Proton beam therapy (PBT) has emerged as an alternative to conventional photon therapy for locally advanced pancreatic cancer (LAPC). This study evaluated the outcomes and adverse events of PBT combined with chemotherapy in LAPC, with outcomes of chemotherapy alone presented for reference. This study included 58 patients diagnosed with LAPC between January 2016 and December 2022. We analyzed data from 14 patients receiving chemoradiotherapy with PBT of 67.5 Gy relative biological effectiveness in 25 fractions (PBT group). As a reference, data from 32 patients receiving chemotherapy alone were analyzed (chemotherapy group). PBT with concurrent chemotherapy was initiated in patients without distant metastasis after upfront chemotherapy, and all patients subsequently underwent maintenance chemotherapy. Overall survival (OS), progression-free survival (PFS), local control (LC), and distant metastasis-free survival (DMFS) were evaluated using the Kaplan-Meier method. In the PBT group, the median interval from chemotherapy initiation to PBT was 180 days. The 1-year/2-year OS and PFS rates were 92.9%/57.1% and 78.6%/42.9%, respectively. The corresponding LC and DMFS rates were 85.7%/77.1% and 85.7%/60.6%. Gastrointestinal adverse events in the PBT group included gastric perforation, gastric antral vascular ectasia, and bile duct stenosis in one patient each (7.1%). In the chemotherapy group, the 1-year/2-year OS and PFS rates were 74.4%/32.0% and 36.8%/13.4%, respectively, while LC and DMFS rates were 44.4%/18.4% and 44.0%/27.0%. Chemoradiotherapy with PBT yielded favorable outcomes in patients with LAPC, suggesting that PBT is a promising treatment option.

We present 18 F-FAPI-74 PET/CT findings before and after proton beam therapy (PBT) in a 71-year-old woman with liver metastasis following pancreatic cancer resection. Before PBT, no uptake was observed on FDG-PET, whereas the lesion was visualized on FAPI-PET, consistent with contrast-enhanced MRI. Follow-up FAPI-PET at 3 and 6 months post-PBT revealed mild, newly developed uptake confined to the high-dose irradiated area. However, contrast-enhanced MRI demonstrated complete tumor disappearance and normalization of serum tumor marker levels. These findings suggest that post-irradiation 18 F-FAPI-74 uptake is more likely attributable to reactive changes, such as radiation-induced hepatic fibrosis, rather than residual or recurrent tumor.

To investigate the use of CBCT projection images for improved setup and gating validation in respiratory gated proton therapy for liver cancer. Fifteen consecutive patients receiving proton therapy with respiratory gating guided by an external gating marker block were analyzed. The amplitude gating level was set to 50% duty-cycle around the exhale phase (50th percentile motion). Implanted markers were retrospectively segmented in the 2D projection images of five free-breathing setup CBCT scans per patient and used to estimate the 3D marker trajectories during CBCT acquisition. The trajectories and synchronized external gating block motion were used to investigate: (1) Setup accuracy of manual online CBCT marker match, (2) motion during CBCT acquisition compared to the planning 4DCT motion, and (3) internal motion during CBCT acquisition in external gate on periods. (1) The mean (±SD) online marker match error was 0.0±0.4mm (left-right), 1.4±0.9mm (cranio-caudal) and -0.6±0.6mm (antero-posterior). (2) The mean full marker motion during CBCT acquisition was 17.7±4.4mm (cranio-caudal). The 50th percentile motion was 5.6±2.4mm. The difference between CBCT and planning 4DCT motion was 5.8±4.0mm for the full motion and reduced to 1.0±2.1mm for the 50th percentile motion. (3) The internal motion during CBCT acquisition in external gate on periods exceeded the 4DCT planned internal 50% gating window by more than 3mm (cranio-caudal) for 1.2±2.6% of the time. Detailed analyses of CBCT projections provided important pre-treatment setup and gating validation for liver cancer proton therapy. Online implementation may be feasible.

