionation scheme from the patient anatomy, so that an hypofractionated schedule can be selectively created inside the tumour, while simultaneously exploiting the fractionation effect in the healthy tissues. In this paper, the authors show the reproducibility of the method on a set of prostate patients, quantifying the dependencies of the achievable benefit with respect to conventional and hypofractionated schemes and the sensitivity of the method to setup errors and range uncertainty. Approach. On a cohort of 9 patients, non-uniform IMPT plans were optimised and compared to conventional and hypofractionated schedules. For each patient, the comparison of the three strategies has been based on the output of the cost function used to optimise the treatments. The analysis has been repeated considering different α / β ratios for the tumour, namely 1.5, 3 and 4.5 Gy. For a single patient, setup errors and beam range uncertainty have been analysed: the plans, for each optimisation strategy, have been iteratively forward planned 500 times with randomly varying the patient position in each fraction, and 200 times for systematic range shift. Main results. An average 10% benefit has been shown for the lowest α / β ratio considered for the tumour, where the non-uniform schedule generally converges to hypofractionation; the benefit decreases to 5%-7% for higher α / β ratios, for which the non-uniform schedule always showed better outcomes with respect to the other fractionation schedules. An increased sensitivity to uncertainty, especially for setup errors, has been shown, which can be associated to the spatial non-uniformity of the dose distributions peculiar of the spatiotemporal plans. Significance. This work represents the first investigation of spatiotemporal fractionation for prostate cancer and the beginning of further investigations before clinical implementation can be considered., (© 2022 Institute of Physics and Engineering in Medicine.)

Objective. This paper presents a new method for fast reconstruction (compatible with in-beam use) of deposited dose during proton therapy using data acquired from a PET scanner. The most innovative feature of this novel method is the production of noiseless reconstructed dose distributions from which proton range can be derived with high precision. Approach. A new MLEM & simulated annealing (MSA) algorithm, developed especially in this work, reconstructs the deposited dose distribution from a realistic pre-calculated activity-dose dictionary. This dictionary contains the contribution of each beam in the plan to the 3D activity and dose maps, as calculated by a Monte Carlo simulation. The MSA algorithm, using a priori information of the treatment plan, seeks for the linear combination of activities of the precomputed beams that best fits the observed PET data, obtaining at the same time the deposited dose. Main results. the method has been tested using simulated data to determine its performance under 4 different test cases: (1) dependency of range detection accuracy with delivered dose, (2) in-beam versus offline verification, (3) ability to detect anatomical changes and (4) reconstruction of a realistic spread-out Bragg peak. The results show the ability of the method to accurately reconstruct doses from PET data corresponding to 1 Gy irradiations, both in intra-fraction and inter-fraction verification scenarios. For this dose level (1 Gy) the method was able to spot range variations as small as 0.6 mm. Significance. out method is able to reconstruct dose maps with remarkable accuracy from clinically relevant dose levels down to 1 Gy. Furthermore, due to the noiseless nature of reconstructed dose maps, an accuracy better than one millimeter was obtained in proton range estimates. These features make of this method a realistic option for range verification in proton therapy., (© 2022 Institute of Physics and Engineering in Medicine.)

Recently, two new treatment techniques, i.e. proton therapy and MR-linac based radiotherapy (RT), have been introduced in Dutch RT centres with major impact on daily practice. The content and context of these techniques are frequently described in scientific literature while little is reported about the implementation phase. This process is complex due to a variety of aspects, such as the involvement of multiple stakeholders, significant unpredictability in the start-up phase, the impact of the learning curve, standard operating procedures under development, new catchment areas, and extensive training programs. Insight about implementation in daily care is utterly important for clinics that are about to introduce these new technologies in order to prevent that every centre needs to reinvent the wheel. This position paper gives an overview of the implementation of proton therapy and MR-linac based RT in two large academic RT centres in the Netherlands, i.e. Maastro and Radboudumc respectively. With this paper we aim to report our lessons learned, in order to facilitate other RT centres that consider introducing these and other new techniques in their departments., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

