Pencil Beam Scanning Technique Research Articles

An artificial neural network based approach for predicting the proton beam spot dosimetric characteristics of a pencil beam scanning technique

Utilising Machine Learning (ML) models to predict dosimetric parameters in pencil beam scanning proton therapy presents a promising and practical approach. The study developed Artificial Neural Network (ANN) models to predict proton beam spot size and relative positional errors using 9000 proton spot data. The irradiation log files as input variables and corresponding scintillation detector measurements as the label values. The ANN models were developed to predict six variables: spot size in the x-axis, y-axis, major axis, minor axis, and relative positional errors in the x-axis and y-axis. All ANN models used a Multi-layer perception (MLP) network using one input layer, three hidden layers, and one output layer. Model performance was validated using various statistical tools. The log file recorded spot size and relative positional errors, which were compared with scintillator-measured data. The Root Mean Squared Error (RMSE) values for the x-spot and y-spot sizes were 0.356 mm and 0.362 mm, respectively. Additionally, the maximum variation for the x-spot relative positional error was 0.910 mm, while for the y-spot, it was 1.610 mm. The ANN models exhibit lower prediction errors. Specifically, the RMSE values for spot size prediction in the x, y, major, and minor axes are 0.053 mm, 0.049 mm, 0.053 mm, and 0.052 mm, respectively. Additionally, the relative spot positional error prediction model for the x and y axes yielded maximum errors of 0.160 mm and 0.170 mm, respectively. The normality of models was validated using the residual histogram and Q-Q plot. The data over fit, and bias were tested using K (k = 5) fold cross-validation, and the maximum RMSE value of the K fold cross-validation among all the six ML models was less than 0.150 mm (R-Square 0.960). All the models showed excellent prediction accuracy. Accurately predicting beam spot size and positional errors enhances efficiency in routine dosimetric checks.

Comprehensive radiotherapy for pediatric Ewing Sarcoma: Outcomes of a prospective proton study

Background and purposePatients with Ewing Sarcoma (EWS) are treated with multimodality therapy which includes radiation therapy (RT) as an option for local control. We report on the efficacy after proton radiation therapy (PRT) to the primary site for localized and metastatic EWS. Materials and methodsForty-two children with EWS (33 localized, 9 metastatic) treated between 2007 and 2020 were enrolled on 2 prospective registry protocols for pediatric patients undergoing PRT. PRT was delivered by passive scatter (74 %), pencil-beam scanning (12 %) or mixed technique (14 %). Treated sites included the spine (45 %), pelvis/sacrum (26 %), skull/cranium (14 %), extraosseous (10 %), and chest wall (5 %). Median radiation dose was 54 Gy-RBE (range 39.6–55.8 Gy-RBE). Patients with metastatic disease received consolidative RT to metastatic sites (4 at the time of PRT to the primary site, 5 after completion of chemotherapy). Median follow-up time was 47 months after PRT. ResultsThe 4-year local control (LC), progression-free survival (PFS), and overall survival (OS) rates were 83 %, 71 %, and 86 %, respectively. All local failures (n = 6) were in-field failures. Tumor size ≥ 8 cm predicted for inferior 4-year LC (69 % vs 95 %, p = 0.04). 4-year PFS and OS rates were not statistically different in patients with localized versus metastatic disease (72 % vs 67 %, p = 0.70; 89 % vs 78 %, p = 0.38, respectively). ConclusionIn conclusion, LC for pediatric patients with EWS treated with PRT was comparable to that of historical patients who received photon-RT. Tumor size ≥ 8 cm predicted increased risk of local failure. Patients with metastatic disease, including non-pulmonary only metastases, received radiation therapy to all metastatic sites and had favorable survival outcomes.

Outcome After Modern Proton Beam Therapy in Childhood Craniopharyngioma: Results of the Prospective Registry Study KiProReg

BackgroundCraniopharyngiomas (CPs) are rare tumours of the sellar region often leading to significant comorbidities due to their close proximity to critical structures. Aim of this study was to analyse survival outcome and late toxicities after surgery and proton beam therapy (PBT) in childhood CPs. Patients and methodsWithin the prospective XXXX study (XXXX), data of 74 childhood patients with CP, receiving PBT between 08/2013-06/2022 were eligible. Late toxicities were analysed according to the grading system of CTCAE 4.0. Results: Median follow-up (FU) since first diagnosis was 4.3 years (range, 0.8-14.7). 75.7% of patients received PBT at time of disease progression or recurrence, whereas 24.3% as part of their primary therapy (definitive or adjuvant). Predominantly (85.1%), pencil beam scanning technique was used. Median total dose and initial tumour volume were 5400 cGyRBE (relative biological effectiveness) and 17.64 cm³ (range, 3.07-300.59), respectively. The estimated (±SE) 3-year overall survival, progression-free and cystic failure-free survival rate after PBT were 98.2% (±1.7), 94.7% (±3.0), and 76.8% (±5.4), respectively. All local failures (n=3) were in-field relapses necessitating intervention and occurred exclusively in patients receiving PBT at progression or recurrence. Early cystic enlargements after PBT were typically asymptomatic and self-limiting. Fatigue, headaches, vision disorders, obesity and endocrinopathies were the predominant late toxicities. No high grade (≥3) new-onset visual impairment or cognitive deterioration occurred compared to baseline. The presence of cognitive impairments at the end of FU correlated with size of the planning target volume (p=0.034), Dmean dose to the temporal lobes (p=0.032,p=0.045) and the number of surgical interventions prior to PBT (p=0.029). Conclusions: Our findings demonstrate favourable local control rates using modern PBT with acceptable late toxicities. Cyst growth within 12 month after radiotherapy is typically not associated with tumour progression. Longer FU has to be awaited to confirm results.