Accurate range verification is crucial in hadrontherapy to fully exploit the ballistic advantages of charged particles and prevent damage to healthy tissues. Among the proposed approaches, prompt gamma imaging (PGI) has emerged as an effective technique for real-time monitoring, but its performance is limited by the intense neutron background generated during irradiation, especially withcarbon-ions. This work presents a Monte Carlo study performed with the FLUKA code to investigate prompt gamma and neutron emission in proton and carbon-ion therapy. A prototype detection system based on a knife-edge collimator coupled to a pixelated LYSO scintillator was simulated to evaluate its capability for range verification. The aim is to quantify how neutron fields and neutron induced signals bias or degrade range related quantities, and how these effects differ between proton and carbon-ionbeams. The analysis includes the characterization of prompt gamma energy spectra and spatial profiles, the assessment of neutron fields within a treatment room, and the decomposition of the detector signal into primary gammas, secondary gammas, andneutrons. Results show that prompt gamma profiles correlate well with the Bragg peak position, particularly within the 3-7MeV energy window, while carbon ions exhibit higher prompt gamma yields but also significantly stronger neutron backgrounds compared to protons. Detector simulations highlight the impact of neutron capture on lutetium, producing distinct peaks that must be accounted for in the detector signal analysis. The fall-off retrieval precision (FRP) analysis indicates that the distal fall-off of prompt gamma profiles can be used to estimate the Bragg peak position, while secondary radiation components introduce additional fluctuations that affect the achievable precision, particularly for carbon-ionbeams. The study provides a detailed characterization of prompt gamma and neutron contributions in proton and carbon-ion therapy and highlights the main physical factors affecting PGI-based range monitoring, particularly in the presence of neutron-induced backgrounds. These results provide useful insights for the design and optimization of prompt gamma detection systems in clinicalapplications.

Pediatric central nervous system (CNS) tumors often recur despite multimodality therapy. Although re-irradiation (re-RT) has historically been limited by concerns for severe late toxicities, modern techniques have renewed interest in this approach. Proton therapy provides dosimetric advantages that may enable curative re-treatment with reduced normal tissue exposure. We retrospectively reviewed 54 pediatric patients who underwent proton re-RT for recurrent CNS tumors at our institution (2010-2024). Eligible patients had received prior CNS-directed RT at ≤20 years of age. Toxicities were graded per Common Terminology Criteria for Adverse Events (CTCAE) v5.0 as acute (<3 months) or late (≥3 months). Cumulative dosimetry was assessed by registering RT1 and RT2 plans and converting doses to EQD2 (α/β=2Gy). Overall survival (OS) and progression-free survival (PFS) were estimated using Kaplan-Meier methods. Median age at re-RT was 11 years, with a median interval of 28.5 months between RT courses. The median prescribed re-RT dose was 54Gy (range, 25-60), yielding a cumulative EQD2 of 102.6Gy (range, 46.8-112.9). Median OS and PFS were 46.0 and 16.5 months, respectively. Among 16 ependymoma patients, all received full-dose proton re-RT (54-59.4Gy), yielding a 1-year OS of 91.7% and PFS of 50.0%. Glioma patients had inferior outcomes (1-year OS 55.4%, PFS 41.6%) with a median re-RT EQD2 of 48.1Gy. An RT interval of ≥12 months was associated with improved OS and PFS. Composite dosimetry in 21 patients showed a median cumulative brain D0.1cc of 109.0Gy; only one patient developed Grade 3 radiation necrosis (RN). High-grade acute toxicity occurred in 13.0% of patients, all manageable with supportive care. Proton re-RT for pediatric CNS tumors is feasible and associated with encouraging survival and low rates of serious late toxicity.

Reirradiation for recurrent head and neck squamous cell carcinoma: international expert consensus recommendations endorsed by the Reirradiation Collaborative Group, the European Society for Radiotherapy and Oncology Reirradiation Focus Group, and the American Society for Radiation Oncology.

