Technical note: Cryostat transmission characterization for MR linac - temporal stability, clinical impact and change implementation.

BACKGROUND: In the Unity MR linac (Elekta AB, Stockholm, Sweden), the radiation beam traverses the cryostat and the coil support structure. The resulting beam attenuation must be considered for output calibration and its variation with gantry angle must be characterized in the treatment planning system (TPS). PURPOSE: The aim of this work was to investigate the impact of a change of the cryostat transmission characterization (CTC) curve, due to the helium level modification, on clinical treatment plan dosimetry and to report on the experience with the CTC curve update. METHODS: Twenty stereotactic body radiotherapy (SBRT) treatment plans: 10 prostate and 10 oligo-metastatic cancer plans, prepared with a beam model incorporating the CTC curve acquired at installation time, were re-calculated using the model implementing CTC curve post helium top-up. To account for the CTC change as well as to align our system to the recent reference conditions recommendations, the new model was commissioned with the emphasis on the specifics associated with the treatment plan adaptation and the existence of the offline and online TPS components. RESULTS: Average CTV mean dose reduction by 0.45% in prostate cases and average GTV mean dose reduction by 0.22% in oligo-metastatic cases was observed. Updated model validation showcased good agreement between measurements and TPS calculations. CONCLUSIONS: The agreement between CTC measurements demonstrates its temporal constancy and robustness of the measurement method employed. A helium fill level change was shown to affect the CTC and led to a small but systematic dose calculation inaccuracy. Finally, model validation and end-to-end testing results presented, underscore the minimal impact of transitioning to the new beam model and new reference conditions.

Magnetic resonance guided adaptive post prostatectomy radiotherapy: Accumulated dose comparison of different workflows.

PURPOSE: The aim of this study was to assess the use of magnetic resonance guided adaptive radiotherapy (MRgART) in the post-prostatectomy setting; comparing dose accumulation for our initial seven patients treated with fully adaptive workflow on the Unity MR-Linac (MRL) and with non-adaptive plans generated offline. Additionally, we analyzed toxicity in patients receiving treatment. METHODS: Seven patients were treated with MRgART. The prescription was 70-72 Gy in 35-36 fractions. Patients were treated with an adapt to shape (ATS) technique. For each clinically delivered plan, a non-adaptive plan based upon the reference plan was generated and compared to the associated clinically delivered plan. A total of 468 plans were analyzed. Concordance Index of target and Organs at Risk (OARs) for each fraction with reference contours was analyzed. Acute toxicity was then assessed at six-months following completion of treatment with Common Terminology for Adverse Events (CTCAE) Toxicity Criteria. RESULTS: A total of 246 fractions were clinically delivered to seven patients; 234 fractions were delivered via MRgART and 12 fractions delivered via a traditional linear accelerator due to machine issues. Pre-treatment reference plans met CTV and OAR criteria. PTV coverage satisfaction was higher in the clinically delivered adaptive plans than non-adaptive comparison plans; 42.93% versus 7.27% respectively. Six-month CTCAE genitourinary and gastrointestinal toxicity was absent in most patients, and mild-to-moderate in a minority of patients (Grade 1 GU toxicity in one patient and Grade 2 GI toxicity in one patient). CONCLUSIONS: Daily MRgART treatment consistently met planning criteria. Target volume variability in prostate bed treatment can be mitigated by using MRgART and deliver satisfactory coverage of CTV whilst minimizing dose to adjacent OARs and reducing toxicity.

Towards simulation-free MR-linac treatment: utilizing male pelvis PSMA-PET/CT and population-based electron density assignments.

