Proton Therapy Research Articles

Radiation-Induced Lymphopenia is a Causal Mediator of Survival After Chemoradiation Therapy for Esophagus Cancer

Purpose: Radiation-induced lymphopenia (RIL) is common during chemoradiotherapy. Severe lymphopenia is associated with reduced survival. Proton beam therapy (PBT), with its substantially more compact dose distributions, spares circulating lymphocytes and immuno-organs at risk to a greater extent than does photon therapy. Recent studies comparing PBT to photon radiotherapy, specifically intensity-modulated radiation therapy (IMRT), for esophageal cancer (EC) showed that the incidence of grade 4 RIL (G4RIL) is significantly reduced among patients receiving PBT for esophageal cancer. However, whether the extent of this reduction has a direct causative link with improved survival is unknown. This study applies causal mediation analysis to answer this question. Methods and Materials: We retrospectively assessed 734 patients treated with concurrent chemoradiotherapy for biopsy-proven EC from 2004 through 2017. To address the potential for bias in the choice of radiation modality, propensity score analysis was used to evaluate and reduce imbalances between the PBT and IMRT cohorts. Causal mediation analysis was applied to decompose the total effect of radiation modality on overall survival (OS) into indirect (mediated through G4RIL) and direct effects. Results: We found that PBT was associated with significantly lower incidence of G4RIL and prolonged OS compared with IMRT (odds ratio [OR]= 0.41, 95% confidence interval [CI] 0.28 to 0.60, P<0.001). In the propensity-matched cohort of 506 patients (253 PBT, 253 IMRT), G4RIL risk reduction with PBT vs. IMRT translated into a 5% reduction in the relative rate of death (P=0.032). Mediation of G4RIL explained ∼14.5% of the difference in OS. Conclusions: G4RIL was found to mediate survival; however, statistically significant direct effect of PBT on survival was not observed. In other words, the survival benefit from protons over photons in this EC cohort was lost in the absence of G4RIL risk reduction.

Incidence of alopecia in brain tumour patients treated with pencil scanning proton therapy and validation of existing NTCP models

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

An experimental validation of a filtering approach for prompt gamma prediction in a research proton treatment planning system

Objective. Prompt gamma (PG) radiation generated from nuclear reactions between protons and tissue nuclei can be employed for range verification in proton therapy. A typical clinical workflow for PG range verification compares the detected PG profile with a predicted one. Recently, a novel analytical PG prediction algorithm based on the so-called filtering formalism has been proposed and implemented in a research version of RayStation (RaySearch Laboratories AB), which is a widely adopted treatment planning system. This work validates the performance of the filtering PG prediction approach. Approach. The said algorithm is validated against experimental data and benchmarked with another well-established PG prediction algorithm implemented in a MATLAB-based software REGGUI. Furthermore, a new workflow based on several PG profile quality criteria and analytical methods is proposed for data selection. The workflow also calculates sensitivity and specificity information, which can help practitioners to decide on irradiation course interruption during treatment and monitor spot selection at the treatment planning stage. With the proposed workflow, the comparison can be performed on a limited number of selected high-quality irradiation spots without neighbouring-spot aggregation. Main results. The mean shifts between the experimental data and the predicted PG detection (PGD) profiles (ΔPGD) by the two algorithms are estimated to be 1.5±2.1 mm and −0.6±2.2 mm for the filtering and REGGUI prediction methods, respectively. The ΔPGD difference between two algorithms is observed to be consistent with the beam model difference within uncertainty. However, the filtering approach requires a much shorter computation time compared to the REGGUI approach. Significance. The novel filtering approach is successfully validated against experimental data and another widely used PG prediction algorithm. The workflow designed in this work selects spots with high-quality PGD shift calculation results, and performs sensitivity and specificity analyses to assist clinical decisions.