We present a visualization design study of creating a collaborative virtual reality (VR) system for radiation treatment planning, with an emphasis on proton therapy. The goal is to support teams of dosimetrists, physicians, and medical physicists as they review and compare multiple possible patient-specific treatment plans, which requires analyzing complex 3D spatial relationships between a radiation dosage volume and anatomical structures. The approach is a novel combination and refinement of interactive visualization techniques including: networked multi-user immersive visualization, interactive volume rendering and slicing with 3D widgets and gestures, superimposed surface rendering with GPU-accelerated curvature-directed lines, smart cursors, teleporting, and avatars. These features are integrated within a workflow that supports three complementary modes of visual data comparison (juxtaposition, interchangeable, and explicit encoding). Results and feedback from multi-year iterative development with users and a summative field deployment in the form of a mock plan-review meeting reveal several advantages relative to current clinical practice and suggest directions for future work.

Assessing the impact of proton versus photon therapy on health-related quality of life in lung cancer.

Respiratory motion remains a major challenge in thoracic and abdominal proton treatments, causing interplay effects and dose distortions. In synchrotron-based systems, conventional gating significantly prolongs beam delivery and overall treatment time, which limits its clinical applicability and patient suitability. The present study was aimed to investigation of the gating system with the novel hybrid phase-amplitude algorithm specified for synchrotron-based proton therapy systems with spot-scanning beam delivery in the phantom test. This system was experimentally evaluated for robustness to target motion irregularities in terms of dose distortion and irradiation time. A dynamic phantom simulated the free-breathing motion using a radiochromic film immersed in water. The film was irradiated in a single fraction with gating for regular and irregular motion patterns. The phase-amplitude gating algorithm was implemented to provide two-signal control of the synchrotron for beam injection and extraction. The measured dose distributions were analyzed using gamma index calculation with a 5%/3mm criterion. Gating mitigated the interplay effect, resulting in a gamma passing rate (GPR) of 98.5±0.1% (mean±SD) at regular motion, but the irradiation time was increased from 155±2 s (mean±SD) to 209±9 s compared to no gating. The GPR fluctuated unsystematically as a function of motion irregularity (p=0.111), resulting in a median GPR of 96.0% (range 89.2%-98.6%), and the irradiation time increased from 209±9 s to 238±8 s compared to regular motion (p=0.002). Robustness to random motion irregularities up to 30% resulted in 67% acceptable dose distributions and 14% increase in irradiation time. The algorithm ensured full synchronization of beam injection and extraction with the respiratory cycle, which allowed a significant reduction in treatment time. The phase-amplitude gating together with fractionation and rescanning can be potentially effective in the treatment of thoracic and abdominal tumors using synchrotron-based systems with scanning beams. The introduction of a system-specific quantitative threshold for patient respiratory irregularity is mandatory for deciding to use gated treatment or not.

Objective. Phase gating is a critical technique to mitigate tumor motion during radiotherapy, particularly in spot-scanned particle therapy where internal motion can interfere with dynamic spot scanning patterns and, simultaneously, introducing substantial range uncertainties. However, the current commercial state of the art in real-time phase prediction is challenged by patient-specific breathing variability as well as detection and delivery system latencies. This leads to suboptimal efficiency, mis-timed radiation delivery and requires frequent manual intervention. This study aims to improve phase prediction accuracy using deep learning (DL)-based time series forecasting to enable more accurate dose delivery.Approach. Retrospective breathing waveforms from 69 proton therapy patients, sampled at 30 Hz, were labeled with inspiratory peaks and assigned subjective regularity scores (four levels). DL models with various architectures were trained using waveform amplitude to predict current or future breathing phases. Model performance was evaluated using mean squared error, phase binning accuracy, and timing deviation for radiation on/off events. Bayesian optimization was used for hyperparameter tuning. Results were compared between models and against a commercial algorithm currently in clinical use.Main Results. The curated waveform dataset included 165 242 s for training, 24 057 s for validation, and 30 322 s for testing, with an additional 40 604 s from separate patients for extended validation. The long short-term memory and temporal fusion transformer models significantly outperformed the commercial algorithm, improving phase prediction accuracy by nearly 20% and reducing timing deviations across all regularity levels.Significance. DL-based time series forecasting may substantially improve breathing phase prediction accuracy over current clinically available methods, offering a more precise and reliable approach to phase-gated radiation delivery.

