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.

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.

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 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.

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.

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.

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.

In vivo dosimetry in pelvic brachytherapy.

ADVANCES IN KNOWLEDGE: This paper describes the potential role for in vivo dosimetry in the reduction of uncertainties in pelvic brachytherapy, the pertinent factors for consideration in clinical practice, and the future potential for in vivo dosimetry in the personalisation of brachytherapy.

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.

3D-printed patient-specific pelvis phantom for dosimetry measurements for prostate stereotactic radiotherapy with dominant intraprostatic lesion boost.

AIM: Developing and assessing the feasibility of using a three-dimensional (3D) printed patient-specific anthropomorphic pelvis phantom for dose calculation and verification for stereotactic ablative radiation therapy (SABR) with dose escalation to the dominant intraprostatic lesions. MATERIAL AND METHODS: A 3D-printed pelvis phantom, including bone-mimicking material, was fabricated based on the computed tomography (CT) images of a prostate cancer patient. To compare the extent to which patient and phantom body and bones overlapped, the similarity Dice coefficient was calculated. Modular cylindrical inserts were created to encapsulate radiochromic films and ionization chamber for absolute dosimetry measurements at the location of prostate and at the boost region. Gamma analysis evaluation with 2%/2mm criteria was performed to compare treatment planning system calculations and measured dose when delivering a 10 flattening filter free (FFF) SABR plan and a 10FFF boost SABR plan. RESULTS: Dice coefficients of 0.98 and 0.91 were measured for body and bones, respectively, demonstrating agreement between patient and phantom outlines. For the boost plans the gamma analysis yielded 97.0% of pixels passing 2%/2mm criteria and these results were supported by the chamber average dose difference of 0.47 ± 0.03%. These results were further improved when overriding the bone relative electron density: 97.3% for the 2%/2mm gamma analysis, and 0.05 ± 0.03% for the ionization chamber average dose difference. CONCLUSIONS: The modular patient-specific 3D-printed pelvis phantom has proven to be a highly attractive and versatile tool to validate prostate SABR boost plans using multiple detectors.

Toxicity and Efficacy of Concurrent Androgen Deprivation Therapy, Pelvic Radiotherapy, and Radium-223 in Patients with De Novo Metastatic Hormone-Sensitive Prostate Cancer.

PURPOSE: Radium-223 is an alpha-emitting radionuclide associated with overall survival (OS) improvement in metastatic castration-resistant prostate cancer (mCRPC). External beam radiotherapy (EBRT) to prostate extends OS in men with metastatic hormone-sensitive prostate cancer (mHSPC) limited to less than 4 metastases. We hypothesized that combination radium-223 + pelvic EBRT could safely deliver maximal radiotherapy doses to primary and metastatic prostate cancer and may improve disease control. PATIENTS AND METHODS: Thirty patients with de novo bone metastatic mHSPC who had commenced androgen deprivation therapy (ADT) and docetaxel were recruited to this single-arm, open-label, prospective clinical trial: Neo-adjuvant Androgen Deprivation Therapy, Pelvic Radiotherapy and RADium-223 (ADRRAD; for new presentation T1-4 N0-1 M1B adenocarcinoma of prostate). Study treatments were: ADT, 6 cycles of radium-223 q28 days, conventionally fractionated prostate radiotherapy (74 Gy) and simultaneous integrated boost to pelvic lymph nodes (60 Gy). RESULTS: No grade 4/5 toxicity was observed. Three patients experienced grade 3 leukopenia, and 1 each experienced grade 3 neutropenia and thrombocytopenia; all were asymptomatic. One patient each experienced grade 3 dysuria and grade 3 urinary infection. No grade 3 gastrointestinal (GI) toxicity was observed. On treatment completion, there was a signal of efficacy; 24 (80%) patients had whole-body MRI evidence of tumor response or stability. Twenty-seven (90%) patients showed a reduction in alkaline phosphatase (ALP) compared with pretreatment levels. Median progression-free survival was 20.5 months. CONCLUSIONS: This is the first trial of combination ADT, radium-223, and EBRT to pelvis, post docetaxel. The combination was safe, with an efficacy signal. Multicenter randomized controlled trials (RCT) are warranted.

A review of dose calculation approaches with cone beam CT in photon and proton therapy.

