Correlation of phantom-based and log file patient-specific QA with complexity scores for VMAT.

The motivation for this study was to reduce physics workload relating to patient- specific quality assurance (QA). VMAT plan delivery accuracy was determined from analysis of pre- and on-treatment trajectory log files and phantom-based ionization chamber array measurements. The correlation in this combination of measurements for patient-specific QA was investigated. The relationship between delivery errors and plan complexity was investigated as a potential method to further reduce patient-specific QA workload. Thirty VMAT plans from three treatment sites - prostate only, prostate and pelvic node (PPN), and head and neck (H&N) - were retrospectively analyzed in this work. The 2D fluence delivery reconstructed from pretreatment and on-treatment trajectory log files was compared with the planned fluence using gamma analysis. Pretreatment dose delivery verification was also car- ried out using gamma analysis of ionization chamber array measurements compared with calculated doses. Pearson correlations were used to explore any relationship between trajectory log file (pretreatment and on-treatment) and ionization chamber array gamma results (pretreatment). Plan complexity was assessed using the MU/ arc and the modulation complexity score (MCS), with Pearson correlations used to examine any relationships between complexity metrics and plan delivery accu- racy. Trajectory log files were also used to further explore the accuracy of MLC and gantry positions. Pretreatment 1%/1 mm gamma passing rates for trajectory log file analysis were 99.1% (98.7%-99.2%), 99.3% (99.1%-99.5%), and 98.4% (97.3%-98.8%) (median (IQR)) for prostate, PPN, and H&N, respectively, and were significantly correlated to on-treatment trajectory log file gamma results (R = 0.989, p < 0.001). Pretreatment ionization chamber array (2%/2 mm) gamma results were also significantly correlated with on-treatment trajectory log file gamma results (R = 0.623, p < 0.001). Furthermore, all gamma results displayed a significant correlation with MCS (R > 0.57, p < 0.001), but not with MU/arc. Average MLC position and gantry angle errors were 0.001 ± 0.002 mm and 0.025° ± 0.008° over all treatment sites and were not found to affect delivery accuracy. However, vari- ability in MLC speed was found to be directly related to MLC position accuracy. The accuracy of VMAT plan delivery assessed using pretreatment trajectory log file fluence delivery and ionization chamber array measurements were strongly correlated with on-treatment trajectory log file fluence delivery. The strong corre- lation between trajectory log file and phantom-based gamma results demonstrates potential to reduce our current patient-specific QA. Additionally, insight into MLC and gantry position accuracy through trajectory log file analysis and the strong cor- relation between gamma analysis results and the MCS could also provide further methodologies to both optimize the VMAT planning and QA process. 

Performance evaluation of an inorganic optical fibre dosimeter for use in external beam radiotherapy with pulsed beams.

\emph{Objective}. Optical fibre dosimeters offer great promise for real-time in vivo dose measurement in radiation-based treatment modalities such as radiotherapy and brachytherapy. This is attributed to their many useful qualities such as high spatial resolution and sensitivity. However, there are several requirements that an optical fibre dosimeter must meet to be acceptable for dose measurement in a specified treatment modality. In this work, the dosimetric performance of a novel optical fibre dosimeter for use in external beam radiotherapy is presented. \emph{Approach}. The dosimeter was characterised for photon beam energies between 6-15 MV using a Varian TrueBeam Linac at dose rates between 100-2400 MU/min and assessed based on its repeatability, dose dependence, dose rate dependence, energy dependence and dose-per-pulse dependence. \emph{Main Results}. The results demonstrated excellent short-term repeatability of 0.3 $\%$, good linearity in response (R$^{2} >$ 0.9997), and minor dose rate dependence between 0.53-2.49 $\%$ for all beam qualities investigated. As the scintillator of the optical fibre dosimeter is non-water equivalent, Monte-Carlo-TOPAS simulations were used to calculate the absorbed dose energy dependence. A dose-per-pulse dependence was also investigated and compared with dosimetry measurements made with an ionisation chamber and simulated from the treatment planning system. An over-response of 20 $\%$ was found at the lowest investigated dose-per-pulse, and an under-response of 34 $\%$ was found at the highest investigated dose-per-pulse. This is believed to be due to an intrinsic energy dependence making this type of optical fibre dosimeter unsuitable for external beam radiotherapy dosimetry. \emph{Significance}. The optical fibre dosimeter evaluated in this work was primarily designed for high-dose-rate brachytherapy whereas this study includes the first measurements made in external beam radiotherapy and highlights the challenges of transferability of the dosimeter to a different radiation source.

Characterisation of quantitative imaging biomarkers for inflammatory and fibrotic radiation-induced lung injuries using preclinical radiomics.