Objective. This study aimed to investigate the dosimetric impact of using population-based relative electron density (RED) overrides in lieu of simulation computerized tomography (CT) in a magnetic resonance linear accelerator (MRL) workflow for male pelvis patients. Additionally, the feasibility of using prostate specific membrane antigen positron emission tomography/CT (PSMA-PET/CT) scans to assess patients' eligibility for this proposed workflow was examined.Approach. In this study, 74 male pelvis patients treated on an Elekta Unity 1.5 T MRL were retrospectively selected. The patients' individual RED values for 8 organs of interest were extracted from their simulation-CT images to establish population-based RED values. These values were used to generate individual (IndD) and population-based (PopD) RED dose plans, representing current and proposed MRL workflows, respectively. Lastly, this study compared RED values obtained from CT and PET-CT scanners in a phantom and a subset of patients.Results. Population-based RED values were mostly within two standard deviations of ICRU Report 46 values. PopD plans were comparable to IndD plans, with the average %difference magnitudes of 0.5%, 0.6%, and 0.6% for mean dose (all organs), D0.1cm3(non-target organs) and D95%/D98% (target organs), respectively. Both phantom and patient PET-CT derived RED values had high agreement with corresponding CT-derived values, with correlation coefficients ≥ 0.9.Significance. Population-based RED values were considered suitable in a simulation-free MRL treatment workflow. Utilizing these RED values resulted in similar dosimetric uncertainties as per the current workflow. Initial findings also suggested that PET-CT scans may be used to assess prospective patients' eligibility for the proposed workflow. Future investigations will evaluate the clinical feasibility of implementing this workflow for prospective patients in the clinical setting. This is aimed to reduce patient burden during radiotherapy and increase department efficiencies.

Clinical target volume delineation quality assurance for MRI-guided prostate radiotherapy using deep learning with uncertainty estimation.

BACKGROUND AND PURPOSE: Previous studies on automatic delineation quality assurance (QA) have mostly focused on CT-based planning. As MRI-guided radiotherapy is increasingly utilized in prostate cancer treatment, there is a need for more research on MRI-specific automatic QA. This work proposes a clinical target volume (CTV) delineation QA framework based on deep learning (DL) for MRI-guided prostate radiotherapy. MATERIALS AND METHODS: The proposed workflow utilized a 3D dropblock ResUnet++ (DB-ResUnet++) to generate multiple segmentation predictions via Monte Carlo dropout which were used to compute an average delineation and area of uncertainty. A logistic regression (LR) classifier was employed to classify the manual delineation as pass or discrepancy based on the spatial association between the manual delineation and the network's outputs. This approach was evaluated on a multicentre MRI-only prostate radiotherapy dataset and compared with our previously published QA framework based on AN-AG Unet. RESULTS: The proposed framework achieved an area under the receiver operating curve (AUROC) of 0.92, a true positive rate (TPR) of 0.92 and a false positive rate of 0.09 with an average processing time per delineation of 1.3 min. Compared with our previous work using AN-AG Unet, this method generated fewer false positive detections at the same TPR with a much faster processing speed. CONCLUSION: To the best of our knowledge, this is the first study to propose an automatic delineation QA tool using DL with uncertainty estimation for MRI-guided prostate radiotherapy, which can potentially be used for reviewing prostate CTV delineation in multicentre clinical trials.

Mid-treatment 18F-FDG PET imaging changes in parotid gland correlates to radiation-induced xerostomia.

BACKGROUND: The aim of this study was to measure functional changes in parotid glands using mid-treatment FDG-PET/CT and correlate early imaging changes to subsequent xerostomia in mucosal head and neck squamous cell carcinoma patients undergoing radiotherapy. MATERIALS AND METHODS: 56 patients from two prospective imaging biomarker studies underwent FDG-PET/CT at baseline and during radiotherapy (week 3). Both parotid glands were volumetrically delineated at each time point. PET parameter SUVmedian were calculated for ipsilateral and contralateral parotid glands. Absolute and relative change (Δ) in SUVmedian were correlated to moderate-severe xerostomia (CTCAE grade ≥ 2) at 6 months. Four predictive models were subsequently created using multivariate logistic regression using clinical and radiotherapy planning parameters. Model performance was calculated using ROC analysis and compared using Akaike information criterion (AIC) RESULTS: 29 patients (51.8%) developed grade ≥ 2 xerostomia. Compared to baseline, there was an increase in SUVmedian at week 3 in ipsilateral (8.4%) and contralateral (5.5%) parotid glands. Increase in ipsilateral parotid Δ SUVmedian (p = 0.04) and contralateral mean parotid dose (p = 0.04) were correlated to xerostomia. The reference 'clinical' model correlated to xerostomia (AUC 0.667, AIC 70.9). Addition of ipsilateral parotid Δ SUVmedian to the clinical model resulted in the highest correlation to xerostomia (AUC 0.777, AIC 65.4). CONCLUSION: Our study shows functional changes occurring in the parotid gland early during radiotherapy. We demonstrate that integration of baseline and mid-treatment FDG-PET/CT changes in the parotid gland with clinical factors has the potential to improve xerostomia risk prediction which could be utilised for personalised head and neck radiotherapy.

