The Image Biomarker Standardization Initiative: Standardized Convolutional Filters for Reproducible Radiomics and Enhanced Clinical Insights.

Filters are commonly used to enhance specific structures and patterns in images, such as vessels or peritumoral regions, to enable clinical insights beyond the visible image using radiomics. However, their lack of standardization restricts reproducibility and clinical translation of radiomics decision support tools. In this special report, teams of researchers who developed radiomics software participated in a three-phase study (September 2020 to December 2022) to establish a standardized set of filters. The first two phases focused on finding reference filtered images and reference feature values for commonly used convolutional filters: mean, Laplacian of Gaussian, Laws and Gabor kernels, separable and nonseparable wavelets (including decomposed forms), and Riesz transformations. In the first phase, 15 teams used digital phantoms to establish 33 reference filtered images of 36 filter configurations. In phase 2, 11 teams used a chest CT image to derive reference values for 323 of 396 features computed from filtered images using 22 filter and image processing configurations. Reference filtered images and feature values for Riesz transformations were not established. Reproducibility of standardized convolutional filters was validated on a public data set of multimodal imaging (CT, fluorodeoxyglucose PET, and T1-weighted MRI) in 51 patients with soft-tissue sarcoma. At validation, reproducibility of 486 features computed from filtered images using nine configurations × three imaging modalities was assessed using the lower bounds of 95% CIs of intraclass correlation coefficients. Out of 486 features, 458 were found to be reproducible across nine teams with lower bounds of 95% CIs of intraclass correlation coefficients greater than 0.75. In conclusion, eight filter types were standardized with reference filtered images and reference feature values for verifying and calibrating radiomics software packages. A web-based tool is available for compliance checking.

Preoperative MRI radiomic analysis for predicting local tumor progression in colorectal liver metastases before microwave ablation.

PURPOSE: Radiomics may aid in predicting prognosis in patients with colorectal liver metastases (CLM). Consistent data is available on CT, yet limited data is available on MRI. This study assesses the capability of MRI-derived radiomic features (RFs) to predict local tumor progression-free survival (LTPFS) in patients with CLMs treated with microwave ablation (MWA). METHODS: All CLM patients with pre-operative Gadoxetic acid-MRI treated with MWA in a single institution between September 2015 and February 2022 were evaluated. Pre-procedural information was retrieved retrospectively. Two observers manually segmented CLMs on T2 and T1-Hepatobiliary phase (T1-HBP) scans. After inter-observer variability testing, 148/182 RFs showed robustness on T1-HBP, and 141/182 on T2 (ICC > 0.7).Cox multivariate analysis was run to establish clinical (CLIN-mod), radiomic (RAD-T1, RAD-T2), and combined (COMB-T1, COMB-T2) models for LTPFS prediction. RESULTS: Seventy-six CLMs (43 patients) were assessed. Median follow-up was 14 months. LTP occurred in 19 lesions (25%).CLIN-mod was composed of minimal ablation margins (MAMs), intra-segment progression and primary tumor grade and exhibited moderately high discriminatory power in predicting LTPFS (AUC = 0.89, p = 0.0001). Both RAD-T1 and RAD-T2 were able to predict LTPFS: (RAD-T1: AUC = 0.83, p = 0.0003; RAD-T2: AUC = 0.79, p = 0.001). Combined models yielded the strongest performance (COMB-T1: AUC = 0.98, p = 0.0001; COMB-T2: AUC = 0.95, p = 0.0003). Both combined models included MAMs and tumor regression grade; COMB-T1 also featured 10th percentile of signal intensity, while tumor flatness was present in COMB-T2. CONCLUSION: MRI-based radiomic evaluation of CLMs is feasible and potentially useful for LTP prediction. Combined models outperformed clinical or radiomic models alone for LTPFS prediction.

External validation of an 18F-FDG-PET radiomic model predicting survival after radiotherapy for oropharyngeal cancer.