BACKGROUND AND PURPOSE: Radiomics is a rapidly evolving area of research that uses medical images to develop prognostic and predictive imaging biomarkers. In this study, we aimed to identify radiomics features correlated with longitudinal biomarkers in preclinical models of acute inflammatory and late fibrotic phenotypes following irradiation. MATERIALS AND METHODS: Female C3H/HeN and C57BL6 mice were irradiated with 20 Gy targeting the upper lobe of the right lung under cone-beam computed tomography (CBCT) image-guidance. Blood samples and lung tissue were collected at baseline, weeks 1, 10 & 30 to assess changes in serum cytokines and histological biomarkers. The right lung was segmented on longitudinal CBCT scans using ITK-SNAP. Unfiltered and filtered (wavelet) radiomics features (n = 842) were extracted using PyRadiomics. Longitudinal changes were assessed by delta analysis and principal component analysis (PCA) was used to remove redundancy and identify clustering. Prediction of acute (week 1) and late responses (weeks 20 & 30) was performed through deep learning using the Random Forest Classifier (RFC) model. RESULTS: Radiomics features were identified that correlated with inflammatory and fibrotic phenotypes. Predictive features for fibrosis were detected from PCA at 10 weeks yet overt tissue density was not detectable until 30 weeks. RFC prediction models trained on 5 features were created for inflammation (AUC 0.88), early-detection of fibrosis (AUC 0.79) and established fibrosis (AUC 0.96). CONCLUSIONS: This study demonstrates the application of deep learning radiomics to establish predictive models of acute and late lung injury. This approach supports the wider application of radiomics as a non-invasive tool for detection of radiation-induced lung complications.

An objective measure of response on whole-body MRI in metastatic hormone sensitive prostate cancer treated with androgen deprivation therapy, external beam radiotherapy, and radium-223.

OBJECTIVES: The aim of this study was to generate an objective method to describe MRI data to assess response in the vertebrae of patients with metastatic hormone sensitive prostate cancer (mHSPC), treated with external beam radiation therapy and systemic therapy with Radium-223 and to correlate changes with clinical outcomes. METHODS: Three sets of whole-body MRI (WBMRI) images were utilized from 25 patients from the neo-adjuvant Androgen Deprivation Therapy pelvic Radiotherapy and RADium-223 (ADRRAD) clinical trial: MRI1 (up to 28 days before Radium-223), MRI2, and MRI3 (2 and 6 months post completion of Radium-223). Radiological response was assessed based on post baseline MRI images. Vertebrae were semi-automatically contoured in the sagittal T1-weighted (T1w) acquisitions, MRI intensity was measured, and spinal cord was used to normalize the measurements. The relationship between MRI intensity vs time to biochemical progression and radiology response was investigated. Survival curves were generated and splitting measures for survival and biochemical progression investigated. RESULTS: Using a splitting measure of 1.8, MRI1 was found to be a reliable quantitative indicator correlating with overall survival (P = 0.023) and biochemical progression (P = 0.014). MRI (3-1) and MRI (3-2) were found to be significant indicators for patients characterized by progressive/non-progressive disease (P = 0.021, P = 0.004) and biochemical progression within/after 12 months (P = 0.007, P = 0.001). CONCLUSIONS: We have identified a potentially useful objective measure of response on WBMRI of vertebrae containing bone metastases in mHSPC which correlates with survival/progression (prognostic) and radiology response (predictive). ADVANCES IN KNOWLEDGE: Measurements of T1w WBMRI normalized intensity may allow identifying potentially useful response biomarkers correlating with survival, radiological response and biochemical progression.

Validation of a Quality Metric Score to Assess the Placement of Hydrogel Rectal Spacer in Patients Treated With Prostate Stereotactic Radiation Therapy.

Purpose: To evaluate the quality of the interspace between the prostate and rectum and assess the effect on the dose to the rectum by measuring the spacer quality score (SQS) before and after implanting a hydrogel rectal spacer. Methods and Materials: Thirty patients with prostate cancer were treated with stereotactic ablative body radiation therapy as part of the SPORT clinical trial. Each patient had a 10 mL polyethylene glycol hydrogel spacer inserted transperineally. Computed tomography scans were acquired before and after spacer insertion, 10MV flattening filter free (FFF) stereotactic ablative body radiation therapy (SABR) treatment plans were generated using each image set. To calculate the SQS, the prostate-rectal interspace (PRI) was measured in the anterior-posterior orientation, parallel to the anatomic midline at the prostate base, apex, and midgland on the prespacer and postspacer computed tomography. Measurements were taken in 3 transverse positions between the prostate and the rectum, and PRI scores of 0, 1, and 2 were assigned if the interspace between prostate and rectum was <0.3, 0.3 to 0.9, or ≥1 cm, respectively. The overall SQS was the lowest of the PRI scores. Differences between prespacer and postspacer PRIs and SQS were investigated by performing Fisher's exact test and differences between doses to the rectum were investigated by performing the paired samples Wilcoxon rank-sum test and Student t test. Results: Statistically significant differences between prespacer versus postspacer patients were found when grouping patients according to their overall SQS. The PRI summary score did not reach statistical significance between prespacer and postspacer at the base but was significantly higher for the prostate midline and apex. Statistically significant differences in some rectum dose-volume metrics were found when grouping patients according to their PRIs and SQS. Conclusions: SQS before and after the spacer insertion was evaluated and was found to be correlated with pre- and postspacer rectal dosimetry. Sources of improvement of the SQS scoring metric and limitations are discussed.