Phantosmia during proton radiation and differences in frequency of phantosmia rates based on proton craniospinal irradiation technique for pediatric brain tumor patients.

Unusual olfactory perception, often referred to as "phantosmia" or "cacosmia" has been reported during brain radiotherapy (RT), but is infrequent and does not typically interfere with the ability to deliver treatment. We seek to determine the rate of phantosmia for patients treated with proton craniospinal irradiation (CSI) and identify any potential clinical or treatment-related associations. We performed a retrospective review of 127 pediatric patients treated with CSI, followed by a boost to the brain for primary brain tumors in a single institution between 2016 and 2021. Proton CSI was delivered with passive scattering (PS) proton technique (n=53) or pencil beam scanning technique (PBS) (n=74). Within the PBS group, treatment delivery to the CSI utilized a single posterior (PA) field (n=24) or two posterior oblique fields (n=50). We collected data on phantom smell, nausea/vomiting, and the use of medical intervention. Our cohort included 80 males and 47 females. The median age of patients was 10years (range: 3-21). Seventy-one patients (56%) received concurrent chemotherapy. During RT, 104 patients (82%) developed worsening nausea, while 63 patients (50%) reported episodes of emesis. Of those patients who were awake during CSI (n=59), 17 (29%) reported phantosmia. In the non-sedated group, we found a higher rate of phantosmia in patients treated with PBS (n=16, 42%) than PS (n=1, 4.7%) (p=.002). Seventy-eight patients (61%) required medical intervention after developing nausea/vomiting or phantosmia during RT. Two patients required sedation due to the malodorous smell during CSI. We did not find any significant difference in nausea/vomiting based on treatment technique. Proton technique significantly influenced olfactory perception with greater rates of phantosmia with PBS compared to PS. Prospective studies should be performed to determine the cause of these findings and determine techniques to minimize phantosmia during radiation therapy.

Pencil Beam Scanning Proton Bragg Peak Conformal FLASH in Prostate Cancer Stereotactic Body Radiotherapy.

Bragg peak FLASH radiotherapy (RT) uses a distal tracking method to eliminate exit doses and can achieve superior OAR sparing. This study explores the application of this novel method in stereotactic body radiotherapy prostate FLASH-RT. An in-house platform was developed to enable intensity-modulated proton therapy (IMPT) planning using a single-energy Bragg peak distal tracking method. The patients involved in the study were previously treated with proton stereotactic body radiotherapy (SBRT) using the pencil beam scanning (PBS) technique to 40 Gy in five fractions. FLASH plans were optimized using a four-beam arrangement to generate a dose distribution similar to the conventional opposing beams. All of the beams had a small angle of two degrees from the lateral direction to increase the dosimetry quality. Dose metrics were compared between the conventional PBS and the Bragg peak FLASH plans. The dose rate histogram (DRVH) and FLASH metrics of 40 Gy/s coverage (V40Gy/s) were investigated for the Bragg peak plans. There was no significant difference between the clinical and Bragg peak plans in rectum, bladder, femur heads, large bowel, and penile bulb dose metrics, except for Dmax. For the CTV, the FLASH plans resulted in a higher Dmax than the clinical plans (116.9% vs. 103.3%). For the rectum, the V40Gy/s reached 94% and 93% for 1 Gy dose thresholds in composite and single-field evaluations, respectively. Additionally, the FLASH ratio reached close to 100% after the application of the 5 Gy threshold in composite dose rate assessment. In conclusion, the Bragg peak distal tracking method can yield comparable plan quality in most OARs while preserving sufficient FLASH dose rate coverage, demonstrating that the ultra-high dose technique can be applied in prostate FLASH SBRT.

Range shifter contribution to neutron exposure of patients undergoing proton pencil beam scanning.

Superficial targets require the use of the lowest energies within the available energy range in proton pencil-beam scanning (PBS) technique. However, the lower efficiency of the energy selection system at these energies and the requirement of a greater number of layers may represent disadvantages for this approach. The alternative is to use a range shifter (RS) at nozzle exit. However, one of the concerns of using this beamline element is that it becomes an additional source of neutrons that could irradiate organs situated far from the target. The purpose of this study is to assess the increase in neutron dose due to the RS in proton PBS technique. Additionally, an analytical model for the neutron production is tested. Two clinical plans, designed to achieve identical target coverage, were created for an anthropomorphic phantom. These plans consisted of a lateral field delivering an absorbed dose of 60Gy (RBE) to the target. One of the plans employed the RS. The MCNP code was used to simulate the plans, evaluating the distribution of neutron dose equivalent (Hn ) and the equivalent dose in organ. In the plan with the RS plan, neutron production from both the patient and the RS were assessed separately. Hn values were also fitted versus the distance to field edge using a Gaussian function. Hn per prescription dose, in the plan using the RS, ranged between 1.4 and 3.7 mSv/Gy at the field edge, whereas doses at 40cm from the edge ranged from 9.9 to 32 μSv/Gy. These values are 1.2 to 10 times higher compared to those obtained without the RS. Both this factor and the contribution of neutrons originating from the RS increases with the distance from field edge. A triple-Gaussian function was able to reproduce the equivalent dose in organs within a factor of 2, although underestimating the values. The dose deposited in the patient by the neutrons originating from the RS predominantly affects areas away from the target (beyond approximately 25cm from field edge), resulting in a neutron dose equivalent of the order of mSv. This indicates an overall low neutron contribution from the use of RS in PBS.