PURPOSE/OBJECTIVE: The purpose of the study is to externally validate published 18F-FDG-PET radiomic models for outcome prediction in patients with oropharyngeal cancer treated with chemoradiotherapy. MATERIAL/METHODS: Outcome data and pre-radiotherapy PET images of 100 oropharyngeal cancer patients (stage IV:78) treated with concomitant chemotherapy to 66-69 Gy/30 fr were available. Tumors were segmented using a previously validated semi-automatic method; 450 radiomic features (RF) were extracted according to IBSI (Image Biomarker Standardization Initiative) guidelines. Only one model for cancer-specific survival (CSS) prediction was suitable to be independently tested, according to our criteria. This model, in addition to HPV status, SUVmean and SUVmax, included two independent meta-factors (Fi), resulting from combining selected RF clusters. In a subgroup of 66 patients with complete HPV information, the global risk score R was computed considering the original coefficients and was tested by Cox regression as predictive of CSS. Independently, only the radiomic risk score RF derived from Fi was tested on the same subgroup to learn about the radiomics contribution to the model. The metabolic tumor volume (MTV) was also tested as a single predictor and its prediction performances were compared to the global and radiomic models. Finally, the validation of MTV and the radiomic score RF were also tested on the entire dataset. RESULTS: Regarding the analysis of the subgroup with HPV information, with a median follow-up of 41.6 months, seven patients died due to cancer. R was confirmed to be associated to CSS (p value = 0.05) with a C-index equal 0.75 (95% CI=0.62-0.85). The best cut-off value (equal to 0.15) showed high ability in patient stratification (p=0.01, HR=7.4, 95% CI=1.6-11.4). The 5-year CSS for R were 97% (95% CI: 93-100%) vs 74% (56-92%) for low- and high-risk groups, respectively. RF and MTV alone were also significantly associated to CSS for the subgroup with an almost identical C-index. According to best cut-off value (RF>0.12 and MTV>15.5cc), the 5-year CSS were 96% (95% CI: 89-100%) vs 65% (36-94%) and 97% (95% CI: 88-100%) vs 77% (58-93%) for RF and MTV, respectively. Results regarding RF and MTV were confirmed in the overall group. CONCLUSION: A previously published PET radiomic model for CSS prediction was independently validated. Performances of the model were similar to the ones of using only the MTV, without improvement of prediction accuracy.

Limited impact of discretization/interpolation parameters on the predictive power of CT radiomic features in a surgical cohort of pancreatic cancer patients.

PURPOSE: To explore the variation of the discriminative power of CT (Computed Tomography) radiomic features (RF) against image discretization/interpolation in predicting early distant relapses (EDR) after upfront surgery. MATERIALS AND METHODS: Data of 144 patients with pre-surgical high contrast CT were processed consistently with IBSI (Image Biomarker Standardization Initiative) guidelines. Image interpolation/discretization parameters were intentionally changed, including cubic voxel size (0.21-27 mm3) and binning (32-128 grey levels) in a 15 parameter's sets. After excluding RF with poor inter-observer delineation agreement (ICC < 0.80) and not negligible inter-scanner variability, the variation of 80 RF against discretization/interpolation was first quantified. Then, their ability in classifying patients with early distant relapses (EDR, < 10 months, previously assessed at the first quartile value of time-to-relapse) was investigated in terms of AUC (Area Under Curve) variation for those RF significantly associated to EDR. RESULTS: Despite RF variability against discretization/interpolation parameters was large and only 30/80 RF showed %COV < 20 (%COV = 100*STDEV/MEAN), AUC changes were relatively limited: for 30 RF significantly associated with EDR (AUC values around 0.60-0.70), the mean values of SD of AUC variability and AUC range were 0.02 and 0.05 respectively. AUC ranges were between 0.00 and 0.11, with values ≤ 0.05 in 16/30 RF. These variations were further reduced when excluding the extreme values of 32 and 128 for grey levels (Average AUC range 0.04, with values between 0.00 and 0.08). CONCLUSIONS: The discriminative power of CT RF in the prediction of EDR after upfront surgery for pancreatic cancer is relatively invariant against image interpolation/discretization within a large range of voxel sizes and binning.

Development and validation of a prognostic model incorporating texture analysis derived from standardised segmentation of PET in patients with oesophageal cancer.

OBJECTIVES: This retrospective cohort study developed a prognostic model incorporating PET texture analysis in patients with oesophageal cancer (OC). Internal validation of the model was performed. METHODS: Consecutive OC patients (n = 403) were chronologically separated into development (n = 302, September 2010-September 2014, median age = 67.0, males = 227, adenocarcinomas = 237) and validation cohorts (n = 101, September 2014-July 2015, median age = 69.0, males = 78, adenocarcinomas = 79). Texture metrics were obtained using a machine-learning algorithm for automatic PET segmentation. A Cox regression model including age, radiological stage, treatment and 16 texture metrics was developed. Patients were stratified into quartiles according to a prognostic score derived from the model. A p-value < 0.05 was considered statistically significant. Primary outcome was overall survival (OS). RESULTS: Six variables were significantly and independently associated with OS: age [HR =1.02 (95% CI 1.01-1.04), p < 0.001], radiological stage [1.49 (1.20-1.84), p < 0.001], treatment [0.34 (0.24-0.47), p < 0.001], log(TLG) [5.74 (1.44-22.83), p = 0.013], log(Histogram Energy) [0.27 (0.10-0.74), p = 0.011] and Histogram Kurtosis [1.22 (1.04-1.44), p = 0.017]. The prognostic score demonstrated significant differences in OS between quartiles in both the development (X2 143.14, df 3, p < 0.001) and validation cohorts (X2 20.621, df 3, p < 0.001). CONCLUSIONS: This prognostic model can risk stratify patients and demonstrates the additional benefit of PET texture analysis in OC staging. KEY POINTS: • PET texture analysis adds prognostic value to oesophageal cancer staging. • Texture metrics are independently and significantly associated with overall survival. • A prognostic model including texture analysis can help risk stratify patients.