BACKGROUND AND PURPOSE: The use of cone beam computed tomography (CBCT) for performing dose calculations in radiation therapy has been widely investigated as it could provide a quantitative analysis of the dosimetric impact of changes in patients during the treatment. The aim of this review was to classify different techniques adopted to perform CBCT dose calculation and to report their dosimetric accuracy with respect to the metrics used. METHODS AND MATERIALS: A literature search was carried out in PubMed and ScienceDirect databases, based upon the following keywords: "cone beam computed tomography", "CBCT", "cone beam CT", "dose calculation", "accuracy". Sixty-nine peer-reviewed relevant articles were included in this review: thirty-one patient studies, fifteen phantom studies and twenty-three patient & phantom studies. Most studies were found to have focused on head and neck, lung and prostate cancers. RESULTS: The techniques adopted to perform CBCT dose calculation have been grouped in six categories labelled as (1) pCT calibration, (2) CBCT calibration, (3) HU override, (4) Deformable image registration, (5) Dose deformation, and (6) Combined techniques. Differences between CBCT dose and reference dose were reported both for target volumes and OARs. CONCLUSIONS: A comparison among the available techniques for CBCT dose calculations is challenging as many variables are involved. Therefore, a set of reporting standards is recommended to enable meaningful comparisons among different studies. The accuracy of the results was strongly dependent on the image quality, regardless of the methods used, highlighting the need for dose validation and quality assurance standards.

Fiducial markers visibility and artefacts in prostate cancer radiotherapy multi-modality imaging.

BACKGROUND: In this study, a novel pelvic phantom was developed and used to assess the visibility and presence of artefacts from different types of commercial fiducial markers (FMs) on multi-modality imaging relevant to prostate cancer. METHODS AND MATERIALS: The phantom was designed with 3D printed hollow cubes in the centre. These cubes were filled with gel to mimic the prostate gland and two parallel PVC rods were used to mimic bones in the pelvic region. Each cube was filled with gelatine and three unique FMs were positioned with a clinically-relevant spatial distribution. The FMs investigated were; Gold Marker (GM) CIVCO, GM RiverPoint, GM Gold Anchor (GA) line and ball shape, and polymer marker (PM) from CIVCO. The phantom was scanned using several imaging modalities typically used to image prostate cancer patients; MRI, CT, CBCT, planar kV-pair, ExacTrac, 6MV, 2.5MV and integrated EPID imaging. The visibility of the markers and any observed artefacts in the phantom were compared to in-vivo scans of prostate cancer patients with FMs. RESULTS: All GMs were visible in volumetric scans, however, they also had the most visible artefacts on CT and CBCT scans, with the magnitude of artefacts increasing with FM size. PM FMs had the least visible artefacts in volumetric scans but they were not visible on portal images and had poor visibility on lateral kV images. The smallest diameter GMs (GA) were the most difficult GMs to identify on lateral kV images. CONCLUSION: The choice between different FMs is also dependent on the adopted IGRT strategy. PM was found to be superior to investigated gold markers in the most commonly used modalities in the management of prostate cancer; CT, CBCT and MRI imaging.

Computed Tomography-based Radiomics for Risk Stratification in Prostate Cancer.

PURPOSE: To explore the role of Computed tomography (CT)-based radiomics features in prostate cancer risk stratification. METHODS AND MATERIALS: The study population consisted of 506 patients with prostate cancer collected from a clinically annotated database. After applying exclusion criteria, 342 patients were included in the final analysis. CT-based radiomics features were extracted from planning CT scans for prostate gland-only structure, and machine learning was used to train models for Gleason score (GS) and risk group (RG) classifications. Repeated cross-validation was used. The discriminatory performance of the developed models was assessed using receiver operating characteristic area under the curve (AUC) analysis. RESULTS: Classifiers using CT-based radiomics features distinguished between GS ≤ 6 versus GS ≥ 7 with AUC = 0.90 and GS 7(3 + 4) versus GS 7(4 + 3) with AUC = 0.98. Developed classifiers also showed excellent performance in distinguishing low versus high RG (AUC = 0.96) and low versus intermediate RG (AUC = 1.00), but poorer performance was observed for GS 7 versus GS > 7 (AUC = 0.69). An overall modest performance was observed for validation on holdout data sets with the highest AUC of 0.75 for classifiers of low versus high RG and an AUC of 0.70 for GS 7 versus GS > 7. CONCLUSIONS: Our results show that radiomics features from routinely acquired planning CT scans could provide insights into prostate cancer aggressiveness in a noninvasive manner. Assessing models on training data sets, the classifiers were especially accurate in discerning high-risk from low-risk patients and in classifying GS 7 versus GS > 7 and GS 7(3 + 4) versus G7(4 + 3); however, classifiers were less adept at distinguishing high RG versus intermediate RG. External validation and prospective studies are warranted to verify the presented findings. These findings could potentially guide targeted radiation therapy strategies in radical intent radiation therapy for prostate cancer.