In recent years, the application of positron emission tomography (PET) for the dose range verification of proton therapy has been proposed. However, the positron distribution is determined by the nuclear reaction cross section; hence, PET may not accurately reflect the dose range primarily influenced by ionization. Consequently, a proton dose range verification system based on scattered proton measurements has been suggested owing to the similarity in the reaction cross section between Rutherford scattering and ionization. While previous investigations have only verified the feasibility of dose range estimation through simple simulations, the objective of this study is to demonstrate this feasibility through experimental investigation. In this paper, we established an experimental framework for capturing scattered protons and introduced an algorithm that compares measured signal patterns with a reference database to estimate the dose range. A therapeutic beam was irradiated onto the abdominal region of a human phantom, and scattered protons were measured using scintillation detectors placed on the phantom surface. Consequently, the dose range was estimated with error margins of 4.22 ± 3.68 and 0.60 ± 1.03 mm along the beam axis and perpendicular directions to the Bragg peak, respectively. While providing the same level of Bragg peak positioning accuracy as conventional methods, our system features small size, cost-effectiveness, and system simplicity. One notable limitation of our method is the challenge in achieving precise detector positioning, which is crucial for accurate dose range estimation. Future research will focus on improving detector-position accuracy and exploring advanced algorithms for signal analysis to further refine dose range estimations. [ABSTRACT FROM AUTHOR]

Simple Summary: Prostate cancer (PCa) is the most common cancer and the second leading cause of cancer-related mortality among males in the US. Definitive radiation therapy (RT) plays an important role in curative-intent treatment for localized PCa and can be delivered with several different techniques, depending on the availability of resources and patient-specific criteria. With an analysis of the extensive National Cancer Database, this paper investigates trends in utilization, survival probability, and factors associated with overall survival of six common RT modalities utilized for the treatment of PCa patients—stratified by the three risk groups. Background: In this study, the utilization rates and survival outcomes of different radiotherapy techniques are compared in prostate cancer (PCa) patients stratified by risk group. Methods: We analyzed an extensive data set of N0, M0, non-surgical PCa patients diagnosed between 2004 and 2015 from the National Cancer Database (NCDB). Patients were grouped into six categories based on RT modality: an intensity-modulated radiation therapy (IMRT) group with brachytherapy (BT) boost, IMRT with/without IMRT boost, proton therapy, stereotactic body radiation therapy (SBRT), low-dose-rate brachytherapy (BT LDR), and high-dose-rate brachytherapy (BT HDR). Patients were also stratified by the National Comprehensive Cancer Network (NCCN) guidelines: low-risk (clinical stage T1–T2a, Gleason Score (GS) ≤ 6, and Prostate-Specific Antigen (PSA) < 10), intermediate-risk (clinical stage T2b or T2c, GS of 7, or PSA of 10–20), and high-risk (clinical stage T3–T4, or GS of 8–10, or PSA > 20). Overall survival (OS) probability was determined using a Kaplan–Meier estimator. Univariate and multivariate analyses were performed by risk group for the six treatment modalities. Results: The most utilized treatment modality for all PCa patients was IMRT (53.1%). Over the years, a steady increase in SBRT utilization was observed, whereas BT HDR usage declined. IMRT-treated patient groups exhibited relatively lower survival probability in all risk categories. A slightly better survival probability was observed for the proton therapy group. Hormonal therapy was used for a large number of patients in all risk groups. Conclusion: This study revealed that IMRT was the most common treatment modality for PCa patients. Brachytherapy, SBRT, and IMRT+BT exhibited similar survival rates, whereas proton showed slightly better overall survival across the three risk groups. However, analysis of the demographics indicates that these differences are at least in part due to selection bias. [ABSTRACT FROM AUTHOR]