Dose calculation and treatment plan optimization including imaging dose from kilovoltage cone beam computed tomography.

BACKGROUND: With the increasing use of cone beam computed tomography (CBCT) for patient position verification and radiotherapy treatment adaptation, there is an increasing need to develop techniques that can take into account concomitant dose using a personalized approach. MATERIAL AND METHODS: A total of 20 patients (10 pelvis and 10 head and neck) who had undergone radiation therapy using intensity modulated radiation therapy (IMRT) were selected and the dose from kV CBCT was retrospectively calculated using a treatment planning system previously commissioned for this purpose. The imaging dose was added to the CT images used for treatment planning and the difference in its addition prior to and after the planning was assessed. RESULTS: The additional isocenter dose as a result of daily CBCT is in the order of 3-4 cGy for 35-fraction head and neck and 23-47 cGy for 25-fraction pelvis cases using the standard head and neck and pelvis image acquisition protocols. The pelvic dose is especially dependent on patient size and body mass index (BMI), being higher for patients with lower BMI. Due to the low energy of the kV CBCT beam, the maximum energy deposition is at or near the surface with the highest dose being on the patient's left side for the head and neck (∼7 cGy) and on the posterior for the pelvic cases (∼80 cGy). Addition of imaging dose prior to plan optimization resulted in an average reduction of 4% in the plan monitor units and 5% in the number of control points. CONCLUSION: Dose from daily kV CBCT has been added to patient treatment plans using previously commissioned kV CBCT beams in a treatment planning system. Addition of imaging dose can be included in IMRT treatment plan optimization and would facilitate customization of imaging protocol based on patient anatomy and location of isocenter.

Multi-institutional evaluation of a Pareto navigation guided automated radiotherapy planning solution for prostate cancer.

BACKGROUND: Current automated planning solutions are calibrated using trial and error or machine learning on historical datasets. Neither method allows for the intuitive exploration of differing trade-off options during calibration, which may aid in ensuring automated solutions align with clinical preference. Pareto navigation provides this functionality and offers a potential calibration alternative. The purpose of this study was to validate an automated radiotherapy planning solution with a novel multi-dimensional Pareto navigation calibration interface across two external institutions for prostate cancer. METHODS: The implemented 'Pareto Guided Automated Planning' (PGAP) methodology was developed in RayStation using scripting and consisted of a Pareto navigation calibration interface built upon a 'Protocol Based Automatic Iterative Optimisation' planning framework. 30 previous patients were randomly selected by each institution (IA and IB), 10 for calibration and 20 for validation. Utilising the Pareto navigation interface automated protocols were calibrated to the institutions' clinical preferences. A single automated plan (VMATAuto) was generated for each validation patient with plan quality compared against the previously treated clinical plan (VMATClinical) both quantitatively, using a range of DVH metrics, and qualitatively through blind review at the external institution. RESULTS: PGAP led to marked improvements across the majority of rectal dose metrics, with Dmean reduced by 3.7 Gy and 1.8 Gy for IA and IB respectively (p < 0.001). For bladder, results were mixed with low and intermediate dose metrics reduced for IB but increased for IA. Differences, whilst statistically significant (p < 0.05) were small and not considered clinically relevant. The reduction in rectum dose was not at the expense of PTV coverage (D98% was generally improved with VMATAuto), but was somewhat detrimental to PTV conformality. The prioritisation of rectum over conformality was however aligned with preferences expressed during calibration and was a key driver in both institutions demonstrating a clear preference towards VMATAuto, with 31/40 considered superior to VMATClinical upon blind review. CONCLUSIONS: PGAP enabled intuitive adaptation of automated protocols to an institution's planning aims and yielded plans more congruent with the institution's clinical preference than the locally produced manual clinical plans.

Sensitivity of standardised radiomics algorithms to mask generation across different software platforms.