Diffusion decrease in normal-appearing white matter structures following photon or proton irradiation indicates differences in regional radiosensitivity

PurposeRadio(chemo)therapy (RCT) as part of the standard treatment of glioma patients, inevitably leads to radiation exposure of the tumor-surrounding normal-appearing (NA) tissues. The effect of radiotherapy on the brain microstructure can be assessed by magnetic resonance imaging (MRI) using diffusion tensor imaging (DTI). The aim of this study was to analyze regional DTI changes of white matter (WM) structures and to determine their dose- and time-dependency. MethodsAs part of a longitudinal prospective clinical study (NCT02824731), MRI data of 23 glioma patients treated with proton or photon beam therapy were acquired at three-monthly intervals until 36 months following irradiation. Mean, radial and axial diffusivity (MD, RD, AD) as well as fractional anisotropy (FA) were investigated in the NA tissue of 15 WM structures and their dependence on radiation dose, follow-up time and distance to the clinical target volume (CTV) was analyzed in a multivariate linear regression model. Due to the small and non-comparable patient numbers for proton and photon beam irradiation, a separate assessment of the findings per treatment modality was not performed. ResultsFour WM structures (i.e., internal capsule, corona radiata, posterior thalamic radiation, and superior longitudinal fasciculus) showed statistically significantly decreased RD and MD after RT, whereas AD decrease and FA increase occurred less frequently. The posterior thalamic radiation showed the most pronounced changes after RCT [i.e., ΔRD = −8.51 % (p = 0.012), ΔMD = −6.14 % (p = 0.012)]. The DTI changes depended significantly on mean dose and time. ConclusionSignificant changes in DTI for WM substructures were found even at low radiation doses. These findings may prompt new radiation dose constraints sparing the vulnerable structures from damage and subsequent side-effects.

Proton therapy reduces the effective dose to immune cells in breast cancer patients.

The effective dose to circulating immune cells (EDIC) is associated with survival in lung and esophageal cancer patients. This study aimed to evaluate the benefit of intensity-modulated proton therapy (IMPT) for EDIC reduction as compared to volumetric modulated arc therapy (VMAT) in patients with locally advanced breast cancer (BC). Ten BC patients treated with locoregional VMAT after breast-conserving surgery were included. Mean dose to the heart (MHD), lungs (MLD), and liver (MlD), as well as the integral dose to the body (ITD), were retrieved, and we calculated EDIC as 0.12 × MLD + 0.08 × MHD + 0.15 × 0.85 × √(n/45) × MlD + (0.45 + 0.35 × 0.85 × √(n/45)) × ITD/(62 × 103), where n is the number of fractions. EDIC was compared between VMAT and IMPT plans. Median EDIC was reduced from 3.37 Gy (range: 2.53-5.99) with VMAT to 2.13 Gy (1.31-3.77) with IMPT (p < 0.01). For left-sided BC patients, EDIC was reduced from 3.15 Gy (2.53-3.78) with VMAT to 1.65 Gy (1.31-3.77) with IMPT (p < 0.01). For right-sided BC patients, EDIC was reduced from 5.60 Gy (5.06-5.99) with VMAT to 3.38 Gy (3.10-3.77) with IMPT (p < 0.01). Right-sided BC patients had ahigher EDIC irrespective of the technique. Integral dose reduction was the main driver of EDIC reduction with IMPT and was associated with lung sparing for left-sided BC patients or liver sparing for right-sided BC patients. IMPT significantly reduced EDIC in BC patients undergoing locoregional adjuvant radiotherapy. Integral total dose reduction, associated with improved lung sparing in left-sided BC patients or liver sparing in right-sided BC patients, mainly drove EDIC reduction with IMPT. The emergence of dynamic models taking into account the circulatory kinetics of immune cells may improve the accuracy of the estimate of the dose received by the immune system compared to calculation of the EDIC, which is based solely on static dosimetric data.