Simple Summary: Adaptive proton therapy requires taking images over the course of treatment to correct the plan for anatomy changes. Most workflows assume daily imaging for this purpose. The associated imaging doses can be significant, which may compromise one of the proton therapy aims: minimizing the dose to healthy tissue. Low-dose scanning protocols address this problem. In this paper, we evaluate the influence of low-dose CT protocols on adaptation. We used a head phantom to define the protocols and simulated adaptive treatments of 10 head-and-neck patients with our established adaptation framework. We assessed the influence of lower image quality on the contour propagation and dose calculation. We demonstrated that decreasing the imaging dose by a factor of 40 with respect to our standard CT scanning protocol does not affect the adaptation performance. Purpose: To evaluate the suitability of low-dose CT protocols for online plan adaptation of head-and-neck patients. Methods: We acquired CT scans of a head phantom with protocols corresponding to CT dose index volume CTDIvol in the range of 4.2–165.9 mGy. The highest value corresponds to the standard protocol used for CT simulations of 10 head-and-neck patients included in the study. The minimum value corresponds to the lowest achievable tube current of the GE Discovery RT scanner used for the study. For each patient and each low-dose protocol, the noise relative to the standard protocol, derived from phantom images, was applied to a virtual CT (vCT). The vCT was obtained from a daily CBCT scan corresponding to the fraction with the largest anatomical changes. We ran an established adaptive workflow twice for each low-dose protocol using a high-quality daily vCT and the corresponding low-dose synthetic vCT. For a relative comparison of the adaptation efficacy, two adapted plans were recalculated in the high-quality vCT and evaluated with the contours obtained through deformable registration of the planning CT. We also evaluated the accuracy of dose calculation in low-dose CT volumes using the standard CT protocol as reference. Results: The maximum differences in D98 between low-dose protocols and the standard protocol for the high-risk and low-risk CTV were found to be 0.6% and 0.3%, respectively. The difference in OAR sparing was up to 3%. The Dice similarity coefficient between propagated contours obtained with low-dose and standard protocols was above 0.982. The mean 2%/2 mm gamma pass rate for the lowest-dose image, using the standard protocol as reference, was found to be 99.99%. Conclusion: The differences between low-dose protocols and the standard scanning protocol were marginal. Thus, low-dose CT protocols are suitable for online adaptive proton therapy of head-and-neck cancers. As such, considering scanning protocols used in our clinic, the imaging dose associated with online adaption of head-and-neck cancers treated with protons can be reduced by a factor of 40. [ABSTRACT FROM AUTHOR]

Radiation therapy is a critical component of oncologic management, with more than half of all cancer patients requiring radiotherapy at some point during their disease course. Over the last decade, there has been increasing interest in charged particle therapy due to its advantageous physical and radiobiologic properties, with the therapeutic use of proton beam therapy (PBT) expanding worldwide. However, there remain large gaps in our knowledge of the radiobiologic mechanisms that underlie key aspects of PBT, such as variations in relative biologic effectiveness (RBE), radioresistance, DNA damage response and repair pathways, as well as immunologic effects. In addition, while the emerging technique of ultra-high dose rate or FLASH radiotherapy, with its potential to further reduce normal tissue toxicities, is an exciting development, in-depth study is needed into the postulated biochemical mechanisms that underpin the FLASH effect such as the oxygen depletion hypothesis as well as the relative contributions of immune responses and the tumor microenvironment. Further investigation is also required to ensure that the FLASH effect is not diminished or lost in PBT. Current methods to evaluate the biologic effects of charged particle therapy rely heavily on 2D cell culture systems and/or animal models. However, both of these methods have well-recognized limitations which limit translatability of findings from bench to bedside. The advent of novel three-dimensional in-vitro tumor models offers a more physiologically relevant and high throughput in-vitro system for the study of tumor development as well as novel therapeutic approaches such as PBT. Advances in 3D cell culture methods, together with knowledge of disease mechanism, biomarkers, and genomic data, can be used to design personalized 3D models that most closely recapitulate tumor microenvironmental factors promoting a particular disease phenotype, moving 3D models and PBT into the age of precision medicine., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Sinonasal teratocarcinosarcoma is a rare aggressive malignant tumor with a primary setting involving the nasal cavity followed by the ethmoid sinus and maxillary sinus. It accounts for approximately 3% of all head and neck cancers and less than 1% of all tumors. Nasal obstruction, recurrent epistaxis and headache represent the typical clinical presentation. Imaging shows the presence of a mass in the nasal cavity. The treatment usually consists of surgery and adjuvant intensity modulated radiotherapy. The rarity and the variability of the histological features make its diagnosis particularly difficult., In this paper, we report a case of sinonasal teratocarcinosarcoma in a 62-year-old male treated with a multidisciplinary approach. As an alternative to intensity modulated radiotherapy, we proposed proton beam therapy for the first time. The patient benefited from the new and personalized protocol that provided excellent results and few adverse effects. At 45 months follow-up there is no evidence of relapse and the patient is in good health., (Copyright © 2021 Società Italiana di Anatomia Patologica e Citopatologia Diagnostica, Divisione Italiana della International Academy of Pathology.)

