Evaluation of Deep Learning Clinical Target Volumes Auto-Contouring for Magnetic Resonance Imaging-Guided Online Adaptive Treatment of Rectal Cancer.

Purpose: Segmentation of clinical target volumes (CTV) on medical images can be time-consuming and is prone to interobserver variation (IOV). This is a problem for online adaptive radiation therapy, where CTV segmentation must be performed every treatment fraction, leading to longer treatment times and logistic challenges. Deep learning (DL)-based auto-contouring has the potential to speed up CTV contouring, but its current clinical use is limited. One reason for this is that it can be time-consuming to verify the accuracy of CTV contours produced using auto-contouring, and there is a risk of bias being introduced. To be accepted by clinicians, auto-contouring must be trustworthy. Therefore, there is a need for a comprehensive commissioning framework when introducing DL-based auto-contouring in clinical practice. We present such a framework and apply it to an in-house developed DL model for auto-contouring of the CTV in rectal cancer patients treated with MRI-guided online adaptive radiation therapy. Methods and Materials: The framework for evaluating DL-based auto-contouring consisted of 3 steps: (1) Quantitative evaluation of the model's performance and comparison with IOV; (2) Expert observations and corrections; and (3) Evaluation of the impact on expected volumetric target coverage. These steps were performed on independent data sets. The framework was applied to an in-house trained nnU-Net model, using the data of 44 rectal cancer patients treated at our institution. Results: The framework established that the model's performance after expert corrections was comparable to IOV, and although the model introduced a bias, this had no relevant impact on clinical practice. Additionally, we found a substantial time gain without reducing quality as determined by volumetric target coverage. Conclusions: Our framework provides a comprehensive evaluation of the performance and clinical usability of target auto-contouring models. Based on the results, we conclude that the model is eligible for clinical use.

A network score-based metric to optimize the quality assurance of automatic radiotherapy target segmentations.

Background and purpose: Existing methods for quality assurance of the radiotherapy auto-segmentations focus on the correlation between the average model entropy and the Dice Similarity Coefficient (DSC) only. We identified a metric directly derived from the output of the network and correlated it with clinically relevant metrics for contour accuracy. Materials and Methods: Magnetic Resonance Imaging auto-segmentations were available for the gross tumor volume for cervical cancer brachytherapy (106 segmentations) and for the clinical target volume for rectal cancer external-beam radiotherapy (77 segmentations). The nnU-Net's output before binarization was taken as a score map. We defined a metric as the mean of the voxels in the score map above a threshold (λ). Comparisons were made with the mean and standard deviation over the score map and with the mean over the entropy map. The DSC, the 95th Hausdorff distance, the mean surface distance (MSD) and the surface DSC were computed for segmentation quality. Correlations between the studied metrics and model quality were assessed with the Pearson correlation coefficient (r). The area under the curve (AUC) was determined for detecting segmentations that require reviewing. Results: For both tasks, our metric (λ = 0.30) correlated more strongly with the segmentation quality than the mean over the entropy map (for surface DSC, r > 0.65 vs. r < 0.60). The AUC was above 0.84 for detecting MSD values above 2 mm. Conclusions: Our metric correlated strongly with clinically relevant segmentation metrics and detected segmentations that required reviewing, indicating its potential for automatic quality assurance of radiotherapy target auto-segmentations.

Health Research with Data in a Time of Privacy: Which Information do Patients Want?

When hospitals ask broad consent for the secondary use of patient data for scientific research, it is unknown for which studies the data will be used. We investigated what patients at a cancer hospital consider to be an adequate level and most suitable method of information provision using questionnaires (n = 71) and interviews (n = 24). A part of the respondents indicated that they would feel sufficiently informed by either being notified about potential further use, or by receiving a general brochure before being asked for consent. Others stated that additional information would be interesting and appreciated. Yet, when discussing required resources needed to provide additional information, interviewees lowered the bar of what they considered minimally required, voicing the importance of spending resources on research.

Comparing adaptation strategies in MRI-guided online adaptive radiotherapy for prostate cancer: Implications for treatment margins.