Two-dimensional oxygen-diffusion modelling for FLASH proton therapy with pencil beam scanning—Impact of diffusive tissue properties, dose, dose rate and scan patterns

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

Longitudinal Quality-of-Life Outcomes of Skull Base Chondrosarcoma Patients following Surgical Resection

Abstract Objective Owing to the rarity of skull base chondrosarcomas (CS), much of its natural history and long-term impact on patient quality of life (QoL) are not well studied. This novel study demonstrates QoL among CS patients following radical treatment constituting surgery and postoperative radiotherapy over 2 decades. Study Design Retrospective review and prospective data collection to obtain patient demographic, tumor characteristics, clinical symptoms, and patient-reported QoL outcomes using the 36-Item Short Form Health Survey (SF-36). Setting/Participants Patients diagnosed with CS who underwent radical intent surgical resection by the senior author and adjuvant early postoperative proton beam therapy. Results Twenty-eight skull base CS patients were identified, with 19 patients completing full treatment course. Mean long-term follow-up was 148.9 months. Diplopia symptom resolution was high. No significant deterioration in SF-36 Physical Health Component (PHC) and Mental Health Component (MHC) scores was observed at postoperative and long-term follow-up. General health was stable initially but deteriorated in long term (Δ −18.88, minimal clinically important difference [MCID]: 9.86, p = 0.04). Compared with age-matched Canadian control patients, CS patients reported similar PHC scores at baseline and follow-up. CS patients reported lower MHC scores (45.8 vs. 50.9, p = 0.13) preoperatively, which persisted at follow-up decreasing by 1.9 (43.9 vs. 53.7, p = 0.03); this difference, however, did not reach MCID threshold of Δ 5.9. Conclusion We present the longest follow-up data on CS demonstrating stable long-term QoL with aggressive surgery. Tumor control was high and preoperative tumor size did not affect long-term QoL. Preoperative QoL was lower among CS compared with Canadian normative data. Postoperatively, only the decline in physical functioning QoL scores exceeded MCID. At long-term follow-up, the decline in physical functioning, social functioning, and general health exceeded MCID. Overall, QoL among CS patients remained lower at long-term follow-up despite absence of tumor progression and resolution of symptoms.

Proton dose deposition matrix prediction using multi-source feature driven deep learning approach

Proton dose deposition results are influenced by various factors, such as irradiation angle, beamlet energy and other parameters. The calculation of the proton dose deposition matrix (DDM) can be highly complex but is crucial in intensity-modulated proton therapy (IMPT). In this work, we present a novel deep learning (DL) approach using multi-source features for proton DDM prediction. The DL5 proton DDM prediction method involves five input features containing beamlet geometry, dosimetry and treatment machine information like patient CT data, beamlet energy, distance from voxel to beamlet axis, distance from voxel to body surface, and pencil beam (PB) dose. The dose calculated by Monte Carlo (MC) method was used as the ground truth dose label. A total of 40 000 features, corresponding to 8000 beamlets, were obtained from head patient datasets and used for the training data. Additionally, seventeen head patients not included in the training process were utilized as testing cases. The DL5 method demonstrates high proton beamlet dose prediction accuracy, with an average determination coefficient R 2 of 0.93 when compared to the MC dose. Accurate beamlet dose estimation can be achieved in as little as 1.5 milliseconds for an individual proton beamlet. For IMPT plan dose comparisons to the dose calculated by the MC method, the DL5 method exhibited gamma pass rates of γ(2 mm, 2%) and γ(3 mm, 3%) ranging from 98.15% to 99.89% and 98.80% to 99.98%, respectively, across all 17 testing cases. On average, the DL5 method increased the gamma pass rates to γ(2 mm, 2%) from 82.97% to 99.23% and to γ(3 mm, 3%) from 85.27% to 99.75% when compared with the PB method. The proposed DL5 model enables rapid and precise dose calculation in IMPT plan, which has the potential to significantly enhance the efficiency and quality of proton radiation therapy.

DiffuseRT: predicting likely anatomical deformations of patients undergoing radiotherapy