Pulmonary vein dose and risk of atrial fibrillation in patients with non-small cell lung cancer following definitive radiotherapy: An NI-HEART analysis.

BACKGROUND AND PURPOSE: Symptomatic arrhythmia is common following radiotherapy for non-small cell lung cancer (NSCLC), frequently resulting in morbidity and hospitalization. Modern treatment planning technology theoretically allows sparing of cardiac substructures. Atrial fibrillation (AF) comprises the majority of post-radiotherapy arrhythmias, but efforts to prevent this cardiotoxicity have been limited as the causative cardiac substructure is not known. In this study we investigated if incidental radiation dose to the pulmonary veins (PVs) is associated with AF. MATERIAL AND METHODS: A single-centre study of patients completing contemporary (chemo)radiation for NSCLC, with modern planning techniques. Oncology, cardiology and death records were examined, and AF events were verified by a cardiologist. Cardiac substructures were contoured on planning scans for retrospective dose analysis. RESULTS: In 420 eligible patients with NSCLC treated with intensity-modulated (70%) or 3D-conformal (30%) radiotherapy with a median OS of 21.8 months (IQR 10.8-35.1), there were 26 cases of new AF (6%). All cases were grade 3 except two cases of grade 4. Dose metrics for both the left (V55) and right (V10) PVs were associated with the incidence of new AF. Metrics remained statistically significant after accounting for the competing risk of death and cardiovascular covariables for both the left (HR 1.02, 95%CI 1.00-1.03, p = 0.005) and right (HR 1.01 (95%CI 1.00-1.02, p = 0.033) PVs. CONCLUSION: Radiation dose to the PVs during treatment of NSCLC was associated with the onset of AF. Actively sparing the PVs during treatment planning could reduce the incidence of AF during follow-up, and screening for AF may be warranted for select cases.

Baseline Cardiac Parameters as Biomarkers of Radiation Cardiotoxicity in Lung Cancer: An NI-HEART Analysis.

Background: Radiation-induced cardiotoxicity poses a significant challenge in lung cancer management because of the close anatomical proximity of the heart to the lungs, compounded by a high prevalence of cardiovascular risk factors among patients. Objectives: The aim of this study was to assess the predictive value of routinely available clinical and imaging-based cardiac parameters in identifying "high risk" patients for major adverse cardiac events (MACE) and mortality following radiation therapy (RT). Methods: The medical records of patients who underwent definitive RT for non-small cell lung cancer using modern planning techniques at a single center between 2015 and 2020 were retrospectively reviewed. Cardiac events were verified by cardiologists, and mortality data were confirmed with the national registry. Cardiac substructures were autosegmented on RT planning scans for retrospective structure and dose analysis, and their correlation with clinical factors was examined. Fine-Gray models were used to analyze relationships while considering the competing risk for death. Results: Among 478 patients included in the study, 77 (16%) developed 88 MACE, with a median time to event of 16.3 months. A higher burden of pre-existing cardiac diseases was associated with an increased cumulative incidence of MACE (55% [95% CI: 12%-20%] vs 16% [95% CI: 35%-71%]; P < 0.001). Left atrial and left ventricular enlargement on RT planning scans was associated with cumulative incidence of atrial arrhythmia (14% [95% CI: 9%-20%] vs 4% [95% CI: 2%-8%]; P = 0.001) and heart failure (13% [95% CI: 8%-18%] vs 6% [95% CI: 3%-10%]; P = 0.007) at 5 years, respectively. However, myocardial infarction was not associated with the presence of coronary calcium (4.2% [95% CI: 2%-7%] vs 0% [95% CI: 0%-0%]; P = 0.094). No cardiac imaging metrics were found to be both clinically and statistically associated with survival. Conclusions: The present findings suggest that cardiac history and RT planning scan parameters may offer potential utility in prospectively evaluating cardiotoxicity risk following RT for patients with lung cancer.

Assessment of Variabilities in Lung-Contouring Methods on CBCT Preclinical Radiomics Outputs.