Impact of tumour region of interest delineation method for mid-treatment FDG-PET response prediction in head and neck squamous cell carcinoma undergoing radiotherapy.

Background: The aim of this study was to evaluate the impact of tumour region of interest (ROI) delineation method on mid-treatment 18F-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) response prediction in mucosal head and neck squamous cell carcinoma during radiotherapy. Methods: A total of 52 patients undergoing definitive radiotherapy with or without systemic therapy from two prospective imaging biomarker studies were analysed. FDG-PET was performed at baseline and during radiotherapy (week 3). Primary tumour was delineated using a fixed SUV 2.5 threshold (MTV2.5), relative threshold (MTV40%) and a gradient based segmentation method (PET Edge). PET parameters SUVmax, SUVmean, metabolic tumour volume (MTV) and total lesion glycolysis (TLG) were calculated using different ROI methods. Absolute and relative change (∆) in PET parameters were correlated to 2-year locoregional recurrence. Strength of correlation was tested using receiver operator characteristic analysis using area under the curve (AUC). Response was categorized using optimal cut-off (OC) values. Correlation and agreement between different ROI methods was determined using Bland-Altman analysis. Results: A significant difference in SUVmean, MTV and TLG values were noted between ROI delineation methods. When measuring relative change at week 3, a greater agreement was seen between PET Edge and MTV2.5 methods with average difference in ∆SUVmax, ∆SUVmean, ∆MTV and ∆TLG of 0.0%, 3.6%, 10.3% and 13.6% respectively. A total of 12 patients (22.2%) experienced locoregional recurrence. ∆MTV using PET Edge was the best predictor of locoregional recurrence (AUC =0.761, 95% CI: 0.573-0.948, P=0.001; OC ∆>50%). The corresponding 2-year locoregional recurrence rate was 7% vs. 35%, P=0.001. Conclusions: Our findings suggest that it is preferable to use gradient based method to assess volumetric tumour response during radiotherapy and offers advantage in predicting treatment outcomes compared with threshold-based methods. This finding requires further validation and can assist in future response-adaptive clinical trials.

Applicability and usage of dose mapping/accumulation in radiotherapy.

Dose mapping/accumulation (DMA) is a topic in radiotherapy (RT) for years, but has not yet found its widespread way into clinical RT routine. During the ESTRO Physics workshop 2021 on "commissioning and quality assurance of deformable image registration (DIR) for current and future RT applications", we built a working group on DMA from which we present the results of our discussions in this article. Our aim in this manuscript is to shed light on the current situation of DMA in RT and to highlight the issues that hinder consciously integrating it into clinical RT routine. As a first outcome of our discussions, we present a scheme where representative RT use cases are positioned, considering expected anatomical variations and the impact of dose mapping uncertainties on patient safety, which we have named the DMA landscape (DMAL). This tool is useful for future reference when DMA applications get closer to clinical day-to-day use. Secondly, we discussed current challenges, lightly touching on first-order effects (related to the impact of DIR uncertainties in dose mapping), and focusing in detail on second-order effects often dismissed in the current literature (as resampling and interpolation, quality assurance considerations, and radiobiological issues). Finally, we developed recommendations, and guidelines for vendors and users. Our main point include: Strive for context-driven DIR (by considering their impact on clinical decisions/judgements) rather than perfect DIR; be conscious of the limitations of the implemented DIR algorithm; and consider when dose mapping (with properly quantified uncertainties) is a better alternative than no mapping.

ACPSEM position paper: the safety of magnetic resonance imaging linear accelerators.