Pencil Beam Scanning Carbon Ion Radiotherapy for Hepatocellular Carcinoma.

Carbon ion radiotherapy (CIRT) has emerged as a promising treatment modality for hepatocellular carcinoma (HCC). However, evidence of using the pencil beam scanning (PBS) technique to treat moving liver tumors remains lacking. The present study investigated the efficacy and toxicity of PBS CIRT in patients with HCC. Between January 2016 and October 2021, 90 consecutive HCC patients treated with definitive CIRT in our center were retrospectively analyzed. Fifty-eight patients received relative biological effectiveness-weighted doses of 50-70 Gy in 10 fractions, and 32 received 60-67.5 Gy in 15 fractions, which were determined by the tumor location and normal tissue constraints. Active motion-management techniques and necessary strategies were adopted to mitigate interplay effects efficiently. Oncologic outcomes and toxicities were evaluated. The median follow-up time was 28.6 months (range 5.7-74.6 months). The objective response rate was 75.0% for all 90 patients with 100 treated lesions. The overall survival rates at 1-, 2- and 3-years were 97.8%, 83.3% and 75.4%, respectively. The local control rates at 1-, 2- and 3-years were 96.4%, 96.4% and 93.1%, respectively. Radiation-induced liver disease was not documented, and 4 patients (4.4%) had their Child-Pugh score elevated by 1 point after CIRT. No grade 3 or higher acute non-hematological toxicities were observed. Six patients (6.7%) experienced grade 3 or higher late toxicities. The active scanning technique was clinically feasible to treat HCC by applying necessary mitigation measures for interplay effects. The desirable oncologic outcomes as well as favorable toxicity profiles presented in this study will be a valuable reference for other carbon-ion centers using the PBS technique and local effect model-based system, and add to a growing body of evidence about the role of CIRT in the management of HCC.

An investigation into the impact of volumetric rescanning and fractionation treatment on dose homogeneity in liver cancer proton therapy.

The Pencil Beam Scanning (PBS) technique in modern particle therapy offers a highly conformal dose distribution but poses challenges due to the interplay effect, an interaction between respiration-induced organ movement and PBS. This study evaluates the effectiveness of different volumetric rescanning strategies in mitigating this effect in liver cancer proton therapy. We used a Geant4-based Monte Carlo simulation toolkit, 'TOPAS,' and an image registration toolbox, 'Elastix,' to calculate 4D dose distributions from 5 patients' four-dimensional computed tomography (4DCT). We analyzed the homogeneity index (HI) value of the Clinical Tumor Volume (CTV) at different rescan numbers and treatment times. Our results indicate that dose homogeneity stabilizes at a low point after a week of treatment, implying that both rescanning and fractionation treatments help mitigate the interplay effect. Notably, an increase in the number of rescans doesn't significantly reduce the mean dose to normal tissue but effectively prevents high localized doses to tissue adjacent to the CTV. Rescanning techniques, based on statistical averaging, require no extra equipment or patient cooperation, making them widely accessible. However, the number of rescans, tumor location, diaphragm movement, and treatment fractionation significantly influence their effectiveness. Therefore, deciding the number of rescans should involve considering the number of beams, treatment fraction size, and total delivery time to avoid unnecessary treatment extension without significant clinical benefits. The results showed that 2-3 rescans are more clinically suitable for liver cancer patients undergoing proton therapy.

Increased Complication Rates with Proton Therapy in Breast Cancer Patients with Immediate, Implant-Based Reconstruction: Single-Institution Comparative Effectiveness Analysis