PURPOSE: To quantify the difference in accuracy of adapt-to-position (ATP), adapt-to-rotation (ATR) and adapt-to-shape (ATS) workflows used in MRI-guided online adaptive radiotherapy for prostate carcinoma (PCa) by evaluating the margins required to accommodate intra-fraction motion of the clinical target volumes for prostate (CTVpros), prostate including seminal vesicles (CTVpros + sv) and gross tumor volume (GTV). MATERIALS AND METHODS: Clinical delineations of the CTVpros, CTVpros + sv and GTV of 24 patients with intermediate- and high-risk PCa, treated using ATS on a 1.5 T MR-Linac, were used for analysis. Delineations were available pre- and during beam-on. To simulate ATP and ATR workflows, we automatically generated the structures associated with these workflows using rigid transformations from the planning-MRI to the daily online MRIs. Clinical GTVs were analyzed as ATR GTVs and only ATP GTVs were simulated. Planning target volumes (PTVs) were generated with isotropic margins ranging 0.0-5.0 mm. The volumetric overlap was calculated between these PTVs and their corresponding clinical delineation on the MRI acquired during beam-on and averaged over all treatment fractions. RESULTS: The PTV margin required to cover > 95% of the CTVpros was equal (2.5 mm) for all workflows. For the CTVpros + sv, this margin increased to 5.0, 4.0 and 3.5 mm in the ATP, ATR and ATS workflow, respectively. GTV coverage improved from ATP to ATR for margins up to 4.0 mm. CONCLUSION: ATP, ATR and ATS workflows ensure equal coverage of the CTVpros for the current clinical margins. For the CTVpros + sv, ATS showed optimal performance. GTV coverage improves by additional adaptations to prostate rotations.

Towards Response ADAptive Radiotherapy for organ preservation for intermediate-risk rectal cancer (preRADAR): protocol of a phase I dose-escalation trial.

INTRODUCTION: Organ preservation is associated with superior functional outcome and quality of life (QoL) compared with total mesorectal excision (TME) for rectal cancer. Only 10% of patients are eligible for organ preservation following short-course radiotherapy (SCRT, 25 Gy in five fractions) and a prolonged interval (4-8 weeks) to response evaluation. The organ preservation rate could potentially be increased by dose-escalated radiotherapy. Online adaptive magnetic resonance-guided radiotherapy (MRgRT) is anticipated to reduce radiation-induced toxicity and enable radiotherapy dose escalation. This trial aims to establish the maximum tolerated dose (MTD) of dose-escalated SCRT using online adaptive MRgRT. METHODS AND ANALYSIS: The preRADAR is a multicentre phase I trial with a 6+3 dose-escalation design. Patients with intermediate-risk rectal cancer (cT3c-d(MRF-)N1M0 or cT1-3(MRF-)N1M0) interested in organ preservation are eligible. Patients are treated with a radiotherapy boost of 2×5 Gy (level 0), 3×5 Gy (level 1), 4×5 Gy (level 2) or 5×5 Gy (level 3) on the gross tumour volume in the week following standard SCRT using online adaptive MRgRT. The trial starts on dose level 1. The primary endpoint is the MTD based on the incidence of dose-limiting toxicity (DLT) per dose level. DLT is a composite of maximum one in nine severe radiation-induced toxicities and maximum one in three severe postoperative complications, in patients treated with TME or local excision within 26 weeks following start of treatment. Secondary endpoints include the organ preservation rate, non-DLT, oncological outcomes, patient-reported QoL and functional outcomes up to 2 years following start of treatment. Imaging and laboratory biomarkers are explored for early response prediction. ETHICS AND DISSEMINATION: The trial protocol has been approved by the Medical Ethics Committee of the University Medical Centre Utrecht. The primary and secondary trial results will be published in international peer-reviewed journals. TRIAL REGISTRATION NUMBER: WHO International Clinical Trials Registry (NL8997; https://trialsearch.who.int).

Advances in radiotherapy and its impact on second primary cancer risk: A multi-center cohort study in prostate cancer patients.