Magnetic Resonance Imaging linear-accelerator (MRI-linac) equipment has recently been introduced to multiple centres in Australia and New Zealand. MRI equipment creates hazards for staff, patients and others in the MR environment; these hazards must be well understood, and risks managed by a system of environmental controls, written procedures and a trained workforce. While MRI-linac hazards are similar to the diagnostic paradigm, the equipment, workforce and environment are sufficiently different that additional safety guidance is warranted. In 2019 the Australasian College of Physical Scientists and Engineers in Medicine (ACPSEM) formed the Magnetic Resonance Imaging Linear-Accelerator Working Group (MRILWG) to support the safe clinical introduction and optimal use of MR-guided radiation therapy treatment units. This Position Paper is intended to provide safety guidance and education for Medical Physicists and others planning for and working with MRI-linac technology. This document summarises MRI-linac hazards and describes particular effects which arise from the combination of strong magnetic fields with an external radiation treatment beam. This document also provides guidance on safety governance and training, and recommends a system of hazard management tailored to the MRI-linac environment, ancillary equipment, and workforce.

Identifying the location of locoregional recurrences after definitive radiotherapy for head and neck cancer using metabolic parameters of baseline and mid-treatment 18F-FDG-PET scans.

INTRODUCTION: Tumour recurrences after treatment of head and neck squamous cell carcinoma (HNSCC) are more likely to originate from regions of high-baseline FDG-PET uptake. Mid-treatment functional imaging can potentially predict for higher risk of tumour recurrence. The aim of this study is to correlate the location of locoregional tumour recurrence with baseline FDG-PET metabolic volumes and mid-treatment FDG-PET metabolic volumes in patients with HNSCC following definitive radiotherapy. METHODS: A total of 23 patients with 26 local and/or regional recurrences underwent baseline (W0-PET) and mid-treatment (W3-PET) 18F-FDG PET scans as part of their radiotherapy. FDG-PET-based metabolic volumes (MTV20%, MTV40%, MTV60%, MTV80%, SUV2.5, SUVpeak and PET_EDGE) were delineated onto the FDG-PET scans. The recurrence nidus was identified on FDG-PET at the time of recurrence (REC-PET). DIR-based fusion was performed for REC-PET to W0-PET, and REC-PET to W3-PET. The location of the recurrence nidus was correlated with the FDG-PET volumes. Further analysis included a comparison of the recurrence density to FDG-PET metabolic volumes. RESULTS: Most recurrences occurred within the MTV20%, MTV40% and SUV 2.5 volumes. Sixty-nine per cent of recurrences (18 of 26) occurred within both the W0 MTV40% and W3 MTV40% volumes. A higher recurrence density was seen for iso-SUV contours closer to the maximum SUV for both W0 and W3. For a number of the FDG-PET volumes, including MTV20%, MTV40% and SUV2.5, the recurrence density was improved for W3 compared to W0, however, this improvement was small in magnitude. The average volume of MTV40% contours was considerably smaller than MTV20% and SUV2.5 contours. CONCLUSION: The metabolic parameters of SUV2.5, MTV20% and MTV40% delineated on the baseline and mid-treatment FDG-PET scans encompassed the majority of recurrences. The MTV40% is significantly smaller, hence, we prefer this volume for future dose escalation studies.

Delineation uncertainties of tumour volumes on MRI of head and neck cancer patients.

