Cardiac substructure delineation in radiation therapy - A state-of-the-art review.

Delineation of cardiac substructures is crucial for a better understanding of radiation-related cardiotoxicities and to facilitate accurate and precise cardiac dose calculation for developing and applying risk models. This review examines recent advancements in cardiac substructure delineation in the radiation therapy (RT) context, aiming to provide a comprehensive overview of the current level of knowledge, challenges and future directions in this evolving field. Imaging used for RT planning presents challenges in reliably visualising cardiac anatomy. Although cardiac atlases and contouring guidelines aid in standardisation and reduction of variability, significant uncertainties remain in defining cardiac anatomy. Coupled with the inherent complexity of the heart, this necessitates auto-contouring for consistent large-scale data analysis and improved efficiency in prospective applications. Auto-contouring models, developed primarily for breast and lung cancer RT, have demonstrated performance comparable to manual contouring, marking a significant milestone in the evolution of cardiac delineation practices. Nevertheless, several key concerns require further investigation. There is an unmet need for expanding cardiac auto-contouring models to encompass a broader range of cancer sites. A shift in focus is needed from ensuring accuracy to enhancing the robustness and accessibility of auto-contouring models. Addressing these challenges is paramount for the integration of cardiac substructure delineation and associated risk models into routine clinical practice, thereby improving the safety of RT for future cancer patients.

Towards optimal heterogeneous prostate radiotherapy dose prescriptions based on patient-specific or population-based biological features.

BACKGROUND: Escalation of prescribed dose in prostate cancer (PCa) radiotherapy enables improvement in tumor control at the expense of increased toxicity. Opportunities for reduction of treatment toxicity may emerge if more efficient dose escalation can be achieved by redistributing the prescribed dose distribution according to the known heterogeneous, spatially-varying characteristics of the disease. PURPOSE: To examine the potential benefits, limitations and characteristics of heterogeneous boost dose redistribution in PCa radiotherapy based on patient-specific and population-based spatial maps of tumor biological features. METHOD: High-resolution prostate histology images, from a cohort of 63 patients, annotated with tumor location and grade, provided patient-specific "maps" and a population-based "atlas" of cell density and tumor probability. Dose prescriptions were derived for each patient based on a heterogeneous redistribution of the boost dose to the intraprostatic lesions, with the prescription maximizing patient tumor control probability (TCP). The impact on TCP was assessed under scenarios where the distribution of population-based biological data was ignored, partially included, or fully included in prescription generation. Heterogeneous dose prescriptions were generated for three combinations of maps and atlas, and for conventional fractionation (CF), extreme hypo-fractionation (EH), moderate hypo-fractionation (MH), and whole Pelvic RT + SBRT Boost (WPRT + SBRT). The predicted efficacy of the heterogeneous prescriptions was compared with equivalent homogeneous dose prescriptions. RESULTS: TCPs for heterogeneous dose prescriptions were generally higher than those for homogeneous dose prescriptions. TCP escalation by heterogeneous dose prescription was the largest for CF. When only using population-based atlas data, the generated heterogeneous dose prescriptions of 55 to 58 patients (out of 63) had a higher TCP than for the corresponding homogeneous dose prescriptions. The TCPs of the heterogeneous dose prescriptions generated with the population-based atlas and tumor probability maps did not differ significantly from those using patient-specific biological information. The generated heterogeneous dose prescriptions achieved significantly higher TCP than homogeneous dose prescriptions in the posterior section of the prostate. CONCLUSION: Heterogeneous dose prescriptions generated via biologically-optimized dose redistribution can produce higher TCP than the homogeneous dose prescriptions for the majority of the patients in the studied cohort. For scenarios where patient-specific biological information was unavailable or partially available, the generated heterogeneous dose prescriptions can still achieve TCP improvement relative to homogeneous dose prescriptions.

An open source auto-segmentation algorithm for delineating heart and substructures - Development and validation within a multicenter lung cancer cohort.