The field of radiomics continues to converge on a standardised approach to image processing and feature extraction. Conventional radiomics requires a segmentation. Certain features can be sensitive to small contour variations. The industry standard for medical image communication stores contours as coordinate points that must be converted to a binary mask before image processing can take place. This study investigates the impact that the process of converting contours to mask can have on radiomic features calculation. To this end we used a popular open dataset for radiomics standardisation and we compared the impact of masks generated by importing the dataset into 4 medical imaging software. We interfaced our previously standardised radiomics platform with these software using their published application programming interface to access image volume, masks and other data needed to calculate features. Additionally, we used super-sampling strategies to systematically evaluate the impact of contour data pre processing methods on radiomic features calculation. Finally, we evaluated the effect that using different mask generation approaches could have on patient clustering in a multi-center radiomics study. The study shows that even when working on the same dataset, mask and feature discrepancy occurs depending on the contour to mask conversion technique implemented in various medical imaging software. We show that this also affects patient clustering and potentially radiomic-based modelling in multi-centre studies where a mix of mask generation software is used. We provide recommendations to negate this issue and facilitate reproducible and reliable radiomics.

Towards using a multi-material, pellet-fed additive manufacturing platform to fabricate novel imaging phantoms.

The design freedom afforded by additive manufacturing (AM) is now being leveraged across multiple applications, including many in the fields of imaging for personalised medicine. This study utilises a pellet-fed, multi-material AM machine as a route to fabricating new imaging phantoms, used for developing and refining algorithms for the detection of subtle soft tissue anomalies. Traditionally comprising homogeneous materials, higher-resolution scanning now allows for heterogeneous, multi-material phantoms. Polylactic acid (PLA), a thermoplastic urethane (TPU) and a thermoplastic elastomer (TPE) were investigated as potential materials. Manufacturing accuracy and precision were assessed relative to the digital design file, whilst the potential to achieve structural heterogeneity was evaluated by quantifying infill density via micro-computed tomography. Hounsfield units (HU) were also captured via a clinical scanner. The PLA builds were consistently too small, by 0.2 - 0.3%. Conversely, TPE parts were consistently larger than the digital file, though by only 0.1%. The TPU components had negligible differences relative to the specified sizes. The accuracy and precision of material infill were inferior, with PLA exhibiting greater and lower densities relative to the digital file, across the 3 builds. Both TPU and TPE produced infills that were too dense. The PLA material produced repeatable HU values, with poorer precision across TPU and TPE. All HU values tended towards, and some exceeded, the reference value for water (0 HU) with increasing infill density. These data have demonstrated that pellet-fed AM can produce accurate and precise structures, with the potential to include multiple materials providing an opportunity for more realistic and advanced phantom designs. In doing so, this will enable clinical scientists to develop more sensitive applications aimed at detecting ever more subtle variations in tissue, confident that their calibration models reflect their intended designs.

RFS+: A Clinically Adaptable and Computationally Efficient Strategy for Enhanced Brain Tumor Segmentation.

Automated brain tumor segmentation has significant importance, especially for disease diagnosis and treatment planning. The study utilizes a range of MRI modalities, namely T1-weighted (T1), T1-contrast-enhanced (T1ce), T2-weighted (T2), and fluid-attenuated inversion recovery (FLAIR), with each providing unique and vital information for accurate tumor localization. While state-of-the-art models perform well on standardized datasets like the BraTS dataset, their suitability in diverse clinical settings (matrix size, slice thickness, manufacturer-related differences such as repetition time, and echo time) remains a subject of debate. This research aims to address this gap by introducing a novel 'Region-Focused Selection Plus (RFS+)' strategy designed to efficiently improve the generalization and quantification capabilities of deep learning (DL) models for automatic brain tumor segmentation. RFS+ advocates a targeted approach, focusing on one region at a time. It presents a holistic strategy that maximizes the benefits of various segmentation methods by customizing input masks, activation functions, loss functions, and normalization techniques. Upon identifying the top three models for each specific region in the training dataset, RFS+ employs a weighted ensemble learning technique to mitigate the limitations inherent in each segmentation approach. In this study, we explore three distinct approaches, namely, multi-class, multi-label, and binary class for brain tumor segmentation, coupled with various normalization techniques applied to individual sub-regions. The combination of different approaches with diverse normalization techniques is also investigated. A comparative analysis is conducted among three U-net model variants, including the state-of-the-art models that emerged victorious in the BraTS 2020 and 2021 challenges. These models are evaluated using the dice similarity coefficient (DSC) score on the 2021 BraTS validation dataset. The 2D U-net model yielded DSC scores of 77.45%, 82.14%, and 90.82% for enhancing tumor (ET), tumor core (TC), and the whole tumor (WT), respectively. Furthermore, on our local dataset, the 2D U-net model augmented with the RFS+ strategy demonstrates superior performance compared to the state-of-the-art model, achieving the highest DSC score of 79.22% for gross tumor volume (GTV). The model utilizing RFS+ requires 10% less training dataset, 67% less memory and completes training in 92% less time compared to the state-of-the-art model. These results confirm the effectiveness of the RFS+ strategy for enhancing the generalizability of DL models in brain tumor segmentation.