Background: During the last decade, radiotherapy using MR Linac has gone from research to clinical implementation for different cancer locations. For head and neck cancer (HNC), target delineation based only on MR images is not yet standard, and the utilisation of MRI instead of PET/CT in radiotherapy planning is not well established. We aimed to analyse the inter-observer variation (IOV) in delineating GTV (gross tumour volume) on MR images only for patients with HNC. Material/methods: 32 HNC patients from two independent departments were included. Four clinical oncologists from Denmark and four radiation oncologists from Australia had independently contoured primary tumour GTVs (GTV-T) and nodal GTVs (GTV-N) on T2-weighted MR images obtained at the time of treatment planning. Observers were provided with sets of images, delineation guidelines and patient synopsis. Simultaneous truth and performance level estimation (STAPLE) reference volumes were generated for each structure using all observer contours. The IOV was assessed using the DICE Similarity Coefficient (DSC) and mean absolute surface distance (MASD). Results: 32 GTV-Ts and 68 GTV-Ns were contoured per observer. The median MASD for GTV-Ts and GTV-Ns across all patients was 0.17 cm (range 0.08-0.39 cm) and 0.07 cm (range 0.04-0.33 cm), respectively. Median DSC relative to a STAPLE volume for GTV-Ts and GTV-Ns across all patients were 0.73 and 0.76, respectively. A significant correlation was seen between median DSCs and median volumes of GTV-Ts (Spearman correlation coefficient 0.76, p < 0.001) and of GTV-Ns (Spearman correlation coefficient 0.55, p < 0.001). Conclusion: Contouring GTVs in patients with HNC on MRI showed that the median IOV for GTV-T and GTV-N was below 2 mm, based on observes from two separate radiation departments. However, there are still specific regions in tumours that are difficult to resolve as either malignant tissue or oedema that potentially could be improved by further training in MR-only delineation.

Early experience with MR-guided adaptive radiotherapy using a 1.5 T MR-Linac: First 6 months of operation using adapt to shape workflow.

INTRODUCTION: The magnetic resonance linear accelerator (MRL) offers improved soft tissue visualization to guide daily adaptive radiotherapy treatment. This manuscript aims to report initial experience using a 1.5 T MRL in the first 6 months of operation, including training, workflows, timings and dosimetric accuracy. METHODS: All staff received training in MRI safety and MRL workflows. Initial sites chosen for treatment were stereotactic and hypofractionated prostate, thoraco-abdomino-pelvic metastasis, prostate bed and bladder. The Adapt To Shape (ATS) workflow was chosen to be the focus of treatment as it is the most robust solution for daily adaptive radiotherapy. A workflow was created addressing patient suitability, simulation, planning, treatment and peer review. Treatment times were recorded breaking down into the various stages of treatment. RESULTS: A total of 37 patients were treated and 317 fractions delivered (of which 313 were delivered using an ATS workflow) in our initial 6 months. Average treatment times over the entire period were 50 and 38 min for stereotactic and non-stereotactic treatments respectively. Average treatment times reduced each month. The average difference between reference planned and ionization chamber measured dose was 0.0 ± 1.4%. CONCLUSION: The MRL was successfully established in an Australian setting. A focus on training and creating a detailed workflow from patient selection, review and treatment are paramount to establishing new treatment programmes.

Analysis of data to Advance Personalised Therapy with MR-Linac (ADAPT-MRL).

BACKGROUND: Analysis of Data to Advance Personalised Therapy with MR-Linac (ADAPT-MRL) is a multi-site, multinational, observational cohort registry designed to collect data on the use of the magnetic resonance linear accelerator (MR-Linac) for radiation therapy and patient outcomes. The registry will provide a linked repository of technical and clinical data that will form a platform for prospective studies and technology assessment. METHODS: Design: This registry aims to include an estimated 10,000 eligible participants across Australia and other countries over a 7- to 10-year period. Participants will undergo treatment and assessments in accordance with standard practice. Toxicity and survival outcomes will be assessed at baseline, during treatment, and with 3 monthly follow-up until 24 months, patient reported outcome measures will also be collected. Participants with a variety of cancers will be included. DISCUSSION: Data obtained from the ADAPT-MRL registry is expected to provide evidence on the safety and efficacy of the MR-Linac, a new technical innovation in radiation oncology. We expect this registry will generate data that will be used to optimise treatment techniques, MR-Linac software algorithms, evaluate participants' outcomes and toxicities and to create a repository of adapted plans, anatomical and functional MR sequences linked to participants' outcomes.

Automatic radiotherapy delineation quality assurance on prostate MRI with deep learning in a multicentre clinical trial.