To compare the impact of protons vs. photons on breast reconstruction complications, for patients (pts) receiving postmastectomy radiation (PMRT) with either single-stage direct-to-implant (DTI) or two-staged expander/implant (TE/I). We reviewed the charts of 578 pts who underwent immediate reconstruction followed by radiation at our institution between 2010 and 2020. Pts with implant-based reconstruction using either TE/I or DTI and PMRT delivery in the presence of the prosthesis were included. Pts enrolled in active ongoing clinical trials were excluded from the analysis. The photon group received 3D conformal or IMRT/VMAT treatment with a median dose of 50-50.4 Gy in 25 to 28 fractions. For proton pts, treatment was delivered mainly with pencil beam scanning technique (PBS); few pts received passively scattered proton spread-out Bragg peak (SOBP). The complications were defined as infection/skin necrosis (I/N) requiring operative debridement, capsular contracture (CC) necessitating capsulotomy, and overall implant failure (ORF) as the removal of the permanent implant irrespective of replacement outcomes (i.e., with and without salvage reconstruction). We fit inverse-probability weighted cumulative incidence curves to adjust for confounding and non-random loss to follow-up. Various sensitivity analyses were conducted. Four hundred ninety-five pts were available for the final analysis with an overall median follow-up of 55 months. 66 (13%) received protons, of which14 were treated with SOBP protons. 137 (28%) and 256 (56%) received photons with and without chest wall boost (CWB), respectively. The 5-year inverse probability-weighted risk of CC post-PMRT was 31% for protons vs. 10% for photons (RR:3.09, 95% CI: 1.77, 5.40). The 5 years ORF risk was 35.6% in protons compared to 22.7% in photons pts (RR: 1.57; 95% CI 1.0, 2.48). Hazard ratios from the adjusted Cox models were 3.79 (p<0.001) for CC and 2.05 (p<0.01) for ORF. No difference in I/N was noted between protons and photons pts. Sensitivity analysis showed that protons significantly increased CC risk vs photons both with CWB (HR:3.56, P<0.001) and without CWB (HR:3.9, p<0.001). Similar outcomes were observed with ORF, where protons increased the rate of ORF compared to photons, irrespective of CWB (HR 1.8, p = 0.038 with CWB; HR 2.4, p = 0.004 without CWB). No differences between PBS and SOBP proton techniques were noted. Compared to photons, proton therapy increases the risk of capsular contracture requiring surgical intervention and hence overall reconstruction failure. This data should inform discussions about the risks and benefits of protons in patients with reconstruction, while awaiting mature data from ongoing clinical trials (RADCOMP) utilizing protons for breast cancer.

Complications after proton radiotherapy in children, focusing on severe late complications. A complete Swedish cohort 2008–2019

Background Proton radiotherapy (RT) is an attractive tool to deliver local therapy with minimal dose to uninvolved tissue, however, not suitable for all patients. The aim was to explore complications, especially severe late complications (grades 3–4), following proton RT delivered to a complete Swedish cohort of paediatric patients aged <18 years treated 2008–2019. Material and Methods Data was downloaded from a national registry. Complications with a possible causation with RT are reported. Proton treatments until July 2015 was performed with a fixed horizontal 172 MeV beam (The Svedberg Laboratory (TSL), Uppsala) in a sitting position and thereafter with gantry-based pencil-beam scanning technique (Skandion Clinic, Uppsala) in a supine position. Results 219 courses of proton RT (77 at TSL and 142 at Skandion) were delivered to 212 patients (mean age 9.2 years) with various tumour types (CNS tumours 58%, sarcomas 26%, germ cell tumours 7%). Twenty-five patients had severe acute complications (skin, mucous membrane, pharynx/oesophagus, larynx, upper gastrointestinal canal, lower gastrointestinal canal, eyes, ears). Fifteen patients had severe late complications; with increased proportion over time: 4% at 1-year follow-up (FU), 5% at 3-year, 11% at 5-year. Organs affected were skin (1 patient), subcutaneous tissue (4), salivary glands (1), upper GI (1), bone (7), joints (2), CNS (2), PNS (1), eyes (1) and ears (5). Twenty-one of the 28 patients with 10-year FU had at least one late complication grades 1–4 and fourteen of them had more than one (2–5 each). Conclusion The most important result of our study is the relatively low proportion of severe late complications, comparable with other proton studies on various tumours. Furthermore, the numbers of late complications are lower than our own data set on a mixed population of photon and proton treated paediatric patients, assuring the safety of using proton therapy also in the clinical practice.

Secondary radiation dose modeling in passive scattering and pencil beam scanning very high energy electron (VHEE) radiation therapy.

Electrons with kinetic energy up to a few hundred MeV, also called very high energy electrons (VHEE), are currently considered a promising technique for the future of radiation therapy (RT) and in particular ultra-high dose rate (UHDR) therapy. However, the feasibility of a clinical application is still being debated and VHEE therapy remains an active area of research for which the optimal conformal technique is also yet to be determined. In this work, we will apply two existing formalisms based on analytical Gaussian multiple-Coulomb scattering theory and Monte Carlo (MC) simulations to study and compare the electron and bremsstrahlung photon dose distributions arising from two beam delivery systems (passive scattering with or without a collimator or active scanning). We therefore tested the application of analytical and MC models to VHEE beams and assessed their performance and parameterization in the energy range of 6-200MeV. The optimized electron beam fluence, the bremsstrahlung, an estimation of central-axis and off-axis x-ray dose at the practical range and neutron contributions to the total dose, along with an extended parameterization for the photon dose model were developed, together with a comparison between double scattering (DS) and pencil beam scanning (PBS) techniques. MC simulations were performed with the TOPAS/Geant4 toolkit to verify the dose distributions predicted by the analytical calculations. The results for the clinical energy range (between 6 and 20MeV) as well as for higher energies (VHEE range between 20 and 200MeV) and for two treatment field sizes (5×5 and 10×10 cm2 ) are reported, showing a reasonable agreement with MC simulations with mean differences below 2.1%. The relative contributions of photons generated in the medium or by the scattering system along the central-axis (up to 50% of the total dose) are also illustrated, along with their relative variations with electron energy. The fast analytical models parametrized in this study allow an estimation of the amount of photons produced behind the practical range by a DS system with an accuracy lower than 3%, providing important information for the eventual design of a VHEE system. The results of this work could support future research on VHEE radiotherapy.