BACKGROUND: Modelling studies suggest that advanced intensity-modulated radiotherapy may increase second primary cancer (SPC) risks, due to increased radiation exposure of tissues located outside the treatment fields. In the current study we investigated the association between SPC risks and characteristics of applied external beam radiotherapy (EBRT) protocols for localized prostate cancer (PCa). METHODS: We collected EBRT protocol characteristics (2000-2016) from five Dutch RT institutes for the 3D-CRT and advanced EBRT era (N = 7908). From the Netherlands Cancer Registry we obtained patient/tumour characteristics, SPC data, and survival information. Standardized incidence ratios (SIR) were calculated for pelvis and non-pelvis SPC. Nationwide SIRs were calculated as a reference, using calendar period as a proxy to label 3D-CRT/advanced EBRT. RESULTS: From 2000-2006, 3D-CRT with 68-78 Gy in 2 Gy fractions, delivered with 10-23 MV and weekly portal imaging was the most dominant protocol. By the year 2010 all institutes routinely used advanced EBRT (IMRT, VMAT, tomotherapy), mainly delivering 78 Gy in 2 Gy fractions, using various kV/MV imaging protocols. Sixteen percent (N = 1268) developed ≥ 1 SPC. SIRs for pelvis and non-pelvis SPC (all institutes, advanced EBRT vs 3D-CRT) were 1.17 (1.00-1.36) vs 1.39 (1.21-1.59), and 1.01 (0.89-1.07) vs 1.03 (0.94-1.13), respectively. Nationwide non-pelvis SIR was 1.07 (1.01-1.13) vs 1.02 (0.98-1.07). Other RT protocol characteristics did not correlate with SPC endpoints. CONCLUSION: None of the studied RT characteristics of advanced EBRT was associated with increased out-of-field SPC risks. With constantly evolving EBRT protocols, evaluation of associated SPC risks remains important.

Online Adaptive MRI-Guided Radiotherapy for Primary Tumor and Lymph Node Boosting in Rectal Cancer.

The purpose of this study was to characterize the motion and define the required treatment margins of the pathological mesorectal lymph nodes (GTVln) for two online adaptive MRI-guided strategies for sequential boosting. Secondly, we determine the margins required for the primary gross tumor volume (GTVprim). Twenty-eight patients treated on a 1.5T MR-Linac were included in the study. On T2-weighted images for adaptation (MRIadapt) before and verification after irradiation (MRIpost) of five treatment fractions per patient, the GTVln and GTVprim were delineated. With online adaptive MRI-guided radiotherapy, daily plan adaptation can be performed through the use of two different strategies. In an adapt-to-shape (ATS) workflow the interfraction motion is effectively corrected by redelineation and the only relevant motion is intrafraction motion, while in an adapt-to-position (ATP) workflow the margin (for GTVln) is dominated by interfraction motion. The margin required for GTVprim will be identical to the ATS workflow, assuming each fraction would be perfectly matched on GTVprim. The intrafraction motion was calculated between MRIadapt and MRIpost for the GTVln and GTVprim separately. The interfraction motion of the GTVln was calculated with respect to the position of GTVprim, assuming each fraction would be perfectly matched on GTVprim. PTV margins were calculated for each strategy using the Van Herk recipe. For GTVln we randomly sampled the original dataset 20 times, with each subset containing a single randomly selected lymph node for each patient. The resulting margins for ATS ranged between 3 and 4 mm (LR), 3 and 5 mm (CC) and 5 and 6 mm (AP) based on the 20 randomly sampled datasets for GTVln. For ATP, the margins for GTVln were 10-12 mm in LR and AP and 16-19 mm in CC. The margins for ATS for GTVprim were 1.7 mm (LR), 4.7 mm (CC) and 3.2 mm anterior and 5.6 mm posterior. Daily delineation using ATS of both target volumes results in the smallest margins and is therefore recommended for safe dose escalation to the primary tumor and lymph nodes.

A margin recipe for the management of intra-fraction target motion in radiotherapy.

Background and purpose: Strategies to limit the impact of intra-fraction motion during treatment are common in radiotherapy. Margin recipes, however, are not designed to incorporate these strategies. This work aimed to provide a framework to determine how motion management strategies influence treatment margins. Materials and methods: Two models of intra-fraction motion were considered. In model 1 motion was instantaneous, before treatment starts and in model 2 motion was a continuous drift during treatment. Motion management strategies were modelled by truncating the underlying error distribution at cσ, with σ the standard deviation of the distribution and c a free parameter. Using Monte Carlo simulations, we determined how motion management changed the required margin. The analysis was performed for different number of treatment fractions and different standard deviations of the underlying random and systematic errors. Results: The required margin for a continuous drift was found to be well approximated by an average position of the target at ¾ of the drift. Introducing a truncation at cσ, the relative change in the margin was equal to 0.3c. This result held for both models, was independent of σ or the number of fractions and naturally generalizes to the situation with a residual (systematic) error. Conclusion: Treatment margins can be determined when motion management strategies are applied. Moreover, our analysis can be used to study the potential benefit of different motion management strategies. This allows to discuss and determine the most appropriate strategy for margin reduction.