Radiomics image analysis has the potential to uncover disease characteristics for the development of predictive signatures and personalised radiotherapy treatment. Inter-observer and inter-software delineation variabilities are known to have downstream effects on radiomics features, reducing the reliability of the analysis. The purpose of this study was to investigate the impact of these variabilities on radiomics outputs from preclinical cone-beam computed tomography (CBCT) scans. Inter-observer variabilities were assessed using manual and semi-automated contours of mouse lungs (n = 16). Inter-software variabilities were determined between two tools (3D Slicer and ITK-SNAP). The contours were compared using Dice similarity coefficient (DSC) scores and the 95th percentile of the Hausdorff distance (HD95p) metrics. The good reliability of the radiomics outputs was defined using intraclass correlation coefficients (ICC) and their 95% confidence intervals. The median DSC scores were high (0.82-0.94), and the HD95p metrics were within the submillimetre range for all comparisons. the shape and NGTDM features were impacted the most. Manual contours had the most reliable features (73%), followed by semi-automated (66%) and inter-software (51%) variabilities. From a total of 842 features, 314 robust features overlapped across all contouring methodologies. In addition, our results have a 70% overlap with features identified from clinical inter-observer studies.

Evaluation of a novel phantom for the quality assurance of a six-degree-of-freedom couch 3D-printed at multiple centres.

This study aimed to validate a bespoke 3D-printed phantom for use in quality assurance (QA) of a 6 degrees-of-freedom (6DoF) treatment couch. A novel phantom design comprising a main body with internal cube structures, was fabricated at five centres using Polylactic Acid (PLA) material, with an additional phantom produced incorporating a PLA-stone hybrid material. Correctional setup shifts were determined using image registration by 3D-3D matching of high HU cube structures between obtained cone-beam computer tomography (CBCT) images to reference CTs, containing cubes with fabricated rotational offsets of 3.5°, 1.5° and -2.5° in rotation, pitch, and roll, respectively. Average rotational setup shifts were obtained for each phantom. The reproducibility of 3D-printing was probed by comparing the internal cube size as well as Hounsfield Units between each of the uniquely produced phantoms. For the five PLA phantoms, the average rot, pitch and roll correctional differences from the fabricated offsets were -0.3 ± 0.2°, -0.2 ± 0.5° and 0.2 ± 0.3° respectively, and for the PLA hybrid these differences were -0.09 ± 0.14°, 0.30 ± 0.00° and 0.03 ± 0.10°. There was found to be no statistically significant difference in average cube size between the five PLA printed phantoms, with the significant difference (P < 0.05) in HU of one phantom compared to the others attributed to setup choice and material density. This work demonstrated the capability producing a novel 3D-printed 6DoF couch QA phantom design, at multiple centres, with each unique model capable of sub-degree couch correction.

Patient specific evaluation of breathing motion induced interplay effects.

PURPOSE: In lung SABR, interplay between target motion and dynamically changing beam parameters can affect the target coverage. To identify the potential need for motion-management techniques, a comprehensive methodology for pre-treatment estimation of interplay effects has been implemented. METHODS: In conjunction with an alpha-version of VeriSoft and OCTAVIUS 4D (PTW-Freiburg, Germany), a method is presented to calculate a virtual, motion-simulated 3D dose distribution based on measurement data acquired in a stationary phantom and a subsequent correction with time-dependent target-motion patterns. In-house software has been developed to create user-defined motion patterns based on either simplistic or real patient-breathing patterns including the definition of the exact beam starting phase. The approach was validated by programmed couch and phantom motion during beam delivery. Five different breathing traces with extremely altered beam-on phases (0 % and 50 % respiratory phase) and a superior-inferior motion altitude of 25 mm were used to probe the influence of interplay effects for 14 lung SABR plans. Gamma analysis (2 %/2mm) was used for quantification. RESULTS: Validation measurements resulted in >98 % pass rates. Regarding the interplay effect evaluation, gamma pass rates of <92 % were observed for sinusoidal breathing patterns with <25 number of breaths per delivery time (NBs) and realistic patterns with <18 NBs. CONCLUSION: The potential influence of interplay effects on the target coverage is highly dependent on the patient's breathing behaviour. The presented moving-platform-free approach can be used for verification of ITV-based treatment plans to identify whether the clinical goals are achievable without explicit use of a respiratory management technique.

Development and optimisation of a preclinical cone beam computed tomography-based radiomics workflow for radiation oncology research.