An evaluation of techniques for dose calculation on cone beam computed tomography.

OBJECTIVE:: To assess the accuracy and efficiency of four different techniques, thus determining the optimum method for recalculating dose on cone beam CT (CBCT) images acquired during radiotherapy treatments. METHODS:: Four established techniques were investigated and their accuracy assessed via dose calculations: (1) applying a standard planning CT (pCT) calibration curve, (2) applying a CBCT site-specific calibration curve, (3) performing a density override and (4) using deformable registration. Each technique was applied to 15 patients receiving volumetric modulated arc therapy to one of three treatment sites, head and neck, lung and prostate. Differences between pCT and CBCT recalculations were determined with dose volume histogram metrics and 2.0%/0.1 mm gamma analysis using the pCT dose distribution as a reference. RESULTS:: Dose volume histogram analysis indicated that all techniques yielded differences from expected results between 0.0 and 2.3% for both target volumes and organs at risk. With volumetric gamma analysis, the dose recalculation on deformed images yielded the highest pass-rates. The median pass-rate ranges at 50% threshold were 99.6-99.9%, 94.6-96.0%, and 94.8.0-96.0% for prostate, head and neck and lung patients, respectively. CONCLUSION:: Deformable registration, HU override and site-specific calibration curves were all identified as dosimetrically accurate and efficient methods for dose calculation on CBCT images. ADVANCES IN KNOWLEDGE:: With the increasing adoption of CBCT, this study provides clinical radiotherapy departments with invaluable information regarding the comparison of dose reconstruction methods, enabling a more accurate representation of a patient's treatment. It can also integrate studies in which CBCT is used in image-guided radiation therapy and for adaptive radiotherapy planning processes.

Preclinical Evaluation of Dose-Volume Effects and Lung Toxicity Occurring In and Out-of-Field.

PURPOSE: The aim of this study was to define the dose and dose-volume relationship of radiation-induced pulmonary toxicities occurring in and out-of-field in mouse models of early inflammatory and late fibrotic response. MATERIALS AND METHODS: Early radiation-induced inflammation and fibrosis were investigated in C3H/NeJ and C57BL/6J mice, respectively. Animals were irradiated with 20 Gy delivered to the upper region of the right lung as a single fraction or as 3 consecutive fractions using the Small Animal Radiation Research Platform (Xstrahl Inc, Camberley, UK). Cone beam computed tomography was performed for image guidance before irradiation and to monitor late toxicity. Histologic sections were examined for neutrophil and macrophage infiltration as markers of early inflammatory response and type I collagen staining as a marker of late-occurring fibrosis. Correlation was evaluated with the dose-volume histogram parameters calculated for individual mice and changes in the observed cone beam computed tomography values. RESULTS: Mean lung dose and the volume receiving over 10 Gy (V10) showed significant correlation with late responses for single and fractionated exposures in directly targeted volumes. Responses observed outside the target volume were attributed to nontargeted effects and showed no dependence on either mean lung dose or V10. CONCLUSIONS: Quantitative assessment of normal tissue response closely correlates early and late pulmonary response with clinical parameters, demonstrating this approach as a potential tool to facilitate clinical translation of preclinical studies. Out-of-field effects were observed but did not correlate with dosimetric parameters, suggesting that nontargeted effects may have a role in driving toxicities outside the treatment field.

Efficacy of a rectal spacer with prostate SABR-first UK experience.