Adaptive margins for online adaptive radiotherapy.

Objective.In online adaptive radiotherapy a new plan is generated every fraction based on the organ and clinical target volume (CTV) delineations of that fraction. This allows for a planning target volume margin that does not need to be constant over the whole course of treatment, as is the case in conventional radiotherapy. This work aims to introduce an approach to update the margins each fraction based on the per-patient treatment history and explore the potential benefits of such adaptive margins.Approach.We introduce a novel methodology to implement adaptive margins, isotropic and anisotropic, during a treatment course based on the accumulated dose to the CTV. We then simulate treatment histories for treatments delivered in up to 20 fractions using various choices for the standard deviations of the systematic and random errors and homogeneous and inhomogeneous dose distributions. The treatment-averaged adaptive margin was compared to standard constant margins. The change in the minimum dose delivered to the CTV was compared on a patient and a population level. All simulations were performed within the van Herk approach and its known limitations.Main results.The population mean treatment-averaged margins are down to 70% and 55% of the corresponding necessary constant margins for the isotropic and anisotropic approach. The reduction increases with longer fractionation schemes and an inhomogeneous target dose distribution. Most of the benefit can be attributed to the elimination of the effective systematic error over the course of treatment. Interpatient differences in treatment-averaged margins were largest for the isotropic margins. For the 10% of patients that would receive a lower than prescribed dose to the CTV this minimum dose to the CTV is increased using the adaptive margin approaches.Significance.Adaptive margins can allow to reduce margins in most patients without compromising patients with greater than average target motion.

Benchmarking daily adaptation using fully automated radiotherapy treatment plan optimization for rectal cancer.

Background/purpose: In daily plan adaptation the radiotherapy treatment plan is adjusted just prior to delivery. A simple approach is taking the planning objectives of the reference plan and directly applying these in re-optimization. Here we present a tested method to verify whether daily adaptation without tweaking of the objectives can maintain the plan quality throughout treatment. Materials/methods: For fifteen rectal cancer patients, automated treatment planning was used to generate plans mimicking manual reference plans on the planning scans. For 74 fraction scans (4-5 per patient) an automated plan and a daily adapted plan were generated, where the latter re-optimizes the reference plan objectives without any tweaking. To evaluate the robustness of the daily adaptation, the adapted plans were compared to the autoplanning plans. Results: Median differences between the autoplanning plans on the planning scans and the reference plans were between -1 and 0.2 Gy. The largest interquartile range (1 Gy) was seen for the Lumbar Skin D2%. For the daily scans the PTV D2% and D98% differences between autoplanning and adapted plans were within ± 0.7 Gy, with mean differences within ± 0.3 Gy. Positive differences indicate higher values were obtained using autoplanning. For the Bowelarea + Bladder and the Lumbar Skin the D2% and Dmean differences were all within ± 2.6 Gy, with mean differences between -0.9 and 0.1 Gy. Conclusion: Automated treatment planning can be used to benchmark daily adaptation techniques. The investigated adaptation workflow can robustly perform high quality adaptations without daily adjusting of the patient-specific planning objectives for rectal cancer radiotherapy.

Explaining the dosimetric impact of contouring errors in head and neck radiotherapy.