Optimizing 3DCT image registration for interfractional changes in carbon-ion prostate radiotherapy

To perform setup procedures including both positional and dosimetric information, we developed a CT–CT rigid image registration algorithm utilizing water equivalent pathlength (WEPL)-based image registration and compared the resulting dose distribution with those of two other algorithms, intensity-based image registration and target-based image registration, in prostate cancer radiotherapy using the carbon-ion pencil beam scanning technique. We used the data of the carbon ion therapy planning CT and the four-weekly treatment CTs of 19 prostate cancer cases. Three CT–CT registration algorithms were used to register the treatment CTs to the planning CT. Intensity-based image registration uses CT voxel intensity information. Target-based image registration uses target position on the treatment CTs to register it to that on the planning CT. WEPL-based image registration registers the treatment CTs to the planning CT using WEPL values. Initial dose distributions were calculated using the planning CT with the lateral beam angles. The treatment plan parameters were optimized to administer the prescribed dose to the PTV on the planning CT. Weekly dose distributions using the three different algorithms were calculated by applying the treatment plan parameters to the weekly CT data. Dosimetry, including the dose received by 95% of the clinical target volume (CTV-D95), rectal volumes receiving > 20 Gy (RBE) (V20), > 30 Gy (RBE) (V30), and > 40 Gy (RBE) (V40), were calculated. Statistical significance was assessed using the Wilcoxon signed-rank test. Interfractional CTV displacement over all patients was 6.0 ± 2.7 mm (19.3 mm maximum standard amount). WEPL differences between the planning CT and the treatment CT were 1.2 ± 0.6 mm-H2O (< 3.9 mm-H2O), 1.7 ± 0.9 mm-H2O (< 5.7 mm-H2O) and 1.5 ± 0.7 mm-H2O (< 3.6 mm-H2O maxima) with the intensity-based image registration, target-based image registration, and WEPL-based image registration, respectively. For CTV coverage, the D95 values on the planning CT were > 95% of the prescribed dose in all cases. The mean CTV-D95 values were 95.8 ± 11.5% and 98.8 ± 1.7% with the intensity-based image registration and target-based image registration, respectively. The WEPL-based image registration was CTV-D95 to 99.0 ± 0.4% and rectal Dmax to 51.9 ± 1.9 Gy (RBE) compared to 49.4 ± 9.1 Gy (RBE) with intensity-based image registration and 52.2 ± 1.8 Gy (RBE) with target-based image registration. The WEPL-based image registration algorithm improved the target coverage from the other algorithms and reduced rectal dose from the target-based image registration, even though the magnitude of the interfractional variation was increased.

Preclinical Dosimetry for Small Animal Radiation Research in Proton Therapy: A Feasibility Study.

To evaluate the feasibility of the three-dimensional (3D) printed small animal phantoms in dosimetric verification of proton therapy for small animal radiation research. Two different phantoms were modeled using the computed-tomography dataset of real rat and tumor-bearing mouse, retrospectively. Rat phantoms were designed to accommodate both EBT3 film and ionization chamber. A subcutaneous tumor-bearing mouse phantom was only modified to accommodate film dosimetry. All phantoms were printed using polylactic-acid (PLA) filament. Optimal printing parameters were set to create tissue-equivalent material. Then, proton therapy plans for different anatomical targets, including whole brain and total lung irradiation in the rat phantom and the subcutaneous tumor model in the mouse phantom, were created using the pencil-beam scanning technique. Point dose and film dosimetry measurements were performed using 3D-printed phantoms. In addition, all phantoms were analyzed in terms of printing accuracy and uniformity. Three-dimensionally printed phantoms had excellent uniformity over the external body, and printing accuracy was within 0.5 mm. According to our findings, two-dimensional dosimetry with EBT3 showed acceptable levels of γ passing rate for all measurements except for whole brain irradiation (γ passing rate, 89.8%). In terms of point dose analysis, a good agreement (<0.1%) was found between the measured and calculated point doses for all anatomical targets. Three-dimensionally printed small animal phantoms show great potential for dosimetric verifications of clinical proton therapy for small animal radiation research.

Biophysical characterization of collimated and uncollimated fields in pencil beam scanning proton therapy

Objective. The lateral dose fall-off in proton pencil beam scanning (PBS) technique remains the preferred choice for sparing adjacent organs at risk as opposed to the distal edge due to the proton range uncertainties and potentially high relative biological effectiveness. However, because of the substantial spot size along with the scattering in the air and in the patient, the lateral penumbra in PBS can be degraded. Combining PBS with an aperture can result in a sharper dose fall-off, particularly for shallow targets. Approach. The aim of this work was to characterize the radiation fields produced by collimated and uncollimated 100 and 140 MeV proton beams, using Monte Carlo simulations and measurements with a MiniPIX-Timepix detector. The dose and the linear energy transfer (LET) were then coupled with published in silico biophysical models to elucidate the potential biological effects of collimated and uncollimated fields. Main results. Combining an aperture with PBS reduced the absorbed dose in the lateral fall-off and out-of-field by 60%. However, the results also showed that the absolute frequency-averaged LET (LETF) values increased by a maximum of 3.5 keV μm−1 in collimated relative to uncollimated fields, while the dose-averaged LET (LETD) increased by a maximum of 7 keV μm−1. Despite the higher LET values produced by collimated fields, the predicted DNA damage yields remained lower, owing to the large dose reduction. Significance. This work demonstrated the dosimetric advantages of combining an aperture with PBS coupled with lower DNA damage induction. A methodology for calculating dose in water derived from measurements with a silicon-based detector was also presented. This work is the first to demonstrate experimentally the increase in LET caused by combining PBS with aperture, and to assess the potential DNA damage which is the initial step in the cascade of events leading to the majority of radiation-induced biological effects.