Background and purpose: Radiomics features derived from medical images have the potential to act as imaging biomarkers to improve diagnosis and predict treatment response in oncology. However, the complex relationships between radiomics features and the biological characteristics of tumours are yet to be fully determined. In this study, we developed a preclinical cone beam computed tomography (CBCT) radiomics workflow with the aim to use in vivo models to further develop radiomics signatures. Materials and methods: CBCT scans of a mouse phantom were acquired using onboard imaging from a small animal radiotherapy research platform (SARRP, Xstrahl). The repeatability and reproducibility of radiomics outputs were compared across different imaging protocols, segmentation sizes, pre-processing parameters and materials. Robust features were identified and used to compare scans of two xenograft mouse tumour models (A549 and H460). Results: Changes to the radiomics workflow significantly impact feature robustness. Preclinical CBCT radiomics analysis is feasible with 119 stable features identified from scans imaged at 60 kV, 25 bin width and 0.26 mm slice thickness. Large variation in segmentation volumes reduced the number of reliable radiomics features for analysis. Standardization in imaging and analysis parameters is essential in preclinical radiomics analysis to improve accuracy of outputs, leading to more consistent and reproducible findings. Conclusions: We present the first optimised workflow for preclinical CBCT radiomics to identify imaging biomarkers. Preclinical radiomics has the potential to maximise the quantity of data captured in in vivo experiments and could provide key information supporting the wider application of radiomics.

Evaluation of tumour motion and internal/external correlation in lung SABR.

OBJECTIVE: This study aims to analyse lung tumour motion and to investigate the correlation between the internal tumour motion acquired from four-dimensional computed tomography (4DCT) and the motion of an external surrogate. METHODS: A data set of 363 4DCT images was analysed. Tumours were classified based on their anatomical lobes. The recorded gross tumour volume (GTV) information included the centroid GTV motion in the superior-inferior, anteroposterior and left-right directions, and in three-dimensions (3D). For the internal/external correlation, the RPM surrogate breathing signals of 260 patients were analysed via an in-house script. The external motion was correlated with the 3D centroid motion, and the maximum tumour motion via Spearman's correlation. The effect of tumour volume on the amount of motion was evaluated. RESULTS: The greatest 3D tumour amplitude was found for tumours located in the lower part of the lung, with a maximum of 26.7 mm. The Spearman's correlation of the internal 3D motion was weak in the upper (r = 0.21) and moderate in the middle (r = 0.51) and the lower (r = 0.52) lobes. There was no obvious difference in the correlation coefficients between the maximum tumour displacement and the centroid motion. No correlation was found between the tumour volume and the magnitude of motion. CONCLUSION: Our results suggest that tumour location can be a good predictor of its motion. However, tumour size is a poor predictor of the motion. ADVANCES IN KNOWLEDGE: This knowledge of the distribution of tumour motion throughout the thoracic regions will be valuable to research groups investigating the refinement of motion management strategies.

Association between statin therapy dose intensity and radiation cardiotoxicity in non-small cell lung cancer: Results from the NI-HEART study.

INTRODUCTION: Radiation cardiotoxicity is a dose-limiting toxicity and major survivorship issue for patients with non-small cell lung cancer (NSCLC) completing curative-intent radiotherapy, however patients' cardiovascular baseline is not routinely optimised prior to treatment. In this study we examined the impact of statin therapy on overall survival and post-radiotherapy cardiac events. METHODS: Patients treated between 2015-2020 at a regional center were identified. Clinical notes were interrogated for baseline patient, tumor and cardiac details, and both follow-up cancer control and cardiac events. Three cardiologists verified cardiac events. Radiotherapy planning scans were retrieved for application of validated deep learning-based autosegmentation. Pre-specified Cox regression analyses were generated with varying degrees of adjustment for overall survival. Fine and Gray regression for the risk of cardiac events, accounting for the competing risk of death and cardiac covariables was undertaken. RESULTS: Statin therapy was prescribed to 59% of the 478 included patients. The majority (88%) of patients not prescribed a statin had at least one indication for statin therapy according to cardiovascular guidelines. In total, 340 patients (71%) died and 79 patients (17%) experienced a cardiac event. High-intensity (HR 0.68, 95%CI 0.50-0.91, p = 0.012) and medium-intensity (HR 0.70, 95%CI 0.51-0.97, p = 0.033) statin therapy were associated with improved overall survival after adjustment for patient, cancer, treatment, response and cardiovascular clinical factors. There were no consistent differences in the rate or grade of cardiac events according to statin intensity. CONCLUSIONS: Statin therapy is associated with improved overall survival in patients receiving curative-intent radiotherapy for NSCLC, and there is evidence of a dose-response relationship. This study highlights the importance of a pre-treatment cardiovascular risk assessment in this cohort. Further studies are needed to examine if statin therapy is cardioprotective in patients undergoing treatment for NSCLC with considerable incidental cardiac radiation dose and a low baseline cardiac risk.

A Randomized Feasibility Trial of Stereotactic Prostate Radiation Therapy With or Without Elective Nodal Irradiation in High-Risk Localized Prostate Cancer (SPORT Trial).