BACKGROUND AND PURPOSE: Irradiation of the heart in thoracic cancers raises toxicity concerns. For accurate dose estimation, automated heart and substructure segmentation is potentially useful. In this study, a hybrid automatic segmentation is developed. The accuracy of delineation and dose predictions were evaluated, testing the method's potential within heart toxicity studies. MATERIALS AND METHODS: The hybrid segmentation method delineated the heart, four chambers, three large vessels, and the coronary arteries. The method consisted of a nnU-net heart segmentation and partly atlas- and model-based segmentation of the substructures. The nnU-net training and atlas segmentation was based on lung cancer patients and was validated against a national consensus dataset of 12 patients with breast cancer. The accuracy of dose predictions between manual and auto-segmented heart and substructures was evaluated by transferring the dose distribution of 240 previously treated lung cancer patients to the consensus data set. RESULTS: The hybrid auto-segmentation method performed well with a heart dice similarity coefficient (DSC) of 0.95, with no statistically significant difference between the automatic and manual delineations. The DSC for the chambers varied from 0.78-0.86 for the automatic segmentation and was comparable with the inter-observer variability. Most importantly, the automatic segmentation was as precise as the clinical experts in predicting the dose distribution to the heart and all substructures. CONCLUSION: The hybrid segmentation method performed well in delineating the heart and substructures. The prediction of dose by the automatic segmentation was aligned with the manual delineations, enabling measurement of heart and substructure dose in large cohorts. The delineation algorithm will be available for download.

Realistic CT data augmentation for accurate deep-learning based segmentation of head and neck tumors in kV images acquired during radiation therapy.

BACKGROUND: Using radiation therapy (RT) to treat head and neck (H&N) cancers requires precise targeting of the tumor to avoid damaging the surrounding healthy organs. Immobilisation masks and planning target volume margins are used to attempt to mitigate patient motion during treatment, however patient motion can still occur. Patient motion during RT can lead to decreased treatment effectiveness and a higher chance of treatment related side effects. Tracking tumor motion would enable motion compensation during RT, leading to more accurate dose delivery. PURPOSE: The purpose of this paper is to develop a method to detect and segment the tumor in kV images acquired during RT. Unlike previous tumor segmentation methods for kV images, in this paper, a process for generating realistic and synthetic CT deformations was developed to augment the training data and make the segmentation method robust to patient motion. Detecting the tumor in 2D kV images is a necessary step toward 3D tracking of the tumor position during treatment. METHOD: In this paper, a conditional generative adversarial network (cGAN) is presented that can detect and segment the gross tumor volume (GTV) in kV images acquired during H&N RT. Retrospective data from 15 H&N cancer patients obtained from the Cancer Imaging Archive were used to train and test patient-specific cGANs. The training data consisted of digitally reconstructed radiographs (DRRs) generated from each patient's planning CT and contoured GTV. Training data was augmented by using synthetically deformed CTs to generate additional DRRs (in total 39 600 DRRs per patient or 25 200 DRRs for nasopharyngeal patients) containing realistic patient motion. The method for deforming the CTs was a novel deformation method based on simulating head rotation and internal tumor motion. The testing dataset consisted of 1080 DRRs for each patient, obtained by deforming the planning CT and GTV at different magnitudes to the training data. The accuracy of the generated segmentations was evaluated by measuring the segmentation centroid error, Dice similarity coefficient (DSC) and mean surface distance (MSD). This paper evaluated the hypothesis that when patient motion occurs, using a cGAN to segment the GTV would create a more accurate segmentation than no-tracking segmentations from the original contoured GTV, the current standard-of-care. This hypothesis was tested using the 1-tailed Mann-Whitney U-test. RESULTS: The magnitude of our cGAN segmentation centroid error was (mean ± standard deviation) 1.1 ± 0.8 mm and the DSC and MSD values were 0.90 ± 0.03 and 1.6 ± 0.5 mm, respectively. Our cGAN segmentation method reduced the segmentation centroid error (p < 0.001), and MSD (p = 0.031) when compared to the no-tracking segmentation, but did not significantly increase the DSC (p = 0.294). CONCLUSIONS: The accuracy of our cGAN segmentation method demonstrates the feasibility of this method for H&N cancer patients during RT. Accurate tumor segmentation of H&N tumors would allow for intrafraction monitoring methods to compensate for tumor motion during treatment, ensuring more accurate dose delivery and enabling better H&N cancer patient outcomes.