Clinical evaluation of atlas-based auto-segmentation in breast and nodal radiotherapy.

OBJECTIVES: Accurate contouring of anatomical structures allows for high-precision radiotherapy planning, targeting the dose at treatment volumes and avoiding organs at risk. Manual contouring is time-consuming with significant user variability, whereas auto-segmentation (AS) has proven efficiency benefits but requires editing before treatment planning. This study investigated whether atlas-based AS (ABAS) accuracy improves with template atlas group size and character-specific atlas and test case selection. METHODS AND MATERIALS: One clinician retrospectively contoured the breast, nodes, lung, heart, and brachial plexus on 100 CT scans, adhering to peer-reviewed guidelines. Atlases were clustered in group sizes, treatment positions, chest wall separations, and ASs created with Mirada software. The similarity of ASs compared to reference contours was described by the Jaccard similarity coefficient (JSC) and centroid distance variance (CDV). RESULTS: Across group sizes, for all structures combined, the mean JSC was 0.6 (SD 0.3, p = .999). Across atlas-specific groups, 0.6 (SD 0.3, p = 1.000). The correlation between JSC and structure volume was weak in both scenarios (adjusted R2-0.007 and 0.185).Mean CDV was similar across groups but varied up to 1.2 cm for specific structures. CONCLUSIONS: Character-specific atlas groups and test case selection did not improve accuracy outcomes. High-quality ASs were obtained from groups containing as few as ten atlases, subsequently simplifying the application of ABAS. CDV measures indicating auto-segmentation variations on the x, y, and z axes can be utilised to decide on the clinical relevance of variations and reduce AS editing. ADVANCES IN KNOWLEDGE: High-quality ABASs can be obtained from as few as ten template atlases.Atlas and test case selection do not improve AS accuracy.Unlike well-known quantitative similarity indices, volume displacement metrics provide information on the location of segmentation variations, helping assessment of the clinical relevance of variations and reducing clinician editing. Volume displacement metrics combined with the qualitative measure of clinician assessment could reduce user variability.

Efficacy of early PET-CT directed switch to carboplatin and paclitaxel based definitive chemoradiotherapy in patients with oesophageal cancer who have a poor early response to induction cisplatin and capecitabine in the UK: a multi-centre randomised controlled phase II trial.

Background: The utility of early metabolic response assessment to guide selection of the systemic component of definitive chemoradiotherapy (dCRT) for oesophageal cancer is uncertain. Methods: In this multi-centre, randomised, open-label, phase II substudy of the radiotherapy dose-escalation SCOPE2 trial we evaluated the role of 18F-Fluorodeoxyglucose positron emission tomography (PET) at day 14 of cycle 1 of three-weekly induction cis/cap (cisplatin (60 mg/m2)/capecitabine (625 mg/m2 days 1-21)) in patients with oesophageal squamous cell carcinoma (OSCC) or adenocarcinoma (OAC). Non-responders, who had a less than 35% reduction in maximum standardised uptake value (SUVmax) from pre-treatment baseline, were randomly assigned to continue cis/cap or switch to car/pac (carboplatin AUC 5/paclitaxel 175 mg/m2) for a further induction cycle, then concurrently with radiotherapy over 25 fractions. Responders continued cis/cap for the duration of treatment. All patients (including responders) were randomised to standard (50Gy) or high (60Gy) dose radiation as part of the main study. Primary endpoint for the substudy was treatment failure-free survival (TFFS) at week 24. The trial was registered with International Standard Randomized Controlled Trial Number 97125464 and ClinicalTrials.govNCT02741856. Findings: This substudy was closed on 1st August 2021 by the Independent Data Monitoring Committee on the grounds of futility and possible harm. To this point from 22nd November 2016, 103 patients from 16 UK centres had participated in the PET-CT substudy; 63 (61.2%; 52/83 OSCC, 11/20 OAC) of whom were non-responders. Of these, 31 were randomised to car/pac and 32 to remain on cis/cap. All patients were followed up until at least 24 weeks, at which point in OSCC both TFFS (25/27 (92.6%) vs 17/25 (68%); p = 0.028) and overall survival (42.5 vs. 20.4 months, adjusted HR 0.36; p = 0.018) favoured cis/cap over car/pac. There was a trend towards worse survival in OSCC + OAC cis/cap responders (33.6 months; 95%CI 23.1-nr) vs. non-responders (42.5 (95%CI 27.0-nr) months; HR = 1.43; 95%CI 0.67-3.08; p = 0.35). Interpretation: In OSCC, early metabolic response assessment is not prognostic for TFFS or overall survival and should not be used to personalise systemic therapy in patients receiving dCRT. Funding: Cancer Research UK.