PURPOSE: The aim of this study was to establish the feasibility of a randomized clinical trial comparing SABR with prostate-only (P-SABR) or with prostate plus pelvic lymph nodes (PPN-SABR) in patients with unfavorable intermediate- or high-risk localized prostate cancer and to explore potential toxicity biomarkers. METHODS AND MATERIALS: Thirty adult men with at least 1 of the following features were randomized 1:1 to P-SABR or PPN-SABR: clinical magnetic resonance imaging stage T3a N0 M0, Gleason score ≥7 (4+3), and prostate-specific antigen >20 ng/mL. P-SABR patients received 36.25 Gy/5 fractions/29 days, and PPN-SABR patients received 25 Gy/5 fractions to pelvic nodes, with the final cohort receiving a boost to the dominant intraprostatic lesion of 45 to 50 Gy. Phosphorylated gamma-H2AX (γH2AX) foci numbers, citrulline levels, and circulating lymphocyte counts were quantified. Acute toxicity information (Common Terminology Criteria for Adverse Events, version 4.03) was collected weekly at each treatment and at 6 weeks and 3 months. Physician-reported late Radiation Therapy Oncology Group (RTOG) toxicity was recorded from 90 days to 36 months postcompletion of SABR. Patient-reported quality of life (Expanded Prostate Cancer Index Composite and International Prostate Symptom Score) scores were recorded with each toxicity time point. RESULTS: The target recruitment was achieved, and treatment was successfully delivered in all patients. A total of 0% and 6.7% (P-SABR) and 6.7% and 20.0% (PPN-SABR) experienced acute grade ≥2 gastrointestinal (GI) and genitourinary (GU) toxicity, respectively. At 3 years, 6.7% and 6.7% (P-SABR) and 13.3% and 33.3% (PPN-SABR) had experienced late grade ≥2 GI and GU toxicity, respectively. One patient (PPN-SABR) had late grade 3 GU toxicity (cystitis and hematuria). No other grade ≥3 toxicity was observed. In addition, 33.3% and 60% (P-SABR) and 64.3% and 92.9% (PPN-SABR) experienced a minimally clinically important change in late Expanded Prostate Cancer Index Composite bowel and urinary summary scores, respectively. γH2AX foci numbers at 1 hour after the first fraction were significantly higher in the PPN-SABR arm compared with the P-SABR arm (P = .04). Patients with late grade ≥1 GI toxicity had significantly greater falls in circulating lymphocytes (12 weeks post-radiation therapy, P = .01) and a trend toward higher γH2AX foci numbers (P = .09) than patients with no late toxicity. Patients with late grade ≥1 bowel toxicity and late diarrhea experienced greater falls in citrulline levels (P = .05). CONCLUSIONS: A randomized trial comparing P-SABR with PPN-SABR is feasible with acceptable toxicity. Correlations of γH2AX foci, lymphocyte counts, and citrulline levels with irradiated volume and toxicity suggest potential as predictive biomarkers. This study has informed a multicenter, randomized, phase 3 clinical trial in the United Kingdom.

A pulmonary vein atlas for radiotherapy planning.

BACKGROUND AND PURPOSE: Cardiac arrhythmia is a recognised potential complication of thoracic radiotherapy, but the responsible cardiac substructures for arrhythmogenesis have not been identified. Arrhythmogenic tissue is commonly located in the pulmonary veins (PVs) of cardiology patients with arrhythmia, however these structures are not currently considered organs-at-risk during radiotherapy planning. A standardised approach to their delineation was developed and evaluated. MATERIALS AND METHODS: The gross and radiological anatomy relevant to atrial fibrillation was derived from cardiology and radiology literature by a multidisciplinary team. A region of interest and contouring instructions for radiotherapy computed tomography scans were iteratively developed and subsequently evaluated. Radiation oncologists (n = 5) and radiation technologists (n = 2) contoured the PVs on the four-dimensional planning datasets of five patients with locally advanced lung cancer treated with 1.8-2.75 Gy fractions. Contours were compared to reference contours agreed by the researchers using geometric and dosimetric parameters. RESULTS: The mean dose to the PVs was 35% prescription dose. Geometric and dosimetric similarity of the observer contours with reference contours was fair, with an overall mean Dice of 0.80 ± 0.02. The right superior PV (mean DSC 0.83 ± 0.02) had better overlap than the left (mean DSC 0.80 ± 0.03), but the inferior PVs were equivalent (mean DSC of 0.78). The mean difference in mean dose was 0.79 Gy ± 0.71 (1.46% ± 1.25). CONCLUSION: A PV atlas with multidisciplinary approval led to reproducible delineation for radiotherapy planning, supporting the utility of the atlas in future clinical radiotherapy cardiotoxicity research encompassing arrhythmia endpoints.

Murine models of radiation cardiotoxicity: A systematic review and recommendations for future studies.