Objective. Predicting potential deformations of patients can improve radiotherapy treatment planning. Here, we introduce new deep-learning models that predict likely anatomical changes during radiotherapy for head and neck cancer patients. Approach. Denoising diffusion probabilistic models (DDPMs) were developed to generate fraction-specific anatomical changes based on a reference cone-beam CT (CBCT), the fraction number and the dose distribution delivered. Three distinct DDPMs were developed: (1) the image model was trained to directly generate likely future CBCTs, (2) the deformable vector field (DVF) model was trained to generate DVFs that deform a reference CBCT and (3) the hybrid model was trained similarly to the DVF model, but without relying on an external deformable registration algorithm. The models were trained on 9 patients with longitudinal CBCT images (224 CBCTs) and evaluated on 5 patients (152 CBCTs). Results. The generated images mainly exhibited random positioning shifts and small anatomical changes for early fractions. For later fractions, all models predicted weight losses in accordance with the training data. The distributions of volume and position changes of the body, esophagus, and parotids generated with the image and hybrid models were more similar to the ground truth distribution than the DVF model, evident from the lower Wasserstein distance achieved with the image (0.33) and hybrid model (0.30) compared to the DVF model (0.36). Generating several images for the same fraction did not yield the expected variability since the ground truth anatomical changes were only in 76% of the fractions within the 95% bounds predicted with the best model. Using the generated images for robust optimization of simplified proton therapy plans improved the worst-case clinical target volume V95 with 7% compared to optimizing with 3 mm set-up robustness while maintaining a similar integral dose. Significance. The newly developed DDPMs generate distributions similar to the real anatomical changes and have the potential to be used for robust anatomical optimization.

Design of a combined X–Y scanning magnet with high field uniformity for pencil beam scanning proton therapy

In proton therapy, scanning magnets play a crucial role in the treatment equipment. Specifically, in pencil beam scanning, these magnets are responsible for deflecting the proton beam, thereby enabling the illumination of the tumor’s precise location. To reduce the size of the scanning system, a combined X–Y scanning magnet is used instead of separate scanning magnets, which can reduce the overall size of the gantry. The design in this paper combines a window-shaped yoke and three sets of elephant-ear-shaped coils, and one of the coils generates a horizontal magnetic field while the other two coils generate a vertical magnetic field. By adjusting the distance between the coils and the shape of the coils at both ends, the magnetic integral field exhibits higher uniformity compared to other combined scanning magnets. The simulation results show that the integrated field achieves a uniformity of 0.84% in the horizontal direction and 0.60% in the vertical direction. Particle tracking simulation and steady-state thermal analysis were also conducted. After cutting a certain number of slits with the same size at the ends of the magnetic yoke, the magnet can meet the requirements of a suitable working temperature. This magnet design has the capability to effectively decrease the space utilized by the scanning system, consequently reducing the rotational radius of the frame and minimizing the equipment required.

Pencil Beam Scanning Proton Therapy as Single Vocal Cord Irradiation for Early-Stage Glottic Cancer

PurposeSingle vocal cord irradiation (SVCI) is a promising technique to maintain excellent oncologic control and potentially improve upon toxicities for treatment of early-stage glottic squamous cell carcinomas. We sought to investigate whether pencil beam scanning (PBS) proton therapy could improve upon the already favorable dose gradients demonstrated with volumetric modulated arc therapy (VMAT) SVCI. Patients and MethodsA 64-year-old gentleman was treated in our department with 6X-flattening filter-free VMAT SVCI to 58.08 Gy in 16 fractions for a T1a well-differentiated squamous cell carcinoma of the left true vocal cord and tolerated it well with good local control. Comparative PBS plans were created in Raystation for the Varian ProBeam with clinical target volume (CTVs) generated to mimic the prescription target volume extent of the VMAT planning target volumes when accounting for PBS plan robustness (±3 mm translational shifts, 3.5% density perturbation). A 3-field single-field optimization plan was selected as dosimetrically preferable. Dosimetric variables were compared. ResultsSeveral organs at risk doses improved with PBS, including the maximum and mean dose to ipsilateral carotids, maximum and mean dose to contralateral carotid, maximum dose to the spinal cord, maximum and mean dose to inferior constrictor/cricopharyngeus, maximum and mean dose to the uninvolved vocal cord, and mean dose to the thyroid gland. There are tradeoffs in skin dose depending on location relative to the target—with the highest and lowest isodoses extending more into the skin with the VMAT plan but with the moderate isodose lines covering a wider area with the PBS plan, but we deemed it tolerable regardless. ConclusionSVCI is a promising strategy for maintaining the oncologic effectiveness of whole-larynx photon radiation while potentially improving upon the historic toxicity profile. The favorable dose distribution with PBS with respect to organs at risk dosimetry for PBS may allow for further improvements upon VMAT SVCI strategies. Clinical implementation of PBS SVCI may be considered.