Gastroesophageal reflux disease (GERD)—the pathologic reflux of gastric contents into the distal esophagus—is the most common benign disorder of the esophagus. Its incidence is at 10–20% of the Western population and it yearly cost of treatment in the USA in 9.3 billion dollars. Although first line treatment for the disorder is medical therapy with proton pump inhibitors, an estimated 30–40% of patients will continue to experience medically refractory GERD. In this population anti-reflux surgery can be offered. Traditional anti-reflux surgery is done via the Nissen fundoplication, a technically difficult surgery with uncomfortable side effects of bloating and inability to belch. Magnetic sphincter augmentation (MSA) of the lower esophagus via the LINX device was introduced a less technically challenging alternative to the Nissen. The LINX provides fewer side effects of bloating and inability to belch and has been adapted widely to the practice of anti-reflux surgery. In this paper we discuss the progression of surgical practices with the LINX, including an analysis of the laparoscopic and robotic approaches to MSA device implantation. [ABSTRACT FROM AUTHOR]

Purpose/objective: Most dose-escalation trials in glioblastoma patients integrate the escalated dose throughout the standard course by targeting a specific subvolume. We hypothesize that anatomical changes during irradiation may affect the dose coverage of this subvolume for both proton- and photon-based radiotherapy., Material and Methods: For 24 glioblastoma patients a photon- and proton-based dose escalation treatment plan (of 75 Gy/30 fr) was simulated on the dedicated radiotherapy planning MRI obtained before treatment. The escalated dose was planned to cover the resection cavity and/or contrast enhancing lesion on the T1w post-gadolinium MRI sequence. To analyze the effect of anatomical changes during treatment, we evaluated on an additional MRI that was obtained during treatment the changes of the dose distribution on this specific high dose region., Results: The median time between the planning MRI and additional MRI was 26 days (range 16-37 days). The median time between the planning MRI and start of radiotherapy was relatively short (7 days, range 3-11 days). In 3 patients (12.5%) changes were observed which resulted in a substantial deterioration of both the photon and proton treatment plans. All these patients underwent a subtotal resection, and a decrease in dose coverage of more than 5% and 10% was observed for the photon- and proton-based treatment plans, respectively., Conclusion: Our study showed that only for a limited number of patients anatomical changes during photon or proton based radiotherapy resulted in a potentially clinically relevant underdosage in the subvolume. Therefore, volume changes during treatment are unlikely to be responsible for the negative outcome of dose-escalation studies., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

In a medical accelerator, real-time monitoring systems of the beam and dose delivered to the patient are mandatory. In this work, we present a compact current profile detector that has been designed and tested in the framework of the TOP-IMPLART (Intensity Modulated Proton Linear Accelerator for RadioTerapy) project. This project foresees the realization of a proton linear accelerator, currently under construction at ENEA Frascati, for proton therapy applications. The linac produces a pulsed proton beam with 3 µs duration at 50 Hz repetition rate with a pulse current between 0.5 and 50 μA. A large dynamic range and spatial constraints make the use of usual noninterceptive beam diagnostics unfeasible. Therefore, the use of a beam current monitor based on a passive RF cavity working in the TM010 mode has been proposed. This paper reports the electromagnetic design of the device guided by a simplified analytical model. A prototype of such a device has been realized, characterized, and tested on the linac with a 35 MeV beam varying the beam current. The test results in air and in vacuum, together with the signal detection systems used, are presented.