OBJECTIVE: This study assessed the use of implanted hydrogel rectal spacers for stereotactic ablative radiotherapy-volumetric modulated arc therapy (SABR-VMAT) patients, investigating practicality, dosimetric impact, normal tissue complication probability (NTCP) and early toxicity. METHODS: Data from the first 6 patients treated within a prostate SABR and rectal spacer trial were examined to determine spacer insertion tolerability, resultant changes in treatment planning and dosimetry and early toxicity effects. CT scans acquired prior to spacer insertion were used to generate SABR plans which were compared to post-insertion plans. Plans were evaluated for target coverage, conformity, and organs at risk doses with NTCPs also determined from resultant dose fluences. Early toxicity data were also collected. RESULTS: All patients had successful spacer insertion under local anaesthetic with maximal Grade 1 toxicity. All plans were highly conformal, with no significant differences in clinical target volume dose coverage between pre- and post-spacer plans. Substantial improvements in rectal dose metrics were observed in post-spacer plans, e.g. rectal volume receiving 36 Gy reduced by ≥42% for all patients. Median NTCP for Grade 2 + rectal bleeding significantly decreased from 4.9 to 0.8% with the use of a rectal spacer (p = 0.031). To date, two episodes of acute Grade 1 proctitis have been reported following treatment. CONCLUSION: The spacer resulted in clinically and statistically significant reduction in rectal doses for all patients. Advances in knowledge: This is one of the first studies to investigate the efficacy of a hydrogel spacer in prostate SABR treatments. Observed dose sparing of the rectum is predicted to result in meaningful clinical benefit.

Small field dosimetry for the small animal radiotherapy research platform (SARRP).

BACKGROUND: Preclinical radiation biology has become increasingly sophisticated due to the implementation of advanced small animal image guided radiation platforms into laboratory investigation. These small animal radiotherapy devices enable state-of-the-art image guided therapy (IGRT) research to be performed by combining high-resolution cone beam computed tomography (CBCT) imaging with an isocentric irradiation system. Such platforms are capable of replicating modern clinical systems similar to those that integrate a linear accelerator with on-board CBCT image guidance. METHODS: In this study, we present a dosimetric evaluation of the small animal radiotherapy research platform (SARRP, Xstrahl Inc.) focusing on small field dosimetry. Physical dosimetry was assessed using ion chamber for calibration and radiochromic film, investigating the impact of beam focus size on the dose rate output as well as beam characteristics (beam shape and penumbra). Two film analysis tools) have been used to assess the dose output using the 0.5 mm diameter aperture. RESULTS: Good agreement (between 1.7-3%) was found between the measured physical doses and the data provided by Xstrahl for all apertures used. Furthermore, all small field dosimetry data are in good agreement for both film reading methods and with our Monte Carlo simulations for both focal spot sizes. Furthermore, the small focal spot has been shown to produce a more homogenous beam with more stable penumbra over time. CONCLUSIONS: FilmQA Pro is a suitable tool for small field dosimetry, with a sufficiently small sampling area (0.1 mm) to ensure an accurate measurement. The electron beam focus should be chosen with care as this can potentially impact on beam stability and reproducibility.

The Impact of Hypoxia on Out-of-Field Cell Survival after Exposure to Modulated Radiation Fields.

Advanced radiotherapy techniques such as intensity modulated radiation therapy achieve highly conformal dose distributions within target tumor volumes through the sequential delivery of multiple spatially and temporally modulated radiation fields and have been shown to influence radiobiological response. The goals of this study were to determine the effect of hypoxia on the cell survival responses of different cell models (H460, DU145, A549, MDA231 and FADU) to modulated fields and to characterize the time dependency of signaling under oxic conditions, following reoxygenation and after prolonged hypoxia. Hypoxia was induced by incubating cells at 95% nitrogen and 5% carbon dioxide for 4 h prior to irradiation. The out-of-field response in MDA231 cells was oxygen dependent and therefore selected for co-culture studies to determine the signaling kinetics at different time intervals after irradiation under oxic and hypoxic conditions. Under both oxic and hypoxic conditions, significant increases in cell survival were observed in-field with significant decreases in survival observed out-of-field (P < 0.05), which were dependent on intercellular communication. The in-field response of MDA231 cells showed no significant time dependency up to 24 h postirradiation, while out-of-field survival decreased significantly during the first 6 h postirradiation (P < 0.05). While in-field responses were oxygen dependent, out-of-field effects were observed to be independent of oxygen, with similar or greater cell killing under hypoxic conditions. This study provides further understanding of intercellular signaling under hypoxic conditions and highlights the need for further refinement of established radiobiological models for future applications in advanced radiotherapies.