Investigation of intra-fractionated range guided adaptive proton therapy (RGAPT): II. Range-shift compensated on-line treatment adaptation and verification

We previously proposed range-guided adaptive proton therapy (RGAPT) that uses mid-range treatment beams as probing beams and intra-fractionated range measurements for online adaptation. In this work, we demonstrated experimental verification and reported the dosimetric accuracy for RGAPT. A STEEV phantom was used for the experiments, and a 3 × 3 × 3 cm3 cube inside the phantom was assigned to be the treatment target. We simulated three online range shift scenarios: reference, overshoot, and undershoot, by placing upstream Lucite sheets, 4, 0, and 8 that corresponded to changes of 0, 6.8, and −6.8 mm, respectively, in water-equivalent path length. The reference treatment plan was to deliver single-field uniform target doses in pencil beam scanning mode and generated on the Eclipse treatment planning system. Different numbers of mid-range layers, including single, three, and five layers, were selected as probing beams to evaluate beam range (BR) measurement accuracy in positron emission tomography (PET). Online plans were modified to adapt to BR shifts and compensate for probing beam doses. In contrast, non-adaptive plans were also delivered and compared to adaptive plans by film measurements. The mid-range probing beams of three (5.55MU) and five layers (8.71MU) yielded accurate range shift measurements in 60 s of PET acquisition with uncertainty of 0.5 mm while the single-layer probing (1.65MU) was not sufficient for measurements. The adaptive plans achieved an average gamma (2%/2 mm) passing rate of 95%. In contrast, the non-adaptive plans only had an average passing rate of 69%. RGAPT planning and delivery are feasible and verified by the experiments. The probing beam delivery, range measurements, and adaptive planning and delivery added a small increase in treatment delivery workflow time but resulted in substantial dose improvement. The three-layer mid-range probing was most suitable considering the balance of high range measurement accuracy and the low number of probing beam layers.

Investigation of intra-fractionated range guided adaptive proton therapy: I. On-line PET imaging and range measurement

Objective. Develop a prototype on-line positron emission tomography (PET) scanner and evaluate its capability of on-line imaging and intra-fractionated proton-induced radioactivity range measurement. Approach. Each detector consists of 32 × 32 array of 2 × 2 × 30 mm3 Lutetium–Yttrium Oxyorthosilicate scintillators with single-scintillator-end readout through a 20 × 20 array of 3 × 3 mm2 Silicon Photomultipliers. The PET can be configurated with a full-ring of 20 detectors for conventional PET imaging or a partial-ring of 18 detectors for on-line imaging and range measurement. All detector-level readout and processing electronics are attached to the backside of the system gantry and their output signals are transferred to a field-programable-gate-array based system electronics and data acquisition that can be placed 2 m away from the gantry. The PET imaging performance and radioactivity range measurement capability were evaluated by both the offline study that placed a radioactive source with known intensity and distribution within a phantom and the online study that irradiated a phantom with proton beams under different radiation and imaging conditions. Main results. The PET has 32 cm diameter and 6.5 cm axial length field-of-view (FOV), ∼2.3–5.0 mm spatial resolution within FOV, 3% sensitivity at the FOV center, 18%–30% energy resolution, and ∼9 ns coincidence time resolution. The offline study shows the PET can determine the shift of distal falloff edge position of a known radioactivity distribution with the accuracy of 0.3 ± 0.3 mm even without attenuation and scatter corrections, and online study shows the PET can measure the shift of proton-induced positron radioactive range with the accuracy of 0.6 ± 0.3 mm from the data acquired with a short-acquisition (60 s) and low-dose (5 MU) proton radiation to a human head phantom. Significance. This study demonstrated the capability of intra-fractionated PET imaging and radioactivity range measurement and will enable the investigation on the feasibility of intra-fractionated, range-shift compensated adaptive proton therapy.