Patient-specific voxel-level dose prescription for prostate cancer radiotherapy considering tumor cell density and grade distribution.

BACKGROUND: In prostate radiation therapy, recent studies have indicated a benefit in increasing the dose to intraprostatic lesions (IPL) compared with standard whole gland radiation therapy. Such approaches typically aim to deliver a target dose to the IPL(s) with no deliberate effort to modulate the dose within the IPL. Prostate cancers demonstrate intra-tumor heterogeneity and hence it is hypothesized that further gains in the optimal delivery of radiation therapy can be achieved through modulation of the dose distribution within the tumor. To account for tumor heterogeneity, biologically targeted radiation therapy (BiRT) aims to utilize a voxel-wise approach to IPL dose prescription by incorporating knowledge of the spatial distribution of tumor characteristics. PURPOSE: The aim of this study was to develop a workflow for generating voxel-wise optimal dose prescriptions that maximize patient tumor control probability (TCP), and evaluate the feasibility and benefits of applying this workflow on a cohort of 62 prostate cancer patients. METHOD: The source data for this proof-of-concept study included high resolution histology images annotated with tumor location and grade. Image processing techniques were used to compute voxel-level cell density distribution maps. An absolute tumor cell distribution was calculated via linearly scaling according to published estimated tumor cell numbers. For the IPLs of each patient, optimal dose prescriptions were obtained via three alternative methods for redistribution of IPL boost doses according to maximization of TCP. The radiosensitivity uncertainties were considered using a truncated log-normally distributed linear radiosensitivity parameter ( α k ${\alpha }_k$ ) and compared with Gleason pattern (GP) dependent radiosensitivity parameters that were derived based on previously published methods. An ensemble machine learning method was implemented to identify patient-specific features that predict the TCP improvement resulting from dose redistribution relative to a uniform dose distribution. RESULTS: The Gleason pattern-dependent radiosensitivity parameters were calculated for 20 published prostate cancer α / ß ${{\alpha}}/{{\beta}}$ ratios. Optimal voxel-level dose prescriptions were generated for all 62 PCa patients. For all dose redistribution scenarios, the optimal dose distribution always shows a higher (or equivalent) TCP level than the uniform dose distribution. The applied random forest regressor could predict patient-specific TCP improvement with low root mean square error (≤1.5%) by using total tumor number, volume of IPLs and the standard deviation of tumor cell number among all voxels. CONCLUSION: Biologically-optimized redistribution of a boost dose can yield TCP improvement relative to a uniform-boost dose distribution. Patient-specific tumor characteristics can be used to predict the likelihood of benefit from a redistribution approach for the individual patient.

Open-source, fully-automated hybrid cardiac substructure segmentation: development and optimisation.

Radiotherapy for thoracic and breast tumours is associated with a range of cardiotoxicities. Emerging evidence suggests cardiac substructure doses may be more predictive of specific outcomes, however, quantitative data necessary to develop clinical planning constraints is lacking. Retrospective analysis of patient data is required, which relies on accurate segmentation of cardiac substructures. In this study, a novel model was designed to deliver reliable, accurate, and anatomically consistent segmentation of 18 cardiac substructures on computed tomography (CT) scans. Thirty manually contoured CT scans were included. The proposed multi-stage method leverages deep learning (DL), multi-atlas mapping, and geometric modelling to automatically segment the whole heart, cardiac chambers, great vessels, heart valves, coronary arteries, and conduction nodes. Segmentation performance was evaluated using the Dice similarity coefficient (DSC), mean distance to agreement (MDA), Hausdorff distance (HD), and volume ratio. Performance was reliable, with no errors observed and acceptable variation in accuracy between cases, including in challenging cases with imaging artefacts and atypical patient anatomy. The median DSC range was 0.81-0.93 for whole heart and cardiac chambers, 0.43-0.76 for great vessels and conduction nodes, and 0.22-0.53 for heart valves. For all structures the median MDA was below 6 mm, median HD ranged 7.7-19.7 mm, and median volume ratio was close to one (0.95-1.49) for all structures except the left main coronary artery (2.07). The fully automatic algorithm takes between 9 and 23 min per case. The proposed fully-automatic method accurately delineates cardiac substructures on radiotherapy planning CT scans. Robust and anatomically consistent segmentations, particularly for smaller structures, represents a major advantage of the proposed segmentation approach. The open-source software will facilitate more precise evaluation of cardiac doses and risks from available clinical datasets.