Background & Purpose: In infants with rhabdomyosarcoma, young age is considered an adverse prognostic factor and treatment is often attenuated to reduce side effects. Proton therapy may improve the therapeutic ratio in these patients. We report outcomes in infants with rhabdomyosarcoma treated with proton therapy., Materials & Methods: Between 2009 and 2019, 37 infants <24 months old with non-metastatic rhabdomyosarcoma received proton therapy. Local control (LC), progression-free survival (PFS), and overall survival (OS) were estimated using the Kaplan-Meier product limit. The log-rank test assessed significance between selected prognostic factors. Toxicity was graded per CTCAEv5.0., Results: Median follow-up was 5.1 years. Overall, 76% of patients had an unfavorable primary site. Median dose was 50.4GyRBE. At 5 years, LC, PFS, and OS rates were 83%, 78%, and 83%. On univariate analysis, 5-year LC and OS were inferior for favorable versus unfavorable disease sites (67% vs 89%, 67% vs 89%, respectively; p < .05) and 5-year OS was superior in stage 3 versus stage 1-2 disease (91% vs 69%; p = .05), owing to inclusion of nasal ala patients among stage 1. Of 9 recurrences, 7 were in-field, 4 occurring in infants with nasal ala primaries. Recategorizing nasal ala as an unfavorable site resulted in 100% 5-year LC and OS for favorable sites. Six infants experienced late grade 3 toxicity. None developed grade 4 or 5 late toxicity., Conclusions: Young age alone may not be an adverse prognostic factor provided infants receive local therapy similar to older children. Consideration should be given to classifying nasal ala primaries as an unfavorable site., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Published data from cell survival experiments are frequently used as training data for models of proton relative biological effectiveness (RBE). The publications rarely provide full information about the primary particle spectrum of the used beam, or its content of heavy secondary particles. The purpose of this paper is to assess to what extent heavy secondary particles may have been present in published cell survival experiments, and to investigate the impact of non-primary protons for RBE calculations in treatment planning. We used the Monte Carlo code Geant4 to calculate the occurrence of non-primary protons and heavier secondary particles for clinical protons beams in water for four incident energies in the [100, 250] MeV interval. We used the resulting spectra together with a conservative RBE parameterization and an RBE model to map both the rise of RBE at the beam entry surface due to heavy secondary particle buildup, and the difference in estimated RBE if non-primary protons are included or not in the beam quality metric. If included, non-primary protons cause a difference of 2% of the RBE in the plateau region of an spread out Bragg peak and 1% in the Bragg peak. Including non-primary protons specifically for RBE calculations will consequently have a negligible impact and can be ignored. A buildup distance in water of one millimeter was sufficient to reach an equilibrium state of RBE for the four incident energies selected. For the investigated experimental data, 83 out of the 86 data points were found to have been determined with at least that amount of buildup material. Hence, RBE model training data should be interpreted to include the contribution of heavy secondaries., (Creative Commons Attribution license.)

Purpose: A high-precision rotated elliptical beam profiling method based on pixel ion chamber is proposed in this paper. This method aims to improve the accuracy by modeling the transverse profile of rotated beam as an ellipse with additional correlation coefficient and eliminating the fitting error due to the volume averaging effect of pixel ion chamber., Methods: In pencil beam scanning (PBS) proton therapy systems, the transverse beam profile model is generally represented as a standard Gaussian distribution. Considering the elliptical spots, two-dimensional (2D) joint Gaussian distribution characterized with the correlation coefficient ρ is adopted in this study. Gaussian-type particle distribution with white noise was generated and processed in MATLAB to simulate the secondary particle collection in the pixel ion chamber. The simulated pixel ion chamber is a commercially available ion chamber which consists of 12 × 12 small square pixels (3.75 × 3.75 mm 2 ) with a 0.05 mm interval. The simulated signals were preprocessed by filtering with the noise threshold and extracting the maximum simply connected domain (MSCD) of the signal. Then, five geometric parameters that identify the transverse beam profiles were fitted under different signal-to-noise ratio (SNR) conditions: the center of the beam (x 0 , y 0 ), the spot size (σ major , σ minor ), and the rotation angle θ formed between the major axes of elliptical spot and the x axes of the ion chamber. First, the simulated signals were preprocessed by filtering with the noise threshold and extracting the MSCD of the signal. Second, a rectification curve of systematic error in fitted spot size versus the prescribed spot size was used to predict the systematic error due to the volume averaging effect. Finally, the effects of fitting errors on therapeutic dose were evaluated in terms of gamma index and relative dose difference., Results: When the SNR is not less than 20 dB, the relative fitting error of spot size and the absolute fitting error of angle θ are less than 1% and 6.1°, respectively. The fitting error of beam center increases with spot size and will not exceed 0.22 mm when spot size reaches up to 12 mm. At a SNR equal to 20 dB, neither cold nor hot spots were presented in dose distribution calculated with the fitted spot parameters., Conclusion: The improved Gaussian fitting algorithm performs well when SNR is not less than 20 dB. This method can effectively distinguish the nominal beam and rotated elliptical beam. An ideal systematic error curve can be predicted and used to correct the fitted spot size, thus eliminating the systematic error due to the volume averaging effect of the pixel ion chamber. The fitting error of spot size cannot be fully corrected, but it is negligible and shows little effect on the overall therapeutic dose., (© 2021 American Association of Physicists in Medicine.)