Comprehensive Radiotherapy For Pediatric Ewing Sarcoma: Outcomes of a Prospective Proton Study

<h3>Objectives</h3> Patients with Ewing Sarcoma (EWS) are treated with multimodal therapy, with radiation therapy (RT) as an option for local control. We report on the efficacy after proton radiation therapy (PRT) for localized and metastatic EWS. <h3>Methods</h3> Fifty children with EWS (39 localized, 11 metastatic) treated between 2007 and 2020 were enrolled on a prospective IRB-approved protocol for pediatric patients undergoing PRT. Median age at time of PRT was 11.5y (range 0.9-19.6y); 62% were male. Median tumor size was 6.4cm (range 2.5-21cm). All patients received induction chemotherapy; 38 patients had definitive PRT and 12 had surgery followed by PRT. PRT was delivered by passive scatter (74%), pencil-beam scanning (12%) or mixed technique (14%). Treated sites included the spine (40%), pelvis/sacrum (26%), skull (18%), extraosseous (10%), and axial-skeleton (6%). Median radiation dose was 51Gy-RBE (range 39.6-55.8Gy-RBE). All patients with metastatic disease received consolidative RT to metastatic sites (5 at the time of local control [LC], 6 after completion of chemotherapy). Long-term follow-up data was available for 41 patients and median follow-up time was 47m after PRT. <h3>Results</h3> The 4-year LC, progression-free survival (PFS), and overall survival (OS) rates were 83.2%, 71.4%, and 86.3%, respectively. All local failures (n=6) were in-field failures. Tumor size ≥8cm predicted both inferior 4-year LC and PFS (69% vs 95%, p=0.04; 55% vs 86%, p=0.03, respectively). The 4-year PFS and OS rates were not statistically different in patients with localized versus metastatic disease (72% vs 67%, p=0.70; 89% vs 78%, p=0.38, respectively). Long-term toxicity included a grade 3 esophageal stricture in 1 patient. <h3>Conclusion</h3> We report one of the largest series of pediatric patients with EWS treated with PRT. LC was comparable to that of historical patients who received photon-RT and there were no marginal failures. Larger initial tumor size predicted increased risk of local failure and disease progression, which supports current efforts to dose-escalate treatment of tumors ≥8cm. Finally, patients with metastatic disease had survival outcomes comparable to those of patients with localized disease, suggesting a benefit to using RT for consolidation in metastatic EWS.

Computation of Voxel-by-Voxel Dose Rates in Patients for Proton Pencil Beam Dose Delivery

<h3>Purpose/Objective(s)</h3> Proton beam radiotherapy is most commonly delivered using the pencil beam scanning (PBS) technique. However, the vast majority of clinical outcome data is based on patients treated with the passive scattering technique. The overall dose distributions delivered with these techniques are fairly similar, with an advantage in conformity noted for PBS. Major differences between these two modalities can be observed in the temporal dose delivery pattern. The passive scattering technique uniformly delivers dose across the cross section of the entire target simultaneously, while the dose in PBS is delivered point-by-point, resulting in a much higher local instantaneous dose rate. Recent studies have shown that ultra-high dose rate (FLASH) irradiations can change the biological response to radiation. This work presents an analytical tool to compute voxel-wise maximum dose rates for clinical PBS treatment plans. <h3>Materials/Methods</h3> The scripting environment of our treatment planning system was used to develop software to compute dose rate distributions for clinical pencil beam scanning treatment plans. The basis of the computation is an accurate model of the delivery timing properties of the accelerator and scanning system. The minimum temporal resolution supported is 1 ms. This captures the timing of single spots but excludes the beam pulse structure of our cyclotron (ns). With the timing model and a given spot map we compute the average dose rate over a time interval of interest for each voxel. The latter is an input parameter determined by the user. To validate the tool, test beams in a simple solid water geometry were generated in the treatment planning system and corresponding dose rate distributions produced. Single point measurements with custom-made diode and electronics were used to verify computations against experimentation for a range of proton energies and depths. <h3>Results</h3> For dose rate calculations recording the maximum value observed in any 1 ms time interval during the field's delivery, we observe peak values of 186 Gy/min and 273 Gy/min for 110 MeV and 150 MeV protons, respectively. On average, the agreement of calculations and measurements was -0.9% with a standard deviation of 4.1%. <h3>Conclusion</h3> The software enables accurate local instantaneous dose rate calculations for clinically deliverable treatment plans. This may be important to use as a basis to better understand clinical results. In addition to standard PBS treatments, the observed dose rates may be relevant when considering the out of field areas in FLASH treatments.