Commissioning kilovoltage cone-beam CT beams in a radiation therapy treatment planning system.

The feasibility of accounting of the dose from kilovoltage cone-beam CT in treatment planning has been discussed previously for a single cone-beam CT (CBCT) beam from one manufacturer. Modeling the beams and computing the dose from the full set of beams produced by a kilovoltage cone-beam CT system requires extensive beam data collection and verification, and is the purpose of this work. The beams generated by Elekta X-ray volume imaging (XVI) kilovoltage CBCT (kV CBCT) system for various cassettes and filters have been modeled in the Philips Pinnacle treatment planning system (TPS) and used to compute dose to stack and anthropomorphic phantoms. The results were then compared to measurements made using thermoluminescent dosimeters (TLDs) and Monte Carlo (MC) simulations. The agreement between modeled and measured depth-dose and cross profiles is within 2% at depths beyond 1 cm for depth-dose curves, and for regions within the beam (excluding penumbra) for cross profiles. The agreements between TPS-calculated doses, TLD measurements, and Monte Carlo simulations are generally within 5% in the stack phantom and 10% in the anthropomorphic phantom, with larger variations observed for some of the measurement/calculation points. Dose computation using modeled beams is reasonably accurate, except for regions that include bony anatomy. Inclusion of this dose in treatment plans can lead to more accurate dose prediction, especially when the doses to organs at risk are of importance.

Development and validation of prognostic models for anal cancer outcomes using distributed learning: protocol for the international multi-centre atomCAT2 study.

BACKGROUND: Anal cancer is a rare cancer with rising incidence. Despite the relatively good outcomes conferred by state-of-the-art chemoradiotherapy, further improving disease control and reducing toxicity has proven challenging. Developing and validating prognostic models using routinely collected data may provide new insights for treatment development and selection. However, due to the rarity of the cancer, it can be difficult to obtain sufficient data, especially from single centres, to develop and validate robust models. Moreover, multi-centre model development is hampered by ethical barriers and data protection regulations that often limit accessibility to patient data. Distributed (or federated) learning allows models to be developed using data from multiple centres without any individual-level patient data leaving the originating centre, therefore preserving patient data privacy. This work builds on the proof-of-concept three-centre atomCAT1 study and describes the protocol for the multi-centre atomCAT2 study, which aims to develop and validate robust prognostic models for three clinically important outcomes in anal cancer following chemoradiotherapy. METHODS: This is a retrospective multi-centre cohort study, investigating overall survival, locoregional control and freedom from distant metastasis after primary chemoradiotherapy for anal squamous cell carcinoma. Patient data will be extracted and organised at each participating radiotherapy centre (n = 18). Candidate prognostic factors have been identified through literature review and expert opinion. Summary statistics will be calculated and exchanged between centres prior to modelling. The primary analysis will involve developing and validating Cox proportional hazards models across centres for each outcome through distributed learning. Outcomes at specific timepoints of interest and factor effect estimates will be reported, allowing for outcome prediction for future patients. DISCUSSION: The atomCAT2 study will analyse one of the largest available cross-institutional cohorts of patients with anal cancer treated with chemoradiotherapy. The analysis aims to provide information on current international clinical practice outcomes and may aid the personalisation and design of future anal cancer clinical trials through contributing to a better understanding of patient risk stratification.

Use of knowledge based DVH predictions to enhance automated re-planning strategies in head and neck adaptive radiotherapy.

This study aimed to investigate if a commercial, knowledge-based tool for radiotherapy planning could be used to estimate the amount of sparing in organs at risk (OARs) in the re-planning strategy for adaptive radiotherapy (ART). Eighty head and neck (HN) VMAT Pareto plans from our institute's database were used to train a knowledge-based planning (KBP) model. An evaluation set of another 20 HN patients was randomly selected. For each patient in the evaluation set, the planning computed tomography (CT) and 2 sets of on-board cone-beam CT, corresponding to the middle and second half of the radiotherapy treatment course, were extracted. The original plan was re-calculated on a daily deformed CT (delivered dose-volume histogram (DVH)) and compared with the KBP DVH predictions and with the final KBP DVH after optimisation of the plan, which was performed on the same image sets. To evaluate the feasibility of this method, the range of KBP DVH uncertainties was compared with the gains obtained from re-planning. DVH differences and receiver operating characteristic (ROC) curve analysis were used for this purpose. On average, final KBP uncertainties were smaller than the gain in re-planning. Statistical tests confirmed significant differences between the two groups. ROC analysis showed KBP performance in terms of area under the curve values higher than 0.7, which confirmed a good accuracy in predicted values. Overall, for 48% of cases, KBP predicted a desirable outcome from re-planning, and the final dose confirmed an effective gain in 47% of cases. We have established a systematic workflow to identify effective OAR sparing in re-planning based on KBP predictions that can be implemented in an on-line, ART process.