Proton Beam Therapy for Cancer in Children and Adolescents: A Retrospective Canadian Paediatric Tumour Consortium Study.

De-escalation of elective radiotherapy guided by FDG-PET lowers modeled late swallowing-related toxicity in head and neck cancer.

Radiation Therapy for Spinal Cord Tumors.

Objective.Real-time gated proton therapy (RGPT) enables precise irradiation of moving targets and is an important motion-management technique in proton therapy. Uninterrupted continuous delivery (UCD) avoids frequent gating interruptions, which improves proton beam extraction stability and treatment efficiency in synchrotron-based systems. However, because fluoroscopic x-rays remain on during proton irradiation in UCD, scattered fluoroscopic x-rays may be detected by the dose monitor (DM) and mistakenly counted as proton monitor units (MUs), potentially causing beam aborts. This study aimed to quantify scattered fluoroscopic x-rays detected by the DM during RGPT and evaluate their impact on beam delivery during simultaneous fluoroscopy and proton irradiation.Methods.Scattered fluoroscopic x-ray signals detected by the DM were measured using an RGPT system. Phantom experiments evaluated scattered x-ray dose rates using plastic water® (PW) and anthropomorphic phantoms while varying phantom thickness, fluoroscopic parameters, and range-shifter conditions. Beam-abort simulations were conducted under UCD conditions for both phantom and clinical liver treatment plans. Abort probability was assessed as a function of proton MU per spot, scattered x-ray MU per frame, and fluoroscopy frames per second.Results.DM signals from scattered fluoroscopic x-rays increased with tube voltage, tube current, field size, and phantom thickness, and were higher without a range shifter (RS). The maximum dose rate was 0.0211 MU/frame at 125 kV, 80 mA, 200 × 200 mm2, and PW-30 cm without a RS, representing an 11.7-fold increase compared to the in-air conditions. The results obtained from the anthropomorphic phantom experiments further validated the findings observed in the PW phantom study. Beam-abort simulations showed abort proportions below 2% for monoenergetic fields and below 3% for clinical liver plans across all tested conditions.Significance.With the DM positioned closer to the x-ray tube, scattered fluoroscopic x-ray contamination increased with phantom thickness, differing from prior reports. Optimization of proton dose rate, imaging parameters, and system geometry can minimize beam interruptions, supporting the clinical feasibility of UCD.

The full potential of proton therapy is limited by uncertainties that prevent optimal dose distribution. Monitoring techniques can reduce these uncertainties and enable adaptive treatment planning. Spatiotemporal Emission Reconstruction from Prompt-Gamma Timing (SER-PGT) is a promising method that provides insights into both particle range and stopping power, the calculation of which normally requires knowledge about patient tissue properties that cannot be directly measured. We present the first experimental proof of principle obtained using a 226.9 MeV synchrotron-proton beam impinging on a homogeneous phantom at a subclinical intensity (2 - [Formula: see text] pps). SER-PGT uses data from a multidetector setup: a thin and segmented Low Gain Avalanche Diode for proton detection and Lanthanum Bromide-based crystals for photon detection. The estimated stopping power profile showed an 8%± 3% average error compared with the NIST PSTAR values, and a 2%± 2% deviation relative to water at 100 MeV. Range assessment in a phantom with a 4 cm air gap successfully identified the range shift with a 3 mm standard deviation. For this proof-of-principle irradiation scenario, the experimental results demonstrate the recovery of both range and stopping power information through SER-PGT, particle kinematics and PGT measurements in a homogeneous target.