A Phase I/II Clinical Trial of Proton Therapy for Chordomas and Chondrosarcomas

<h3>Purpose/Objective(s)</h3> Radiation therapy (RT) for chordomas and chondrosarcomas typically requires doses >70 Gy for optimal local tumor control. Proton therapy may afford safer dose escalation to the tumor, however, prospective data on outcomes and toxicity are lacking. We report results from a prospective clinical trial of proton beam radiation for the treatment of chordomas and chondrosarcomas. <h3>Materials/Methods</h3> Fifty-five patients with pathologically confirmed, non-metastatic chordoma or chondrosarcoma with an ECOG score <=2 were enrolled in a single-institution prospective trial of proton therapy from 2010-2018. Forty-seven patients received adjuvant RT, 5 received definitive RT, 1 received neoadjuvant RT, and 1 received RT for recurrence; 1 patient enrolled did not receive RT and was excluded from toxicity and survival analyses. Median dose was 78.3 Gy (cobalt Gray equivalent [CGE]) (range 50.4 – 79.2 Gy [CGE]) using protons only (n=21), combination protons/IMRT (n=33) with double-scatter or pencil beam scanning techniques, or IMRT only (n=2). Patients were followed with MRI or CT at three-month intervals. The primary endpoints were feasibility and <=20% rate of unexpected acute grade ≥3 toxicity. Secondary endpoints included cancer-specific outcomes and toxicity. Toxicities were scored using CTCAEv4.0. Kaplan Meier analysis was used to estimate local control, progression-free survival, and overall survival with respect to the date of RT completion. Local control was defined by most recent imaging; progression-free and overall survival were defined by most recent follow-up. <h3>Results</h3> Of the 54 patients who were analyzed (22 males, 32 female) with a median age of 54, 26 had skull base chordomas, 10 had sacral chordomas, 6 had spinal chordomas, 9 had base of skull chondrosarcomas, 1 had sacral chondrosarcoma, and 2 had sinonasal chondrosarcomas. Positive margins or gross disease was noted in 67% of patients at the time of RT. Median follow-up was 72 months, with an Overall survival of 45/54 (83%) patients alive at last follow-up. Local failure-free survival and progression-free survival were 70% and 68% respectively at a median follow up of 69 months. Feasibility endpoints were met, with only 3/55 (5.5%) patient RT plans failing to meet dosimetric constraints with protons and 4/54 (7.4%) experiencing a delay or treatment break >5 days. Five patients developed distant disease, 3 with a metastasis in the craniospinal axis, and 1 with a biopsy-confirmed inguinal lymph node metastasis, and 1 with distal iliac and femur metastases. Among the 9/54 patients who died, 4 deaths were not attributed to treatment or recurrence. There were no grade 4 toxicities. One grade 3 acute toxicity (sensory neuropathy) was recorded. The only 2 grade 3 late toxicities recorded, osteoradionecrosis and intranasal carotid blowout, occurred in a single patient. <h3>Conclusion</h3> We report favorable feasibility, local tumor control, survival, and toxicity following high-dose proton therapy for chordomas and chondrosarcomas.

Proton Beam Therapy for Pancreas Cancer: PTCOG Consensus Recommendations for Simulation, Treatment Planning and Treatment Delivery

<h3>Purpose/Objective(s)</h3> The proximity of gastrointestinal (GI) luminal organs-at-risk (OAR) poses a challenge to radiotherapy (RT) for pancreas cancer (PC). Proton beam therapy (PBT) may reduce toxicities compared to photon therapy by avoiding radiation exposure to large volumes of the abdomen while enabling safe dose escalation. The purpose of this study is to create recommendations for the safe treatment of PC with PBT. <h3>Materials/Methods</h3> The Particle Therapy Co-Operative Group (PTCOG) Gastrointestinal Subcommittee consisting of radiation oncologists and medical physicists with extensive clinical experience using PBT for GI cancers developed expert consensus recommendations for PC describing simulation, treatment planning, and treatment delivery through their collective experience and systematic review of the literature. <h3>Results</h3> The following general recommendations were established: <i>Simulation</i>: Indexed immobilization is recommended to reduce patient setup variability. Patients should be supine with arms above the head. Additional imaging such as PET/CT and/or MRI should be considered for target delineation. Contrast CT is recommended but should be performed subsequent to the planning CT at simulation to avoid the need to override Hounsfield Units. Dual-energy CT should be used, if available, to reduce CT-related proton range uncertainties. Motion management strategies are imperative, including 4DCT for motion accounting and breath-hold, or other techniques for motion mitigation. Patients should also have an empty stomach. <i>Treatment planning</i>: Beam angle selection is critical. Posterior and lateral beam angles are preferred to minimize the dosimetric impact of variable anatomy such as bowel. Robust optimization should be used for pencil beam scanning (PBS) techniques. When treating with PBS, single-field optimization (SFO) is often preferrable to increase robustness. If OAR constraints cannot be met with SFO, then multi-field optimization may be used. Higher linear energy transfer (LET) at the end of range should be considered in the context of sparing distal OARs. Increased beam angle separation should be used to reduce skin dose and mitigate the impact of higher LET. <i>Treatment delivery</i>: Volumetric image guidance, where available, should be used daily. Verification CT scans should be acquired <i>ad-hoc</i> as deemed necessary, or at least every other week, to assess the dosimetric impact of changes in anatomy, such as weight changes and variation in bowel gas and gastric filling. Adaptive re-planning should be performed as required. <h3>Conclusion</h3> The PTCOG Gastrointestinal Subcommittee has developed PBT expert consensus recommendations for PC. These recommendations enable PBT facilities to develop protocols for safe dose escalation studies.