Volume delineation quality assurance (QA) is particularly important in clinical trial settings where consistent protocol implementation is required, as outcomes will affect future as well current patients. Currently, where feasible, this is conducted manually, which is time consuming and resource intensive. Although previous studies mostly focused on automating delineation QA on CT, magnetic resonance imaging (MRI) is being increasingly used in radiotherapy treatment. In this work, we propose to perform automatic delineation QA on prostate MRI for both the clinical target volume (CTV) and organs-at-risk (OARs) by using delineations generated by 3D Unet variants as benchmarks for QA. These networks were trained on a small gold standard atlas set and applied on a multicentre radiotherapy clinical trial dataset to generate benchmark delineations. Then, a QA stage was designed to recommend 'pass', 'minor correction' and 'major correction' for each manual delineation in the trial set by thresholding its Dice similarity coefficient to the network generated delineation. Among all 3D Unet variants explored, the Unet with anatomical gates in an AtlasNet architecture performed the best in delineation QA, achieving an area under the receiver operating characteristics curve of 0.97, 0.92, 0.89 and 0.97 for identifying unacceptable (major correction) delineations with a sensitivity of 0.93, 0.73, 0.74 and 0.90 at a specificity of 0.93, 0.86, 0.86 and 0.95 for bladder, prostate CTV, rectum and gel spacer respectively. To the best of our knowledge, this is the first study to propose automated delineation QA for a multicentre radiotherapy clinical trial with treatment planning MRI. The methods proposed in this work can potentially improve the accuracy and consistency of CTV and OAR delineation in radiotherapy treatment planning.

Cautiously optimistic: A survey of radiation oncology professionals' perceptions of automation in radiotherapy planning.

INTRODUCTION: While there is evidence to show the positive effects of automation, the impact on radiation oncology professionals has been poorly considered. This study examined radiation oncology professionals' perceptions of automation in radiotherapy planning. METHOD: An online survey link was sent to the chief radiation therapists (RT) of all Australian radiotherapy centres to be forwarded to RTs, medical physicists (MP) and radiation oncologists (RO) within their institution. The survey was open from May-July 2019. RESULTS: Participants were 204 RTs, 84 MPs and 37 ROs (response rates ∼10% of the overall radiation oncology workforce). Respondents felt automation resulted in improvement in consistency in planning (90%), productivity (88%), quality of planning (57%), and staff focus on patient care (49%). When asked about perceived impact of automation, the responses were; will change the primary tasks of certain jobs (66%), will allow staff to do the remaining components of their job more effectively (51%), will eliminate jobs (20%), and will not have an impact on jobs (6%). 27% of respondents believe automation will reduce job satisfaction. 71% of respondents strongly agree/agree that automation will cause a loss of skills, while only 25% strongly agree/agree that the training and education tools in their department are sufficient. CONCLUSION: Although the effect of automation is perceived positively, there are some concerns on loss of skillsets and the lack of training to maintain this. These results highlight the need for continued education to ensure that skills and knowledge are not lost with automation.

An international survey on the clinical use of rigid and deformable image registration in radiotherapy.

OBJECTIVES: Rigid image registration (RIR) and deformable image registration (DIR) are widely used in radiotherapy. This project aims to capture current international approaches to image registration. METHODS: A survey was designed to identify variations in use, resources, implementation, and decision-making criteria for clinical image registration. This was distributed to radiotherapy centers internationally in 2018. RESULTS: There were 57 responses internationally, from the Americas (46%), Australia/New Zealand (32%), Europe (12%), and Asia (10%). Rigid image registration and DIR were used clinically for computed tomography (CT)-CT registration (96% and 51%, respectively), followed by CT-PET (81% and 47%), CT-CBCT (84% and 19%), CT-MR (93% and 19%), MR-MR (49% and 5%), and CT-US (9% and 0%). Respondent centers performed DIR using dedicated software (75%) and treatment planning systems (29%), with 84% having some form of DIR software. Centers have clinically implemented DIR for atlas-based segmentation (47%), multi-modality treatment planning (65%), and dose deformation (63%). The clinical use of DIR for multi-modality treatment planning and accounting for retreatments was considered to have the highest benefit-to-risk ratio (69% and 67%, respectively). CONCLUSIONS: This survey data provides useful insights on where, when, and how image registration has been implemented in radiotherapy centers around the world. DIR is mainly in clinical use for CT-CT (51%) and CT-PET (47%) for the head and neck (43-57% over all use cases) region. The highest benefit-risk ratio for clinical use of DIR was for multi-modality treatment planning and accounting for retreatments, which also had higher clinical use than for adaptive radiotherapy and atlas-based segmentation.