A statistical, voxelised model of prostate cancer for biologically optimised radiotherapy.

Background and purpose: Radiation therapy (RT) is commonly indicated for treatment of prostate cancer (PC). Biologicallyoptimised RT for PC may improve disease-free survival. This requires accurate spatial localisation and characterisation of tumour lesions. We aimed to generate a statistical, voxelised biological model to complement in vivomultiparametric MRI data to facilitate biologically-optimised RT. Material and methods: Ex vivo prostate MRI and histopathological imaging were acquired for 63 PC patients. These data were co-registered to derive three-dimensional distributions of graded tumour lesions and cell density. Novel registration processes were used to map these data to a common reference geometry. Voxelised statistical models of tumour probability and cell density were generated to create the PC biological atlas. Cell density models were analysed using the Kullback-Leibler divergence to compare normal vs. lognormal approximations to empirical data. Results: A reference geometry was constructed using ex vivo MRI space, patient data were deformably registered using a novel anatomy-guided process. Substructure correspondence was maintained using peripheral zone definitions to address spatial variability in prostate anatomy between patients. Three distinct approaches to interpolation were designed to map contours, tumour annotations and cell density maps from histology into ex vivo MRI space. Analysis suggests a log-normal model provides a more consistent representation of cell density when compared to a linear-normal model. Conclusion: A biological model has been created that combines spatial distributions of tumour characteristics from a population into three-dimensional, voxelised, statistical models. This tool will be used to aid the development of biologically-optimised RT for PC patients.

Feasibility of using a novel automatic cardiac segmentation algorithm in the clinical routine of lung cancer patients.

Incidental radiation exposure to the heart during lung cancer radiotherapy is associated with radiation-induced heart disease and increased rates of mortality. By considering the respiratory-induced motion of the heart it is possible to create a radiotherapy plan that results in a lower overall cardiac dose. This approach is challenging using current clinical practices: manual contouring of the heart is time consuming, and subject to inter- and intra-observer variability. In this work, we investigate the feasibility of our previously developed, atlas-based, automatic heart segmentation tool to delineate the heart in four-dimensional x-ray computed tomography (4D-CT) images. We used a dataset comprising 19 patients receiving radiotherapy for lung cancer, with 4D-CT imaging acquired at 10 respiratory phases and with a maximum intensity projection image generated from these. For each patient, one of four experienced radiation oncologists contoured the heart on each respiratory phase image and the maximum intensity image. Automatic segmentation of the heart on these same patient image sets was achieved using a leave-one-out approach, where for each patient the remaining 18 were used as an atlas set. The consistency of the automatic segmentation relative to manual contouring was evaluated using the Dice similarity coefficient (DSC) and mean absolute surface-to-surface distance (MASD). The DSC and MASD are comparable to inter-observer variability in clinically acceptable whole heart delineations (average DSC > 0.93 and average MASD < 2.0 mm in all the respiratory phases). The comparison between automatic and manual delineations on the maximum intensity images produced an overall mean DSC of 0.929 and a mean MASD of 2.07 mm. The automatic, atlas-based segmentation tool produces clinically consistent and robust heart delineations and is easy to implement in the routine care of lung cancer patients.

Validation of a new open-source method for automatic delineation and dose assessment of the heart and LADCA in breast radiotherapy with simultaneous uncertainty estimation.