Objective. Auto-contouring of organs at risk (OAR) is becoming more common in radiotherapy. An important issue in clinical decision making is judging the quality of the auto-contours. While recent studies considered contour quality by looking at geometric errors only, this does not capture the dosimetric impact of the errors. In this work, we studied the relationship between geometrical errors, the local dose and the dosimetric impact of the geometrical errors.Approach. For 94 head and neck patients, unmodified atlas-based auto-contours and clinically used delineations of the parotid glands and brainstem were retrieved. VMAT plans were automatically optimized on the auto-contours and evaluated on both contours. We defined the dosimetric impact on evaluation (DIE) as the difference in the dosimetric parameter of interest between the two contours. We developed three linear regression models to predict the DIE using: (1) global geometric metrics, (2) global dosimetric metrics, (3) combined local geometric and dosimetric metrics. For model (3), we next determined the minimal amount of editing information required to produce a reliable prediction. Performance was assessed by the root mean squared error (RMSE) of the predicted DIE using 5-fold cross-validation.Main results. In model (3), the median RMSE of the left parotid was 0.4 Gy using 5% of the largest editing vectors. For the right parotid and brainstem the results were 0.5 Gy using 10% and 0.4 Gy using 1% respectively. The median RMS of the DIE was 0.6 Gy, 0.7 Gy and 0.9 Gy for the left parotid, the right parotid and the brainstem, respectively. Model (3), combining local dosimetric and geometric quantities, outperformed the models that used only geometric or dosimetric information.Significance. We showed that the largest local errors plus the local dose suffice to accurately predict the dosimetric impact, opening the door to automated dosimetric QA of auto-contours.

Effect of intrafraction adaptation on PTV margins for MRI guided online adaptive radiotherapy for rectal cancer.

PURPOSE: To determine PTV margins for intrafraction motion in MRI-guided online adaptive radiotherapy for rectal cancer and the potential benefit of performing a 2nd adaptation prior to irradiation. METHODS: Thirty patients with rectal cancer received radiotherapy on a 1.5 T MR-Linac. On T2-weighted images for adaptation (MRIadapt), verification prior to (MRIver) and after irradiation (MRIpost) of 5 treatment fractions per patient, the primary tumor GTV (GTVprim) and mesorectum CTV (CTVmeso) were delineated. The structures on MRIadapt were expanded to corresponding PTVs. We determined the required expansion margins such that on average over 5 fractions, 98% of CTVmeso and 95% of GTVprim on MRIpost was covered in 90% of the patients. Furthermore, we studied the benefit of an additional adaptation, just prior to irradiation, by evaluating the coverage between the structures on MRIver and MRIpost. A threshold to assess the need for a secondary adaptation was determined by considering the overlap between MRIadapt and MRIver. RESULTS: PTV margins for intrafraction motion without 2nd adaptation were 6.4 mm in the anterior direction and 4.0 mm in all other directions for CTVmeso and 5.0 mm isotropically for GTVprim. A 2nd adaptation, applied for all fractions where the motion between MRIadapt and MRIver exceeded 1 mm (36% of the fractions) would result in a reduction of the PTVmeso margin to 3.2 mm/2.0 mm. For PTVprim a margin reduction to 3.5 mm is feasible when a 2nd adaptation is performed in fractions where the motion exceeded 4 mm (17% of the fractions). CONCLUSION: We studied the potential benefit of intrafraction motion monitoring and a 2nd adaptation to reduce PTV margins in online adaptive MRIgRT in rectal cancer. Performing 2nd adaptations immediately after online replanning when motion exceeded 1 mm and 4 mm for CTVmeso and GTVprim respectively, could result in a 30-50% margin reduction with limited reduction of dose to the bowel.

Clinical rationale for in vivo portal dosimetry in magnetic resonance guided online adaptive radiotherapy.

Background and purpose: In magnetic resonance guided online adaptive radiotherapy, the patient model used for plan adaptation and dose calculation is created online under stringent time constraints. This study investigated the ability of in vivo portal dosimetry to detect deviations between the online patient model used for plan adaptation and the actual anatomy of the patient during delivery. Materials and methods: Portal images acquired during treatment were used to reconstruct the delivered dose corresponding to online adapted plans of 42 prostate and 20 rectal cancer patients. The reconstructed dose distributions were compared with the dose distributions calculated online by the treatment planning system by γ-analysis and by the difference in median dose to the high-dose volume. Results: Out of 245 prostate and 145 rectal cancer adapted plans, deviations were detected in 5 prostate and in 17 rectal adapted plans corresponding to 3 prostate and 6 rectal patients, respectively. For all but one of the alerts, deviations were explained due to discrepancies observed between the patient model used for plan adaptation and online magnetic resonance images. A single workflow incident in which the supporting arm of the anterior receive coil was accidentally moved in the treatment field was also detected. Conclusion: There is need for independent end-to-end checks in magnetic resonance guided online adaptive workflows including the verification of the online patient model. In vivo portal dosimetry can be used for such purpose as it can detect both patient related deviations and workflow incidents.