Increased Dose to Organs in Urinary Tract Associates With Measures of Genitourinary Toxicity in Pooled Voxel-Based Analysis of 3 Randomized Phase III Trials.

Purpose: Dose information from organ sub-regions has been shown to be more predictive of genitourinary toxicity than whole organ dose volume histogram information. This study aimed to identify anatomically-localized regions where 3D dose is associated with genitourinary toxicities in healthy tissues throughout the pelvic anatomy. Methods and Materials: Dose distributions for up to 656 patients of the Trans-Tasman Radiation Oncology Group 03.04 RADAR trial were deformably registered onto a single exemplar CT dataset. Voxel- based multiple comparison permutation dose difference testing, Cox regression modeling and LASSO feature selection were used to identify regions where 3D dose-increase was associated with late grade ≥ 2 genitourinary dysuria, incontinence and frequency, and late grade ≥ 1 haematuria. This was externally validated by registering dose distributions from the RT01 (up to n = 388) and CHHiP (up to n = 247) trials onto the same exemplar and repeating the voxel-based tests on each of these data sets. All three datasets were then combined, and the tests repeated. Results: Voxel-based Cox regression and multiple comparison permutation dose difference testing revealed regions where increased dose was correlated with genitourinary toxicity. Increased dose in the vicinity of the membranous and spongy urethra was associated with dysuria for all datasets. Haematuria was similarly correlated with increased dose at the membranous and spongy urethra, for the RADAR, CHHiP, and combined datasets. Some evidence was found for the association between incontinence and increased dose at the internal and external urethral sphincter for RADAR and the internal sphincter alone for the combined dataset. Incontinence was also strongly correlated with dose from posterior oblique beams. Patients with fields extending inferiorly and posteriorly to the CTV, adjacent to the membranous and spongy urethra, were found to experience increased frequency. Conclusions: Anatomically-localized dose-toxicity relationships were determined for late genitourinary symptoms in the urethra and urinary sphincters. Low-intermediate doses to the extraprostatic urethra were associated with risk of late dysuria and haematuria, while dose to the urinary sphincters was associated with incontinence.

Relationships between rectal and perirectal doses and rectal bleeding or tenesmus in pooled voxel-based analysis of 3 randomised phase III trials.

BACKGROUND AND PURPOSE: This study aimed to identify anatomically-localised regions where planned radiotherapy dose is associated with gastrointestinal toxicities in healthy tissues throughout the pelvic anatomy. MATERIALS AND METHODS: Planned dose distributions for up to 657 patients of the Trans Tasman Radiation Oncology Group 03.04 RADAR trial were deformably registered onto a single exemplar computed tomography dataset. Voxel-based multiple comparison permutation dose difference testing, Cox regression modelling and LASSO feature selection were used to identify regions where dose-increase was associated with grade ≥2 rectal bleeding (RB) or tenesmus, according to the LENT/SOMA scale. This was externally validated by registering dose distributions from the RT01 (n = 388) and CHHiP (n = 241) trials onto the same exemplar and repeating the tests on each of these data sets, and on all three datasets combined. RESULTS: Voxel-based Cox regression and permutation dose difference testing revealed regions where increased dose was correlated with gastrointestinal toxicity. Grade ≥2 RB was associated with posteriorly extended lateral beams that manifested high doses (>55 Gy) in a small rectal volume adjacent to the clinical target volume. A correlation was found between grade ≥2 tenesmus and increased low-intermediate dose (∼25 Gy) at the posterior beam region, including the posterior rectum and perirectal fat space (PRFS). CONCLUSIONS: The serial response of the rectum with respect to RB has been demonstrated in patients with posteriorly extended lateral beams. Similarly, the parallel response of the PRFS with respect to tenesmus has been demonstrated in patients treated with the posterior beam.