BACKGROUND AND PURPOSE: The effects of radiation on the heart are dependent on dose, fractionation, overall treatment time, and pre-existing cardiovascular pathology. Murine models have played a central role in improving our understanding of the radiation response of the heart yet a wide range of exposure parameters have been used. We evaluated the study design of published murine cardiac irradiation experiments to assess gaps in the literature and to suggest guidance for the harmonisation of future study reporting. METHODS AND MATERIALS: A systematic review of mouse/rat studies published 1981-2021 that examined the effect of radiation on the heart was performed. The protocol was published on PROSPERO (CRD42021238921) and the findings were reported in accordance with the PRISMA guidance. Risk of bias was assessed using the SYRCLE checklist. RESULTS: 159 relevant full-text original articles were reviewed. The heart only was the target volume in 67% of the studies and simulation details were unavailable for 44% studies. Dosimetry methods were reported in 31% studies. The pulmonary effects of whole and partial heart irradiation were reported in 13% studies. Seventy-eight unique dose-fractionation schedules were evaluated. Large heterogeneity was observed in the endpoints measured, and the reporting standards were highly variable. CONCLUSIONS: Current murine models of radiation cardiotoxicity cover a wide range of irradiation configurations and latency periods. There is a lack of evidence describing clinically relevant dose-fractionations, circulating biomarkers and radioprotectants. Recommendations for the consistent reporting of methods and results of in vivo cardiac irradiation studies are made to increase their suitability for informing the design of clinical studies.

Simultaneous integrated boost (SIB) to dominant intra-prostatic lesions during extreme hypofractionation for prostate cancer: the impact of rectal spacers.

PURPOSE: Boosting dominant intra-prostatic lesions (DILs) has the potential to increase the therapeutic ratio in prostate cancer radiotherapy. In this study, employing 5-fraction stereotactic ablative radiotherapy (SABR) volumetric modulated arc therapy (VMAT) to deliver 40 Gy to the prostate clinical target volume (CTV) while boosting the DIL up to 50 Gy was evaluated for patients before and after rectal spacer insertion. MATERIALS AND METHODS: 24 Computed Tomography (CT) scans of 12 prostate cancer patients with unfavourable intermediate or high risk prostate cancer were employed in this study. At least two treatment plans were generated for each patient to compare pre- and post-spacer insertion plans. Plans were evaluated for target coverage, organs-at-risk doses, and the achievable boost dose level. RESULTS: The CTV coverage was significantly better in plans with a spacer, V40Gy 98.4% versus 97.0% (p = 0.012). Using spacers significantly reduced rectal dose in all 12 patients in this study. It was possible to boost DIL to 50 Gy to without violating dose constraints in 6 of 12 patients and to 47.5 Gy in 3 patients post-spacer insertion. For 3 patients (25%) it was not possible to boost DIL above 45 Gy even with a spacer in situ. Without a spacer, for 6 patient (50%) clinically acceptable plan were only achieved when the DIL dose was lowered to 45 Gy. In five of these 6 patients the dose limiting structure was the urethra (urethra planning risk volume V45Gy [cc] ≤ 0.1 cc constraint). CONCLUSIONS: Clinically acceptable plans for 5 fraction SABR, 40 Gy to the prostate CTV, with a SIB to DIL (45-50 Gy) were achieved. The boost dose achieved was DIL location dependent and primarily affected by DIL's proximity to the urethra. Compared to plans before spacer insertion, higher DIL dose were achieved with spacer in situ for 25% of the patients. Moreover, significant reduction in rectal dose and better target coverage were also achieved for all patients with spacers in situ.

Validation of an established deep learning auto-segmentation tool for cardiac substructures in 4D radiotherapy planning scans.

Background: Emerging data suggest that dose-sparing several key cardiac regions is prognostically beneficial in lung cancer radiotherapy. The cardiac substructures are challenging to contour due to their complex geometry, poor soft tissue definition on computed tomography (CT) and cardiorespiratory motion artefact. A neural network was previously trained to generate the cardiac substructures using three-dimensional radiotherapy planning CT scans (3D-CT). In this study, the performance of that tool on the average intensity projection from four-dimensional (4D) CT scans (4D-AVE), now commonly used in lung radiotherapy, was evaluated. Materials and Methods: The 4D-AVE of n=20 patients completing radiotherapy for lung cancer 2015-2020 underwent manual and automated cardiac substructure segmentation. Manual and automated substructures were compared geometrically and dosimetrically. Two senior clinicians also qualitatively assessed the auto-segmentation tool's output. Results: Geometric comparison of the automated and manual segmentations exhibited high levels of similarity across parameters, including volume difference (11.8% overall) and Dice similarity coefficient (0.85 overall), and were consistent with 3D-CT performance. Differences in mean (median 0.2 Gy, range -1.6-0.3 Gy) and maximum (median 0.4 Gy, range -2.2-0.9 Gy) doses to substructures were generally small. Nearly all structures (99.5 %) were deemed to be appropriate for clinical use without further editing. Conclusions: Cardiac substructure auto-segmentation using a deep learning-based tool trained on a 3D-CT dataset was feasible on the 4D-AVE scan, meaning this tool is suitable for use on 4D-CT radiotherapy planning scans. Application of this tool would increase the practicality of routine clinical cardiac substructure delineation, and enable further cardiac radiation effects research.