First multicentre experience of SABR for lymph node and liver oligometastatic disease on the unity MR-Linac.

The treatment of oligometastatic disease using MR guidance is an evolving field. Since August 2018 patients are treated on a 1.5 Tesla MR-Linac (MRL). We present current workflows and practice standards from seven institutions for the initial patients treated for lymph node and liver metastases.

Reduction of systematic dosimetric uncertainties in volumetric modulated arc therapy triggered by patient-specific quality assurance.

BACKGROUND AND PURPOSE: Dosimetric patient-Specific Quality Assurance (PSQA) data contain in addition to cases with alerts, many cases without alerts. The aim of this study was to present a procedure to investigate long-term trend analysis of the complete set of PSQA data for the presence of site-specific deviations to reduce underlying systematic dose uncertainties. MATERIALS AND METHODS: The procedure started by analysing a large set of prostate Volumetric Modulated Arc Therapy (VMAT) PSQA data obtained by comparing 3D electronic portal image device (EPID)_based in vivo dosimetry measurements with dose values predicted by the Treatment Planning System (TPS). If systematic deviations were present, several actions were required. These included confirmation of these deviations with an independent dose verification system for which a 2D detector array in a phantom was used, and analysing calculated with measured PSQA data, or delivery machine characteristics. Further analysis revealed that the under-dosage correlated with plan complexity and coincided with changes in clinically applied planning techniques. RESULTS: Prostate VMAT PSQA data showed an under-dosage gradual increasing to about 2% in 3 years, which was confirmed by the measurements with the 2D detector array in a phantom. The implementation of new beam fits in the TPS led to a reduction of the observed deviations. CONCLUSION: Long-term analysis of site-specific PSQA data is a useful method to monitor incremental changes in a radiotherapy department due to various changes in the treatment planning and delivery of prostate VMAT, and may lead to a reduction of systematic dose uncertainties in complex treatments.

The dosimetric and clinical advantages of the GTV-CTV-PTV margins reduction by 6 mm in head and neck squamous cell carcinoma: Significant acute and late toxicity reduction.

PURPOSE: We aim to identify the dosimetric and clinical impact of reducing the total GTV-CTV-PTV margins in head-and-neck squamous cell carcinoma (HNSCC) treated with definitive (chemo)radiation. MATERIALS AND METHODS: The acute and late toxicity and outcomes of 155 consecutive patients treated between February 2017 and March 2019 with GTV-CTV-PTV margins of 9 mm were compared to those of 155 consecutive patients treated with total margin of 15 mm margin, before April 2015. All patients were treated with VMAT with daily-image guidance using CBCT. RESULTS: Reducing the GTV-CTV-PTV by 6 mm resulted in significant reduction of total irradiated volume (PTV-total) by a median of 28.1% and significant reduction of doses to all salivary glands (largest reduction ipsilateral parotid gland; median -9.6 Gy) and constrictor muscle (-6.1 Gy) with subsequent reduction of the incidence of overall acute grade 3 toxicity (47.7% for 9 mm and 66.5% for 15 mm groups, p = 0.001), grade 3 mucositis (18.1% vs. 35.5%, p < 0.001) and feeding tube-dependency at the end of treatment (24.5% vs. 40%, p = 0.005). The incidence of late grade ≥ 2 xerostomia and dysphagia were also significantly lower in the 9 mm group (31.7% vs. 58.6% p < 0.001, and 15.4% vs. 26.7%, p = 0.04). The 2-year rates of loco-regional control, disease-free and overall survival were 78.8% vs.75.8%, 70.9% vs. 64.4%, and 83.8% vs. 67.6%, (p > 0.05, all). CONCLUSION: Reduction of the total GTV-CTV-PTV margins from 15 to 9 mm in HNSCC significantly reduced the irradiated volumes and the dose to salivary glands and constrictor muscle with significant reduction of radiation-related toxicity. The loco-regional control rates of both groups were comparable.

Master protocol trial design for technical feasibility of MR-guided radiotherapy.

The master protocol trial design aims to increase efficiency in terms of trial infrastructure and protocol administration which may accelerate development of (technical) innovations in radiation oncology. A master protocol to study feasibility of techniques/software for MR-guided adaptive radiotherapy with the MR-Linac is described and discussed.