NTRK-fused central nervous system tumours: clinicopathological and genetic insights and response to TRK inhibitors

Background Neurotrophic tropomyosin receptor kinase (NTRK) gene fusions are found in 1% of gliomas across children and adults. TRK inhibitors are promising therapeutic agents for NTRK-fused gliomas because they are tissue agnostic and cross the blood–brain barrier (BBB). Methods We investigated twelve NGS-verified NTRK-fused gliomas from a single institute, Seoul National University Hospital. Results The patient cohort included six children (aged 1–15 years) and six adults (aged 27–72 years). NTRK2 fusions were found in ten cerebral diffuse low-grade and high-grade gliomas (DLGGs and DHGGs, respectively), and NTRK1 fusions were found in one cerebral desmoplastic infantile ganglioglioma and one spinal DHGG. In this series, the fusion partners of NTRK2 were HOOK3, KIF5A, GKAP1, LHFPL3, SLMAP, ZBTB43, SPECC1L, FKBP15, KANK1, and BCR, while the NTRK1 fusion partners were TPR and TPM3. DLGGs tended to harbour only an NTRK fusion, while DHGGs exhibited further genetic alterations, such as TERT promoter/TP53/PTEN mutation, CDKN2A/2B homozygous deletion, PDGFRA/KIT/MDM4/AKT3 amplification, or multiple chromosomal copy number aberrations. Four patients received adjuvant TRK inhibitor therapy (larotrectinib, repotrectinib, or entrectinib), among which three also received chemotherapy (n = 2) or proton therapy (n = 1). The treatment outcomes for patients receiving TRK inhibitors varied: one child who received larotrectinib for residual DLGG maintained stable disease. In contrast, another child with DHGG in the spinal cord experienced multiple instances of tumour recurrence. Despite treatment with larotrectinib, ultimately, the child died as a result of tumour progression. An adult patient with glioblastoma (GBM) treated with entrectinib also experienced tumour progression and eventually died. However, there was a successful outcome for a paediatric patient with DHGG who, after a second gross total tumour removal followed by repotrectinib treatment, showed no evidence of disease. This patient had previously experienced relapse after the initial surgery and underwent autologous peripheral blood stem cell therapy with carboplatin/thiotepa and proton therapy. Conclusions Our study clarifies the distinct differences in the pathology and TRK inhibitor response between LGG and HGG with NTRK fusions.

Efficacy and safety of proton therapy versus intensity-modulated radiation therapy in the treatment of head and neck tumors: A systematic review and meta-analysis.

To comprehensively evaluate the therapeutic efficacy and safety when utilizing proton therapy (PT) versus intensity-modulated radiation therapy (IMRT) in head and neck cancer patients. Pubmed, ScienceDirect, Embase, Scopus, and Web of Science were systematically searched for studies on comparative PT and IMRT outcomes. We performed a random effect model meta-analysis to estimate the hazard ratio (HR) and odds ratio (OR) for efficacy and safety outcome variables between PT and IMRT. From 641 identified articles, 11 studies met the inclusion criteria, comprising 3087 patients (606 treated with PT and 2481 with IMRT). On toxicity analysis, PT is associated with decreased acute grade 1 nausea (OR = 0.34, 95% CI: 0.13-0.84, p = 0.02) compared to IMRT. In grade 2 toxicity, PT showed significant advantages over IMRT in mucositis (OR = 0.44, p < 0.0001), dysgeusia (OR = 0.35, p = 0.02), dysphagia (OR = 0.36, p < 0.0001), fatigue (OR = 0.29, p = 0.001), pain (OR = 0.34, p = 0.01), and weight loss (OR = 0.54, p = 0.02). Proton therapy also exhibited increased safety in grade 3 dysphagia incidence (OR = 0.44, p < 0.0001) compared to IMRT. PT demonstrated improved overall survival (OS) compared to IMRT across multiple time points: 1-year OS (HR = 0.43, p = 0.02), 2-year OS (HR = 0.44, p < 0.0001), and 5-year OS (HR = 0.78, p = 0.004). In terms of disease-free survival (DFS), PT also showed improved outcomes at 2-year DFS (HR = 0.65, p = 0.03) and 5-year DFS (HR = 0.81, p = 0.03). Proton therapy demonstrated superior overall survival (OS), disease-free survival (DFS), and better local control rate (LCR) compared to IMRT. The data also showed better safety outcomes in PT patients, particularly when involving grade 2 acute toxicity events.