Oesophageal cancer is a major cause of morbidity and mortality. Around 40% of patients present with locally advanced disease. Outcomes are poor, with 5-year survival of around 50% for locally advanced oesophageal adenocarcinoma (OAC) and 60% for oesophageal squamous cell carcinoma (OSCC). Over a fifth of recurrences are locoregional. These may be reduced by the addition of chemoradiotherapy (CRT) to best pre-operative systemic anti-cancer therapy (SACT). However, photon-based CRT is associated with a higher frequency of complications than chemotherapy alone. This study will explore whether, in patients with locally advanced OAC and OSCC managed with hypofractionated CRT following best pre-operative systemic therapy, the use of proton beam therapy (PBT) reduces post-operative complications when compared with photon-based treatment. PROTIEUS is an investigator-initiated randomised multi-centre phase 2 trial aiming to recruit 170 patients with locally advanced OAC (n = 130) or OSCC (n = 40) from the UK National Health Service. Patients with locally advanced cT ≥ 2, N0-2 non-metastatic disease are eligible for inclusion and will be randomised 1:1 to receive 40.05Gy (RBE) in 15 fractions over three weeks using either PBT or intensity modulated/rotational arc photon radiotherapy. All patients will receive three one-week cycles of concurrent intravenous carboplatin/paclitaxel. CRT will be delivered following best pre-operative SACT. The primary endpoint is the rate of severe post-operative complications within 90 days post-surgery (grade 3 or higher Clavien-Dindo classification and CTCAE v5.0). Secondary endpoints relate to efficacy (pathological complete response and clear resection margin rate, disease-free and overall survival), tolerability (completion of planned CRT regime, time to and completion of adjuvant therapy), morbidity (long-term quality of life measures) and health economics (cost-effectiveness analyses using EQ-5D-5L and resource use assessments). There is a need to improve local control in OAC and OSCC. Given only modest gains with perioperative immune checkpoint inhibition and a disease landscape in which there are few targets for precision or personalised therapies, there are limited options to achieve further gains across the disease population using SACT. This study will therefore determine which of PBT or photon-based pre-operative CRT is the most tolerable and least toxic for integration into existing systemic treatment paradigms. https://doi.org/10.1186/ISRCTN50098578.

The International Atomic Energy Agency (IAEA) revised the TRS398 Code of Practice in 2024, incorporating dosimetry protocol for pencil beam scanning (PBS) beam delivery system with updated beam quality correction factors (kQ,Qo) for the majority of ionization chambers used in proton beam therapy. This study aims to evaluate the revised TRS398 protocol for dosimetry in an established isochronous cyclotron-based PBS proton therapy system and to quantify its impact on absorbed dose determination. The reference dosimetry measurements were performed using three plane parallel ionization chambers (IBA PPC05, IBA PPC40, PTW Roos) and one cylindrical chamber (IBA FC65-G) in a water phantom on a Proteus Plus PBS proton therapy system. Uniform single-energy scanned fields (10 × 10 cm²) were delivered across 33 clinical proton beam energies ranging from 70.18 MeV to 226.2 MeV. Absorbed dose to water was calculated using kQ,Qo from both the previous and revised TRS398 protocols. Ion recombination (ks) and polarity (kpol) correction factors were determined and evaluated for all chambers for 17 proton energies. The absorbed dose measurements demonstrated good inter-chamber agreement, with a maximum deviation of 2.72% at the lowest energy. Implementation of the revised kQ,Qo values resulted in mean absorbed dose differences of -1.07%, -0.66%, -0.50%, and -1.77% for the PPC05, PPC40, Roos, and FC65-G chambers, respectively, compared to the previous TRS398. The combined relative uncertainty in absorbed dose determination using the revised TRS398 was estimated to be 1.6%. This study assesses the impact of the revised TRS398 dosimetry protocol on absorbed dose determination in PBS proton beams. Experimental measurements using four dosimeters in an isochronous cyclotron-based system show that the revised TRS398 provides a robust framework for PBS reference dosimetry, with the effect of updated kQ,Qo values remaining within the combined measurement uncertainty.