FIELDRT: an open-source platform for the assessment of target volume delineation in radiation therapy.

OBJECTIVES: Target volume delineation (TVD) has been identified as a weakness in the accuracy of radiotherapy, both within and outside of clinical trials due to the intra/interobserver variations affecting the TVD quality. Sources of variations such as poor compliance or protocol violation may have adverse effect on treatment outcomes. In this paper, we present and describe the FIELDRT software developed for the ARENA project to improve the quality of TVD through qualitative and quantitative feedbacks and individual and personalized summary of trainee"s performance. METHODS: For each site-specific clinical case included in the FIELDRT software, reference volumes, minimum and maximum "acceptable" volumes and organ at risk were derived by outlines of consultants and senior trainees. The software components currently developed include: (a) user-friendly importing interface (b) analysis toolbox to compute quantitative and qualitative (c) visualiser and (d) structured report generator for personalised feedback. The FIELDRT software was validated by comparing the performance of 63 trainees and by measuring performance over time. In addition, a trainee evaluation day was held in 2019 to collect feedback on FIELDRT. RESULTS: Results show the trainees' improvement when reoutlining a case after reviewing the feedback generated from the FIELDRT software. Comments and feedback received after evaluation day were positive and confirmed that FIELDRT can be a useful application for training purposes. CONCLUSION: We presented a new open-source software to support education in TVD and ongoing continuous professional development for clinical oncology trainees and consultants. ARENA in combination with FIELDRT implements site-specific modules with reference target and organs at risk volumes and automatically evaluates individual performance using several quantitative and qualitative feedbacks. Pilot results suggests this software could be used as an education tool to reduce variation in TVD so to guarantee high quality in radiotherapy. ADVANCES IN KNOWLEDGE: FIELDRT is a new easy and free to use software aiming at supporting education in TVD and ongoing continuous professional development. The software provides quantitative/qualitative feedback and an exportable report with an individual and personalised summary of trainee's performance.

Variations in Head and Neck Treatment Plan Quality Assessment Among Radiation Oncologists and Medical Physicists in a Single Radiotherapy Department.

BACKGROUND: Agreement between planners and treating radiation oncologists (ROs) on plan quality criteria is essential for consistent planning. Differences between ROs and planning medical physicists (MPs) in perceived quality of head and neck cancer plans were assessed. MATERIALS AND METHODS: Five ROs and four MPs scored 65 plans for in total 15 patients. For each patient, the clinical (CLIN) plan and two or four alternative plans, generated with automated multi-criteria optimization (MCO), were included. There was always one MCO plan aiming at maximally adhering to clinical plan requirements, while the other MCO plans had a lower aimed quality. Scores were given as follows: 1-7 and 1-2, not acceptable; 3-5, acceptable if further planning would not resolve perceived weaknesses; and 6-7, straightway acceptable. One MP and one RO repeated plan scoring for intra-observer variation assessment. RESULTS: For the 36 unique observer pairs, the median percentage of plans for which the two observers agreed on a plan score (100% = 65 plans) was 27.7% [6.2, 40.0]. In the repeat scoring, agreements between first and second scoring were 52.3% and 40.0%, respectively. With a binary division between unacceptable (scores 1 and 2) and acceptable (3-7) plans, the median inter-observer agreement percentage was 78.5% [63.1, 86.2], while intra-observer agreements were 96.9% and 86.2%. There were no differences in observed agreements between RO-RO, MP-MP, and RO-MP pairs. Agreements for the highest-quality, automatically generated MCO plans were higher than for the CLIN plans. CONCLUSIONS: Inter-observer differences in plan quality scores were substantial and could result in inconsistencies in generated treatment plans. Agreements among ROs were not better than between ROs and MPs, despite large differences in training and clinical role. High-quality automatically generated plans showed the best score agreements.

Prediction of lymph node metastases using pre-treatment PET radiomics of the primary tumour in esophageal adenocarcinoma: an external validation study.