Proton therapy is one of the rapidly developing types of radiation therapy for oncological diseases. The use of proton imaging, a method in which the relative stopping power for protons is reconstructed directly, can significantly increase the accuracy and effectiveness of the proton therapy. This paper demonstrates the results of experimental work that was carried out at the synchrotron of the Prometheus proton therapy complex. The optimization of the synchrotron operating mode with low-intensity beam extraction was done for proton radiography and tomography purposes. Data about key changes of the beam extraction parameters for low-particles flux, as well as low-intensity beam control methods, are described. [ABSTRACT FROM AUTHOR]

The clinical translation of FLASH radiotherapy (RT) requires challenges related to dosimetry and beam monitoring of ultra‐high dose rate (UHDR) beams to be addressed. Detectors currently in use suffer from saturation effects under UHDR regimes, requiring the introduction of correction factors. There is significant interest from the scientific community to identify the most reliable solutions and suitable experimental approaches for UHDR dosimetry. This interest is manifested through the increasing number of national and international projects recently proposed concerning UHDR dosimetry. Attaining the desired solutions and approaches requires further optimization of already established technologies as well as the investigation of novel radiation detection and dosimetry methods. New knowledge will also emerge to fill the gap in terms of validated protocols, assessing new dosimetric procedures and standardized methods. In this paper, we discuss the main challenges coming from the peculiar beam parameters characterizing UHDR beams for FLASH RT. These challenges vary considerably depending on the accelerator type and technique used to produce the relevant UHDR radiation environment. We also introduce some general considerations on how the different time structure in the production of the radiation beams, as well as the dose and dose‐rate per pulse, can affect the detector response. Finally, we discuss the requirements that must characterize any proposed dosimeters for use in UDHR radiation environments. A detailed status of the current technology is provided, with the aim of discussing the detector features and their performance characteristics and/or limitations in UHDR regimes. We report on further developments for established detectors and novel approaches currently under investigation with a view to predict future directions in terms of dosimetry approaches, practical procedures, and protocols. Due to several on‐going detector and dosimetry developments associated with UHDR radiation environment for FLASH RT it is not possible to provide a simple list of recommendations for the most suitable detectors for FLASH RT dosimetry. However, this article does provide the reader with a detailed description of the most up‐to‐date dosimetric approaches, and describes the behavior of the detectors operated under UHDR irradiation conditions and offers expert discussion on the current challenges which we believe are important and still need to be addressed in the clinical translation of FLASH RT. [ABSTRACT FROM AUTHOR]

Simple Summary: Proton therapy is a promising type of radiation therapy used to destroy tumor cells. It has the potential to further improve the outcomes for patients with head and neck cancer since it allows to minimize the radiation dose to vital structures around the tumor, leading to less toxicity. This paper describes the current experience worldwide with proton therapy in head and neck cancer. Proton therapy (PT) is a promising development in radiation oncology, with the potential to further improve outcomes for patients with squamous cell carcinoma of the head and neck (HNSCC). By utilizing the finite range of protons, healthy tissue can be spared from beam exit doses that would otherwise be irradiated with photon-based treatments. Current evidence on PT for HNSCC is limited to comparative dosimetric analyses and retrospective single-institution series. As a consequence, the recognized indications for the reimbursement of PT remain scarce in most countries. Nevertheless, approximately 100 PT centers are in operation worldwide, and initial experiences for HNSCC are being reported. This review aims to summarize the results of the early clinical experience with PT for HNSCC and the challenges that are currently faced. [ABSTRACT FROM AUTHOR]