Induced mutagenesis is a cornerstone of crop functional genomics, yet the extent to which distinct radiation sources reshape the spatial distribution of mutations remains difficult to evaluate in reduced-representation datasets. Here, we analyze a published genotyping-by-sequencing (GBS) panel (192,040 loci) to compare proton-beam and gamma-ray mutagenesis in Sorghum bicolor. Because GBS sampling is nonuniform, all analyses were conducted within an explicitly defined GBS-callable sequence space. Within this callable space, 96-channel trinucleotide spectra were broadly similar between radiation types, whereas spatial summaries differed. Macroscale analysis using the Gini coefficient indicated that proton-treated lines exhibit a highly unequal, spike-like distribution of mutations, whereas gamma-treated lines show a more diffuse window-level distribution. Microscale spatial statistics were consistent with clustering patterns that were more prominent in proton-treated lines, including an aggregation scale of ∼500kb, with a substantial fraction of the mutational burden falling into high-density tracks. Within the callable locus set, coding- and promoter-proximal categories were not depleted of induced mutation events (single-nucleotide variants) across treatments. Furthermore, we did not detect a negative association between total mutational load and the coding-region mutation fraction in this dataset. These findings suggest that, within this dataset, proton mutagenesis is characterized not by unique chemical signatures but by a distinct spatial geometry that concentrates detectable mutation events. Because proton irradiation was represented by a single dose, whether proton treatment produces stronger clustering than gamma irradiation at equal mutational burden remains to be directly tested.

Objective. Real-time adaptive proton range verification systems based on produced neutrons require accurate information on their non-isotropic momentum distributions within seconds, for which general-purpose Monte Carlo (MC) methods are too computationally expensive. We therefore present a first study for a surrogate model based on Fourier neural operators (FNO) for fast prediction of angle- and energy-resolved proton transport and neutron production within proton therapy.Approach. We treat the phantom and the proton beam's state as depth-evolving series, respectively of different materials, and of spatial, angular, and energy phase space density distributions. FNO models were trained to compute changes in proton distributions along with those of produced neutrons per unit of depth, and they were used auto-regressively to simulate the entire phantom. For training and evaluation, two datasets of 47 MC simulations featuring different primary intensities were produced. Simulated geometries were extracted from a thoracic CT scan as series of laterally homogeneous materials.Main Results. An average relativeL2-norm error of0.067and0.137was achieved by the predicted proton and neutron distributions, respectively. This corresponded to an average spatial gamma passing rate (2 %, 2 mm) of99.95%and99.40%, and an average error in the mean of the longitudinal intensity distribution of 0.238 mm and 0.871 mm. Training with higher primary intensities improved neutron density metrics by up to30%. Inference over depths of 40 cm at a resolution of 0.5 mm required on average 23.17 s per beam.Significance. Our proton beam surrogate generates accurate phase space distributions of neutrons at MC-level accuracy within seconds, while demonstrating robust generalization with respect to irradiated geometry and beam characteristics. This first study is relevant for prototyping and operation of range verification systems and for other tasks such as neutron dose estimation, with methods being extendable to other kinds of secondary particles.

Objective. Clinical proton therapy assumes a constant relative biological effectiveness (RBE) of 1.1, although proton RBE varies with linear energy transfer (LET). High-energy transmission beams (TBs) deposit dose entirely within the low-LET entrance plateau, suggesting a potentially distinct radiobiological behavior compared with conventional spread-out Bragg peaks (SOBP).Approach.We performedin vitroclonogenic survival experiments with four cell lines (A431, CRL2189, V79, A253) irradiated with TB, SOBP, mixed fields (SOBP + TB), and reference photons. Early post-irradiation metabolic viability was also assessed using the MTT assay.Main results. TB irradiation produced RBE values close to unity at 2 Gy (median 1.04-1.07), comparable to photons, whereas SOBP beams showed higher RBE values (≈1.10-1.35). In the tested 40% TB/60% SOBP configuration, the mixed-field response remained biologically indistinguishable from conventional SOBP and was well described by the prediction of the theory of dual radiation action (TDRA) derived from the independently measured TB and SOBP survival parameters. MTT viability measurements showed the same overall hierarchy, with TB responses close to photons and stronger effects observed for SOBP and SOBP + TB.Significance. High-energy proton TBs operate in a near-photon radiobiological regime. A mixed field containing 40% TB remained biologically indistinguishable from conventional SOBP and was well described by the TDRA. Complementary viability measurements showed the same modality-dependent pattern.