Stopping power and range estimations in proton therapy based on prompt gamma timing: motion models and automated parameter optimization

Objective. Particle therapy treatments are currently limited by uncertainties of the delivered dose. Verification techniques like Prompt-Gamma-Timing-based Stopping Power Estimation (PGT-SPE) may allow for reduction of safety margins in treatment planning. Approach. From Prompt-Gamma-Timing measurements, we reconstruct the spatiotemporal distribution of prompt gamma emissions, which is linked to the average motion of the primary particles. The stopping power is determined by fitting a model of the average particle motion. Here, we compare a previously published implementation of the particle motion model with an alternative formulation and present two formulations to automatically select the hyperparameters of our procedure. The performance was assessed using Monte-Carlo simulations of proton beams (60 MeV–219 MeV) impinging on a homogeneous PMMA phantom. Main results. The range was successfully determined within a standard deviation of 3 mm for proton beam energies from 70 MeV to 219 MeV. Stopping power estimates showed errors below 5% for beam energies above 160 MeV. At lower energies, the estimation performance degraded to unsatisfactory levels due to the short range of the protons. The new motion model improved the estimation performance by up to 5% for beam energies from 100 MeV to 150 MeV with mean errors ranging from 6% to 18%. The automated hyperparameter optimization matched the average error of previously reported manual selections, while significantly reducing the outliers. Significance. The data-driven hyperparameter optimization allowed for a reproducible and fast evaluation of our method. The updated motion model and evaluation at new beam energies bring us closer to applying PGT-SPE in more complex scenarios. Direct comparison of stopping power estimates between treatment planning and measurements during irradiation would offer a more direct verification than other secondary-particle-based techniques.

Radiation-Induced Acquired Lacrimal Drainage Obstructions: Management and Outcomes

ABSTRACT Objective To describe the management and outcomes of patients with radiation-induced acquired lacrimal duct obstructions (RALDO). Methods A retrospective chart review from July 2018 to December 2023 of all cases undergoing surgical intervention for RALDO by a single surgeon. Data collected included demographics, tumor type and anatomic location, radiation treatment (including radiation type, dosage, and duration), interval between radiation and reported onset of epiphora, oculoplastic clinical examination, management, and outcomes. Lacrimal irrigation was done prior to surgery in all patients. Results Seventeen eyes of 16 patients with a mean age at presentation of 63.3 years and over half the patients being females (56.3%) were included in the study. The right lacrimal drainage system (LDS) was involved in 4 (23.6%), and the left side was involved in 13 (76.4%). The mean onset of epiphora symptoms after radiation was 9.5 months. The underlying tumor type were intraocular having uveal melanoma in four, cutaneous squamous cell carcinoma in 2, basal cell carcinoma involving forehead and nose in one and sino-nasal indications present in 8 patients. One patient had metastasis to the orbit and eyelid. Four patients (25%) received external beam radiotherapy (XRT) (one case had bilateral LDS involvement), 6 patients (37.5%) received intensity-modulated radiation therapy (IMRT), 5 patients (31.25%) received proton beam irradiation (PBI), and one (6.25%) received stereotactic body radiotherapy (SBRT). Mean radiation dosage was 61.31 Gy in 15 patients (data was missing in 1 patient). Punctum was effaced in 3, canalicular stenosis in 1, proximal canalicular obstruction in 8, distal canalicular obstruction in 2, and nasolacrimal duct obstruction (NLDO) in 3. Treatment was based on the site and nature of obstruction and varied from minimally invasive techniques like serial dilatation with bicanalicular silicone tube or Guibor tube to surgical interventions like dacryocystorhinostomy (DCR) or conjunctivo-dacryocystorhinostomy (C-DCR). Only 10% with primary lacrimal intubation had good response. Of the six cases that underwent C-DCR with Jones tube either as primary or secondary procedure, four cases showed improvement in epiphora (67%). Three with NLDO did well after external DCR. In total, four patients had a secondary procedure after the first failed while 7 with failed initial surgery elected against secondary surgery. The mean follow-up was 9.6 months (range 2–24 months). Conclusions In patients with RALDO, salvage treatment with silicone lacrimal intubation has poor results, CDCR with Jones tube has better results, although imperfect and in cases with NLDO, DCR has good outcomes.