Reduced Dose Posterior to Prostate Correlates With Increased PSA Progression in Voxel-Based Analysis of 3 Randomized Phase 3 Trials.

PURPOSE: Reducing margins during treatment planning to decrease dose to healthy organs surrounding the prostate can risk inadequate treatment of subclinical disease. This study aimed to investigate whether lack of dose to subclinical disease is associated with increased disease progression by using high-quality prostate radiation therapy clinical trial data to identify anatomically localized regions where dose variation is associated with prostate-specific antigen progression (PSAP). METHODS AND MATERIALS: Planned dose distributions for 683 patients of the Trans-Tasman Radiation Oncology Group 03.04 Randomized Androgen Deprivation and Radiotherapy (RADAR) trial were deformably registered onto a single exemplar computed tomography data set. These were divided into high-risk and intermediate-risk subgroups for analysis. Three independent voxel-based statistical tests, using permutation testing, Cox regression modeling, and least absolute shrinkage selection operator feature selection, were applied to identify regions where dose variation was associated with PSAP. Results from the intermediate-risk RADAR subgroup were externally validated by registering dose distributions from the RT01 (n = 388) and Conventional or Hypofractionated High Dose Intensity Modulated Radiotherapy for Prostate Cancer Trial (CHHiP) (n = 253) trials onto the same exemplar and repeating the tests on each of these data sets. RESULTS: Voxel-based Cox regression revealed regions where reduced dose was correlated with increased prostate-specific androgen progression. Reduced dose in regions associated with coverage at the posterior prostate, in the immediate periphery of the posterior prostate, and in regions corresponding to the posterior oblique beams or posterior lateral beam boundary, was associated with increased PSAP for RADAR and RT01 patients, but not for CHHiP patients. Reduced dose to the seminal vesicle region was also associated with increased PSAP for RADAR intermediate-risk patients. CONCLUSIONS: Ensuring adequate dose coverage at the posterior prostate and immediately surrounding posterior region (including the seminal vesicles), where aggressive cancer spread may be occurring, may improve tumor control. It is recommended that particular care be taken when defining margins at the prostate posterior, acknowledging the trade-off between quality of life due to rectal dose and the preferences of clinicians and patients.

Contour variation is a primary source of error when delivering post prostatectomy radiotherapy: Results of the Trans-Tasman Radiation Oncology Group 08.03 Radiotherapy Adjuvant Versus Early Salvage (RAVES) benchmarking exercise.

INTRODUCTION: Variation in target volume delineation from clinical trial protocols has been shown to contribute to poorer patient outcomes. A clinical trial quality assurance framework can support compliance with trial protocol. Results of the TROG 08.03 RAVES benchmarking exercise considering variation from protocol, inter-observer variability and impact on dosimetry are reported in this paper. METHODS: Clinicians were required to contour and plan a benchmarking case according to trial protocol. Geometric pjmirometers including volume, Hausdorff Distance, Mean Distance to Agreement and DICE similarity coefficient were analysed for targets and organs at risk. Submitted volumes were compared to a STAPLE and consensus 'reference' volume for each structure. Dosimetric analysis was performed using dose volume histogram data. RESULTS: Benchmarking exercise submissions were received from 96 clinicians. In total 205 protocol variations were identified. The most common variation was inadequate contouring of the CTV in 84/205 (41%). The CTV volume ranged from 65.3 to 193.1 cm3 with a median of 113.2 cm3 . The most common dosimetric protocol variation related to rectal dosimetry. The mean submitted rectal volume receiving 40 Gy and 60 Gy, respectively, was 56.14% ± 5.55% and 30.25% ± 6.15%. When corrected to the protocol defined length the mean rectal volume receiving 40 Gy was 60.8% ± 7.92%, while the volume receiving 60 Gy was 33.86% ± 8.21%. CONCLUSION: Variations from protocol were found in the RAVES benchmarking exercise, most notably in CTV and rectum delineation. Inter-observer variability was evident. Incorrect delineation of the rectum impacted on dosimetric compliance with protocol.