Dose estimation after a mixed field exposure: Radium-223 and intensity modulated radiotherapy.

INTRODUCTION: Radium-223 dichloride ([223Ra]RaCl2), a radiopharmaceutical that delivers α-particles to regions of bone metastatic disease, has been proven to improve overall survival of men with metastatic castration resistant prostate cancer (mCRPC). mCRPC patients enrolled on the ADRRAD clinical trial are treated with a mixed field exposure comprising radium-223 (223Ra) and intensity modulated radiotherapy (IMRT). While absorbed dose estimation is an important step in the characterisation of wider systemic radiation risks in nuclear medicine, uncertainties remain for novel radiopharmaceuticals such as 223Ra. METHODS: 24-Colour karyotyping was used to quantify the spectrum of chromosome aberrations in peripheral blood lymphocytes of ADRRAD patients at incremental times during their treatment. Dicentric equivalent frequencies were used in standard models for estimation of absorbed blood dose. To account for the mixed field nature of the treatment, existing models were used to determine the ratio of the component radiation types. Additionally, a new approach (M-FISHLET), based on the ratio of cells containing damage consistent with high-LET exposure (complex chromosomal exchanges) and low-LET exposure (simple exchanges), was used as a pseudo ratio for 223Ra:IMRT dose. RESULTS: Total IMRT estimated doses delivered to the blood after completion of mixed radiotherapy (after 37 IMRT fractions and two [223Ra]RaCl2 injections) were in the range of 1.167 ± 0.092 and 2.148 ± 0.096 Gy (dose range across all models applied). By the last treatment cycle analysed in this study (four [223Ra]RaCl2 injections), the total absorbed 223Ra dose to the blood was estimated to be between 0.024 ± 0.027 and 0.665 ± 0.080 Gy, depending on the model used. Differences between the models were observed, with the observed dose variance coming from inter-model as opposed to inter-patient differences. The M-FISHLET model potentially overestimates the 223Ra absorbed blood dose by accounting for further PBL exposure in the vicinity of metastatic sites. CONCLUSIONS: The models presented provide initial estimations of cumulative dose received during incremental IMRT fractions and [223Ra]RaCl2 injections, which will enable improved understanding of the doses received by individual patients. While the M-FISHLET method builds on a well-established technique for external exposures, further consideration is needed to evaluate this method and its use in assessing non-targeted exposure by 223Ra after its localization at bone metastatic sites.

Assessing software upgrades, plan properties and patient geometry using intensity modulated radiation therapy (IMRT) complexity metrics.

PURPOSE: The aim of this study is to compare the sensitivity of different metrics to detect differences in complexity of intensity modulated radiation therapy (IMRT) plans following upgrades, changes to planning parameters, and patient geometry. Correlations between complexity metrics are also assessed. METHOD: A program was developed to calculate a series of metrics used to describe the complexity of IMRT fields using monitor units (MUs) and multileaf collimator files: Modulation index (MI), modulation complexity score (MCS), and plan intensity map variation (PIMV). Each metric, including the MUs, was used to assess changes in beam complexity for six prostate patients, following upgrades in the inverse planning optimization software designed to incorporate direct aperture optimization (DAO). All beams were delivered to a 2D ionization chamber array and compared to those calculated using gamma analysis. Each complexity metric was then calculated for all beams, on a different set of six prostate IMRT patients, to assess differences between plans calculated using different minimum field sizes and different maximum segment numbers. Different geometries, including CShape, prostate, and head and neck phantoms, were also assessed using the metrics. Correlations between complexity metrics were calculated for 20 prostate IMRT patients. RESULTS: MU, MCS, MI, and PIMV could all detect reduced complexity following an upgrade to the optimization leaf sequencer, although only MI and MCS could detect a reduction in complexity when one-step optimization (DAO) was employed rather than two-step optimization. All metrics detected a reduction in complexity when the minimum field size was increased from 1 to 4 cm and all apart from PIMV detected reduced complexity when the number of segments was significantly reduced. All metrics apart from MI showed differences in complexity depending on the treatment site. Significant correlations exist between all metrics apart from MI and PIMV for prostate IMRT patients. Treatment deliverability appeared to be more correlated with MI and MCS than MU or PIMV. CONCLUSIONS: The application of complexity metrics in the IMRT treatment planning process has been demonstrated. Complexity of treatment plans can vary for different inverse planning software versions and can depend on planning parameters and the treatment site. MCS is most suitable for inclusion within the cost function to limit complexity in IMRT optimization due to its sensitivity to complexity changes and correlation to treatment deliverability.