At the Paul Scherrer Institute (PSI) in Switzerland, cancer patients are treated with protons. The PSI Gantries work with Pencil Beam Scanning (PBS) technology. For beam profile characterization, a new 2-D planar pixel detector based on Printed Circuit Board technology was developed. The main challenge of the design was the limited amount of 256 readout channels while several thousands of detector signals had to be processed. With PBS, only a few pixels will be hit by the proton beam and give a significant signal, while most of them will not capture any signal. On the detector design, the active area was divided into pixel arrays with equal size, while one array is such big to cover the whole size of the proton beam. By a so-called channel recycling technique, the same pixel number of all pixel arrays were connected together to one readout channel. The proof of concept was verified with a small detector. In the next step, the design was changed such, getting a full-scale detector for Gantry 2. The readout electronics board itself is also a development performed at PSI. A core component of the design is the ADAS1128 chip from ANALOG Devices featuring 128 input channels. The pixel detector is fully integrated into the therapy control system (TCS) through readout electronics with a field-programmable gate array (FPGA) technology. The FPGA technology allows to readout the detector synchronized to the beam delivery. This paper summarizes the features of the pixel detector design, the readout electronics, and shows the first experimental results. [ABSTRACT FROM AUTHOR]

Purpose: The field of online monitoring of the beam range is one of the most researched topics in proton therapy over the last decade. The development of detectors that can be used for beam range verification under clinical conditions is a challenging task. One promising possible solution are modalities that record prompt-gamma radiation produced by the interactions of the proton beam with the target tissue. A good understanding of the energy spectra of the prompt gammas and the yields in certain energy regions is crucial for a successful design of a prompt-gamma detector. Monte-Carlo simulations are an important tool in development and testing of detector concepts, thus the proper modelling of the prompt-gamma emission in those simulations are of vital importance. In this paper, we confront a number of GEANT4 simulations of prompt-gamma emission, performed with different versions of the package and different physics lists, with experimental data obtained from a phantom irradiation with proton beams of four different energies in the range 70-230 MeV., Methods: The comparison is made on different levels: features of the prompt-gamma energy spectrum, gamma emission depth profiles for discrete transitions and the width of the distal fall-off in those profiles., Results: The best agreement between the measurements and the simulations is found for the GEANT4 version 10.4.2 and the reference physics list QGSP&#95;BIC&#95;HP., Conclusions: Modifications to prompt-gamma emission modelling in higher versions of the software increase the discrepancy between the simulation results and the experimental data., (Copyright © 2021 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.)

Linear Energy Transfer (LET) is widely used to express the radiation quality of ion beams, when characterizing the biological effectiveness. However, averaged LET may be defined in multiple ways, and the chosen definition may impact the resulting reported value. We review averaged LET definitions found in the literature, and quantify which impact using these various definitions have for different reference setups. We recorded the averaged LET definitions used in 354 publications quantifying the relative biological effectiveness (RBE) of hadronic beams, and investigated how these various definitions impact the reported averaged LET using a Monte Carlo particle transport code. We find that the kind of averaged LET being applied is, generally, poorly defined. Some definitions of averaged LET may influence the reported averaged LET values up to an order of magnitude. For publications involving protons, most applied dose averaged LET when reporting RBE. The absence of what target medium is used and what secondary particles are included further contributes to an ill-defined averaged LET. We also found evidence of inconsistent usage of averaged LET definitions when deriving LET-based RBE models. To conclude, due to commonly ill-defined averaged LET and to the inherent problems of LET-based RBE models, averaged LET may only be used as a coarse indicator of radiation quality. We propose a more rigorous way of reporting LET values, and suggest that ideally the entire particle fluence spectra should be recorded and provided for future RBE studies, from which any type of averaged LET (or other quantities) may be inferred., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)