OBJECTIVES: To improve clinical lymph node staging (cN-stage) in oesophageal adenocarcinoma by developing and externally validating three prediction models; one with clinical variables only, one with positron emission tomography (PET) radiomics only, and a combined clinical and radiomics model. METHODS: Consecutive patients with fluorodeoxyglucose (FDG) avid tumours treated with neoadjuvant therapy between 2010 and 2016 in two international centres (n = 130 and n = 60, respectively) were included. Four clinical variables (age, gender, clinical T-stage and tumour regression grade) and PET radiomics from the primary tumour were used for model development. Diagnostic accuracy, area under curve (AUC), discrimination and calibration were calculated for each model. The prognostic significance was also assessed. RESULTS: The incidence of lymph node metastases was 58% in both cohorts. The areas under the curve of the clinical, radiomics and combined models were 0.79, 0.69 and 0.82 in the developmental cohort, and 0.65, 0.63 and 0.69 in the external validation cohort, with good calibration demonstrated. The area under the curve of current cN-stage in development and validation cohorts was 0.60 and 0.66, respectively. For overall survival, the combined clinical and radiomics model achieved the best discrimination performance in the external validation cohort (X2 = 6.08, df = 1, p = 0.01). CONCLUSION: Accurate diagnosis of lymph node metastases is crucial for prognosis and guiding treatment decisions. Despite finding improved predictive performance in the development cohort, the models using PET radiomics derived from the primary tumour were not fully replicated in an external validation cohort. ADVANCES IN KNOWLEDGE: This international study attempted to externally validate a new prediction model for lymph node metastases using PET radiomics. A model combining clinical variables and PET radiomics improved discrimination of lymph node metastases, but these results were not externally replicated.

Prediction of Early Distant Recurrence in Upfront Resectable Pancreatic Adenocarcinoma: A Multidisciplinary, Machine Learning-Based Approach.

Despite careful selection, the recurrence rate after upfront surgery for pancreatic adenocarcinoma can be very high. We aimed to construct and validate a model for the prediction of early distant recurrence (<12 months from index surgery) after upfront pancreaticoduodenectomy. After exclusions, 147 patients were retrospectively enrolled. Preoperative clinical and radiological (CT-based) data were systematically evaluated; moreover, 182 radiomics features (RFs) were extracted. Most significant RFs were selected using minimum redundancy, robustness against delineation uncertainty and an original machine learning bootstrap-based method. Patients were split into training (n = 94) and validation cohort (n = 53). Multivariable Cox regression analysis was first applied on the training cohort; the resulting prognostic index was then tested in the validation cohort. Clinical (serum level of CA19.9), radiological (necrosis), and radiomic (SurfAreaToVolumeRatio) features were significantly associated with the early resurge of distant recurrence. The model combining these three variables performed well in the training cohort (p = 0.0015, HR = 3.58, 95%CI = 1.98-6.71) and was then confirmed in the validation cohort (p = 0.0178, HR = 5.06, 95%CI = 1.75-14.58). The comparison of survival curves between low and high-risk patients showed a p-value <0.0001. Our model may help to better define resectability status, thus providing an actual aid for pancreatic adenocarcinoma patients' management (upfront surgery vs. neoadjuvant chemotherapy). Independent validations are warranted.

Comparison of different calculation techniques for absorbed dose assessment in patient specific peptide receptor radionuclide therapy.

AIM: The present work concerns the comparison of the performances of three systems for dosimetry in RPT that use different techniques for absorbed dose calculation (organ-level dosimetry, voxel-level dose kernel convolution and Monte Carlo simulations). The aim was to assess the importance of the choice of the most adequate calculation modality, providing recommendations about the choice of the computation tool. METHODS: The performances were evaluated both on phantoms and patients in a multi-level approach. Different phantoms filled with a 177Lu-radioactive solution were used: a homogeneous cylindrical phantom, a phantom with organ-shaped inserts and two cylindrical phantoms with inserts different for shape and volume. A total of 70 patients with NETs treated by PRRT with 177Lu-DOTATOC were retrospectively analysed. RESULTS: The comparisons were performed mainly between the mean values of the absorbed dose in the regions of interest. A general better agreement was obtained between Dose kernel convolution and Monte Carlo simulations results rather than between either of these two and organ-level dosimetry, both for phantoms and patients. Phantoms measurements also showed the discrepancies mainly depend on the geometry of the inserts (e.g. shape and volume). For patients, differences were more pronounced than phantoms and higher inter/intra patient variability was observed. CONCLUSION: This study suggests that voxel-level techniques for dosimetry calculation are potentially more accurate and personalized than organ-level methods. In particular, a voxel-convolution method provides good results in a short time of calculation, while Monte Carlo based computation should be conducted with very fast calculation systems for a possible use in clinics, despite its intrinsic higher accuracy. Attention to the calculation modality is recommended in case of clinical regions of interest with irregular shape and far from spherical geometry, in which Monte Carlo seems to be more accurate than voxel-convolution methods.