Treatment Strategies for Locoregional Recurrence in Esophageal Squamous-Cell Carcinoma: An Updated Review.

Emerging evidence has shown remarkable advances in the multimodal treatment of esophageal squamous-cell carcinoma. Despite these advances, the oncological outcomes for advanced esophageal cancer remain controversial due to the frequent observation of local recurrence in the regional or other lymph nodes and distant metastasis after curative treatment. For cases of locoregional recurrence in the cervical lymph nodes alone, salvage surgery with lymph node dissection generally provides a good prognosis. However, if recurrence occurs in multiple regions, the oncological efficacy of surgery may be limited. Radiotherapy/chemoradiotherapy can be employed for unresectable or recurrent cases, as well as for selected cases in neo- or adjuvant settings. Dose escalation and toxicity are potential issues with conventional three-dimensional conformal radiotherapy; however, more precise therapeutic efficacy can be obtained using technical modifications with improved targeting and conformality, or with the use of proton beam therapy. The introduction of immune checkpoint inhibitors, including pembrolizumab or nivolumab, in addition to chemotherapy, has been shown to improve the overall survival in unresectable, advanced/recurrent cases. For patients with lymph node recurrence in multiple regions, chemotherapy (5-fluorouracil [5-FU] plus cisplatin) and combination therapy with nivolumab and ipilimumab have shown comparable oncological efficacy. Further prospective studies are needed to improve the treatment outcomes in patients with esophageal cancer with locoregional recurrence.

Evolution of hadron therapy from 1935 to 2005: a personal view

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

Proton spot dose estimation based on positron activity distributions with neural network.

Positron emission tomography (PET) has been investigated for its ability to reconstruct proton-induced positron activity distributions in proton therapy. This technique holds potential for range verification in clinical practice. Recently, deep learning-based dose estimation from positron activity distributions shows promise for in vivo proton dose monitoring and guided proton therapy. This study evaluates the effectiveness of three classical neural network models, recurrent neural network (RNN), U-Net, and Transformer, for proton dose estimating. It also investigates the characteristics of these models, providing valuable insights for selecting the appropriate model in clinical practice. Proton dose calculations for spot beams were simulated using Geant4. Computed tomography (CT) images from four head cases were utilized, with three for training neural networks and the remaining one for testing. The neural networks were trained with one-dimensional (1D) positron activity distributions as inputs and generated 1D dose distributions as outputs. The impact of the number of training samples on the networks was examined, and their dose prediction performance in both homogeneous brain and heterogeneous nasopharynx sites was evaluated. Additionally, the effect of positron activity distribution uncertainty on dose prediction performance was investigated. To quantitatively evaluate the models, mean relative error (MRE) and absolute range error (ARE) were used as evaluation metrics. The U-Net exhibited a notable advantage in range verification with a smaller number of training samples, achieving approximately 75% of AREs below 0.5mm using only 500 training samples. The networks performed better in the homogeneous brain site compared to the heterogeneous nasopharyngeal site. In the homogeneous brain site, all networks exhibited small AREs, with approximately 90% of the AREs below 0.5mm. The Transformer exhibited the best overall dose distribution prediction, with approximately 92% of MREs below 3%. In the heterogeneous nasopharyngeal site, all networks demonstrated acceptable AREs, with approximately 88% of AREs below 3mm. The Transformer maintained the best overall dose distribution prediction, with approximately 85% of MREs below 5%. The performance of all three networks in dose prediction declined as the uncertainty of positron activity distribution increased, and the Transformer consistently outperformed the other networks in all cases. Both the U-Net and the Transformer have certain advantages in the proton dose estimation task. The U-Net proves well suited for range verification with a small training sample size, while the Transformer outperforms others at dose-guided proton therapy.