Comprehensive Radiotherapy for Pediatric Ewing Sarcoma: Outcomes of a Prospective Proton Study

<h3>Purpose/Objective(s)</h3> Patients with Ewing Sarcoma (EWS) are treated with multimodal therapy, with radiation therapy (RT) as an option for local control. We report on the efficacy after proton radiation therapy (PRT) for localized and metastatic EWS. <h3>Materials/Methods</h3> Fifty children with EWS (39 localized, 11 metastatic) treated between 2007 and 2020 were enrolled on a prospective IRB-approved protocol for pediatric patients undergoing PRT. Median age at time of PRT was 11.5 years (range 0.9-19.6 years); 62% were male. Median tumor size was 6.4cm (range 2.5-21cm). All patients received induction chemotherapy prior to PRT; 38 patients had definitive PRT and 12 had surgery followed by PRT. PRT was delivered by passive scatter (74%), pencil-beam scanning (12%) or mixed technique (14%). Treated sites included the spine (40%), pelvis/sacrum (26%), skull (18%), extraosseous (10%), and axial-skeleton (6%). Median radiation dose was 54Gy-RBE (range 36.9-55.8Gy-RBE). All patients with metastatic disease (n=11) received consolidative RT to metastatic sites (5 at the time of local control [LC], 6 after completion of chemotherapy). Long-term follow-up data was available for 41 patients which comprise the subjects included in this report. Local failures were classified as in-field (>80% of relapse volume within the 95% isodose line [IDL]), marginal (>20% to ≤80% within the 95% IDL), or out-of-field (≤20% within the 95% IDL). Median follow-up time was 47 months after PRT. <h3>Results</h3> The 4-year LC, progression-free survival (PFS), and overall survival (OS) rates were 83.2%, 71.4%, and 86.3%, respectively. All local failures (n=6) were in-field failures. Tumor size ≥8cm predicted both inferior 4-year LC and PFS (69% vs 95%, p=0.04; 55% vs 86%, p=0.03, respectively). The 4-year PFS and OS rates were not statistically different in patients with localized versus metastatic disease (72% vs 67%, p=0.70; 89% vs 78%, p=0.38, respectively). Long-term toxicity included a grade 3 esophageal stricture in 1 patient. <h3>Conclusion</h3> We report one of the largest series of pediatric patients with EWS treated with PRT. LC was comparable to that of historical patients who received photon-RT and there were no marginal failures. Larger initial tumor size predicted increased risk of local failure and disease progression, which supports current efforts to dose-escalate treatment of tumors ≥8cm. Finally, patients with metastatic disease received radiation therapy to all metastatic sites and had survival outcomes comparable to those of patients with localized disease, suggesting a benefit to using RT for consolidation in metastatic EWS.

Out-of-Field Doses Produced by a Proton Scanning Beam Inside Pediatric Anthropomorphic Phantoms and Their Comparison With Different Photon Modalities.

Since 2010, EURADOS Working Group 9 (Radiation Dosimetry in Radiotherapy) has been involved in the investigation of secondary and scattered radiation doses in X-ray and proton therapy, especially in the case of pediatric patients. The main goal of this paper is to analyze and compare out-of-field neutron and non-neutron organ doses inside 5- and 10-year-old pediatric anthropomorphic phantoms for the treatment of a 5-cm-diameter brain tumor. Proton irradiations were carried out at the Cyclotron Centre Bronowice in IFJ PAN Krakow Poland using a pencil beam scanning technique (PBS) at a gantry with a dedicated scanning nozzle (IBA Proton Therapy System, Proteus 235). Thermoluminescent and radiophotoluminescent dosimeters were used for non-neutron dose measurements while secondary neutrons were measured with track-etched detectors. Out-of-field doses measured using intensity-modulated proton therapy (IMPT) were compared with previous measurements performed within a WG9 for three different photon radiotherapy techniques: 1) intensity-modulated radiation therapy (IMRT), 2) three-dimensional conformal radiation therapy (3D CDRT) performed on a Varian Clinac 2300 linear accelerator (LINAC) in the Centre of Oncology, Krakow, Poland, and 3) Gamma Knife surgery performed on the Leksell Gamma Knife (GK) at the University Hospital Centre Zagreb, Croatia. Phantoms and detectors used in experiments as well as the target location were the same for both photon and proton modalities. The total organ dose equivalent expressed as the sum of neutron and non-neutron components in IMPT was found to be significantly lower (two to three orders of magnitude) in comparison with the different photon radiotherapy techniques for the same delivered tumor dose. For IMPT, neutron doses are lower than non-neutron doses close to the target but become larger than non-neutron doses further away from the target. Results of WG9 studies have provided out-of-field dose levels required for an extensive set of radiotherapy techniques, including proton therapy, and involving a complete description of organ doses of pediatric patients. Such studies are needed for validating mathematical models and Monte Carlo simulation tools for out-of-field dosimetry which is essential for dedicated epidemiological studies which evaluate the risk of second cancers and other late effects for pediatric patients treated with radiotherapy.