Radiotherapy has been shown to increase risks of cardiotoxicities for breast cancer patients. Automated delineation approaches are necessary for consistent and efficient assessment of cardiac doses in large, retrospective datasets, while patient-specific estimation of the uncertainty in these doses provides valuable additional data for modelling and understanding risks. In this work, we aim to validate the consistency of our previously described open-source software model for automatic cardiac delineation in the context of dose assessment, relative to manual contouring. We also extend our software to introduce a novel method to automatically quantify the uncertainty in cardiac doses based on expected inter-observer variability (IOV) in contouring. This method was applied to a cohort of 15 left-sided breast cancer patients treated in Denmark using modern tangential radiotherapy techniques. On each image set, the whole heart and left anterior descending coronary artery (LADCA) were contoured by nine independent experts; the range of doses to these nine volumes provided a reference for the dose uncertainties generated from the automatic method. Local and external atlas sets were used to test the method. Results give confidence in the consistency of automatic segmentations, with mean whole heart dose differences for local and external atlas sets of -0.20 ± 0.17 and -0.10 ± 0.14 Gy, respectively. Automatic estimates of uncertainties in doses are similar to those from IOV for both the whole heart and LADCA. Overall, this study confirms that our automated approach can be used to accurately assess cardiac doses, and the proposed method can provide a useful tool in estimating dose uncertainties.

Analysis of cardiac substructure dose in a large, multi-centre danish breast cancer cohort (the DBCG HYPO trial): Trends and predictive modelling.

BACKGROUND AND PURPOSE: Radiotherapy for breast cancer can increase the risks of heart disease. Patient-specific risk assessment may be improved with the inclusion of doses to cardiac substructures. The purpose of this work was to use automatic segmentation to evaluate substructure doses and develop predictive models for these based on the dose to the whole heart. MATERIAL AND METHODS: Automatic segmentation was used to delineate cardiac substructures in a Danish breast cancer trial (DBCG HYPO) dataset comprising over 1500 Danish women treated between 2009 and 2014. Trends in contouring practices and cardiac doses over time were investigated, and models to predict substructure doses from whole heart dose parameters were fit to the data. RESULTS: Manual contouring consistency improved over the study period when compared with automatic segmentation; systematic differences between automatically and manually defined heart volume decreased from 106 cm3 to 12.0 cm3. Doses to the heart and cardiac substructures also decreased. Mean whole heart doses for left-sided treatments in 2009 and 2014 were 1.94±1.19 Gy and 1.29±0.69 Gy (average ± SD), respectively. Prediction of mean substructure doses is accurate, with R2 scores in the range 0.45-0.95 (average 0.77), depending on the particular structure. CONCLUSION: This study reports heart and cardiac substructure doses in a large breast cancer cohort. Predictive models generated in this work can be used to estimate mean cardiac substructure doses for datasets where patient imaging and dose distributions are not available, provided the tangential field techniques are consistent with those used in the trial.

Localised delineation uncertainty for iterative atlas selection in automatic cardiac segmentation.

The heart is an important organ at risk during thoracic radiotherapy. Many studies have demonstrated a correlation between the mean heart dose and an increase in cardiovascular disease. Different treatments result in significant dose variation within the heart and individualised dose estimation increasingly requires more attention to delineation of various cardiac structures. Automatic segmentation tools are critical for consistent and accurate delineation of organs at risk in large, retrospective studies, however the challenge of ensuring a robust method must be addressed. In a multi-atlas based segmentation framework the uncertainty in delineation can be modelled over the surface of the heart. We extend this concept with an iterative atlas selection procedure designed to remove inconsistent atlas contours, in turn improving the reliability of the segmentation. Two independent datasets comprising 15 and 20 planning computed tomography (CT) images of Danish and Australian breast cancer patients, respectively, had the whole heart and left anterior descending coronary artery (LADCA) delineated. Using a cross-validation strategy, where each dataset is used as an atlas set to segment each image in the other, we assess segmentation performance qualitatively and quantitatively, using the dice similarity coefficient (DSC), mean surface-to-surface distance (MASD) and Hausdorff distance (HD). After using the iterative atlas selection procedure, every segmentation error was removed. For the whole heart, the resulting segmentation achieved a DSC, MASD and HD of [Formula: see text], [Formula: see text] mm, and [Formula: see text] mm.

Feasibility of multi-atlas cardiac segmentation from thoracic planning CT in a probabilistic framework.

Toxicity to cardiac and coronary structures is an important late morbidity for patients undergoing left-sided breast radiotherapy. Many current studies have relied on estimates of cardiac doses assuming standardised anatomy, with a calculated increase in relative risk of 7.4% per Gy (mean heart dose). To provide individualised estimates for dose, delineation of various cardiac structures on patient images is required. Automatic multi-atlas based segmentation can provide a consistent, robust solution, however there are challenges to this method. We are aiming to develop and validate a cardiac atlas and segmentation framework, with a focus on the limitations and uncertainties in the process. We present a probabilistic approach to segmentation, which provides a simple method to incorporate inter-observer variation, as well as a useful tool for evaluating the accuracy and sources of error in segmentation. A dataset consisting of 20 planning computed tomography (CT) images of Australian breast cancer patients with delineations of 17 structures (including whole heart, four chambers, coronary arteries and valves) was manually contoured by three independent observers, following a protocol based on a published reference atlas, with verification by a cardiologist. To develop and validate the segmentation framework a leave-one-out cross-validation strategy was implemented. Performance of the automatic segmentations was evaluated relative to inter-observer variability in manually-derived contours; measures of volume and surface accuracy (Dice similarity coefficient (DSC) and mean absolute surface distance (MASD), respectively) were used to compare automatic segmentation to the consensus segmentation from manual contours. For the whole heart, the resulting segmentation achieved a DSC of [Formula: see text], with a MASD of [Formula: see text] mm. Quantitative results, together with the analysis of probabilistic labelling, indicate the feasibility of accurate and consistent segmentation of larger structures, whereas this is not the case for many smaller structures, where a major limitation in segmentation accuracy is the inter-observer variability in manual contouring.

Pulsed radiofrequency application in treatment of chronic zygapophyseal joint pain.

BACKGROUND CONTEXT: Chronic zygapophyseal joint arthropathy is a cause of back and neck pain. One proposed method of treating facet joint pathology is ablation of medial branches and dorsal rami with pulsed radiofrequency (RF) waves. PURPOSE: Assessment of efficacy of pulsed RF application for treatment of chronic zygapophyseal joint pain. STUDY DESIGN/SETTING: Retrospective study of 114 patients at a pain management clinic. PATIENT SAMPLE: A total of 114 patients with clinical signs of facet joint involvement and a favorable response to a diagnostic medial branch block using local anesthetic, including 82 females and 32 males with a mean age of 52.8+/-12.6 years. Mean duration of pain was 7.52+/-5.26 years. Twenty-seven had previous back surgery, 83 patients had low back pain and 31 had cervical pain. Pain was on the left side in 47 patients, on the right side in 45 patients, bilateral in 22. OUTCOME MEASURES: Result was regarded as successful if pain reduction was more than 50% on visual analog scale and the duration of effect was more than 1.5 months. METHODS: After obtaining positive stimulation, pulsed RF was applied to medial branches of dorsal rami for 120 seconds with temperature at the tip of the electrode 42 C. RESULTS: Of 114 patients, who had positive response to diagnostic block, 46 patients did not respond favorably to pulsed RF application (pain reduction less than 50%). In 68 patients, the procedure was successful and lasted on average 3.93+/-1.86 months. Eighteen patients had the procedure repeated with the same duration of pain relief that was achieved initially. Previous surgery, duration of pain, sex, levels (cervical vs. lumbar) and stimulation levels did not influence outcomes. CONCLUSION: The results of our study showed that the application of pulsed RF to medial branches of the dorsal rami in patients with chronic facet joint arthropathy provided temporary pain relief in 68 of 118 patients.