Quantitative assessment of dosimetric effect of using alternative OAR delineations in treatment planning as functions of delineations, setup uncertainty and planning techniques using an alternative truth assessment method.

PURPOSE: This study aims to quantify the variation in dose-volume histogram (DVH) and normal tissue complication probability(NTCP) metrics for head-and-neck (HN) cancer patients when alternative organ-at-risk(OAR) delineations are used for treatment planning and for treatment plan evaluation. We particularly focus on the effects of daily patient positioning/setup variations(SV) in relation to treatment technique and delineation variability. MATERIALS AND METHODS: We generated two-arc VMAT, 5-beam IMRT, and 9-beam IMRT treatment plans for a cohort of 209 HN patients. These plans incorporated five different OAR delineation sets, including manual and four automated algorithms. Each treatment plan was assessed under various simulated per-fraction patient setup uncertainties, evaluating the potential clinical impacts through DVH and NTCP metrics. RESULTS: The study demonstrates that increasing SV generally reduces differences in DVH metrics between alternative delineations. However, in contrast, differences in NTCP metrics tend to increase with higher setup variability. This pattern is observed consistently across different treatment plans and delineator combinations, illustrating the intricate relationship between SV and delineation accuracy. Additionally, the need for delineation accuracy in treatment planning is shown to be case-specific and dependent on factors beyond geometric variations. CONCLUSIONS: The findings highlight the necessity for comprehensive Quality Assurance programs in radiotherapy, incorporating both dosimetric impact analysis and geometric variation assessment to ensure optimal delineation quality. The study emphasizes the complex dynamics of treatment planning in radiotherapy, advocating for personalized, case-specific strategies in clinical practice to enhance patient care quality and efficacy in the face of varying SV and delineation accuracies.

Dose differentiated high-dose-rate prostate brachytherapy: a feasibility assessment of MRI-guided dose escalation to dominant intra-prostatic lesions.

Purpose: Prostate brachytherapy is routinely performed with trans-rectal ultrasound (TRUS)- or computed tomography (CT)-based planning that cannot delineate dominant intra-prostatic lesions (DILs). In contrast, magnetic resonance imaging (MRI)-based planning allows for more accurate DIL delineation and dose escalation. This study assessed the maximum achievable dose escalation to DILs. Material and methods: We retrospectively identified 24 patients treated with high-dose-rate (HDR) prostate brachytherapy boost (15 Gy in 1 fraction). All patients had a pre-treatment prostate MRI with 1-3 DILs. MRIs were used to delineate DILs and were co-registered to TRUS intra-procedure. Treatment plans were experimentally re-optimized to escalate DIL dose. Dosimetric indices from the original and re-optimized plans were compared using two-tailed paired t-test. Re-optimized plans were deemed acceptable if they achieved all of the following criteria: prostate D90 > 100%, prostate V100 > 90%, urethra D10 < 118%, rectum V80 < 0.5 cc, bladder D1cc < 75%, or if they did not exceed organs at risk (OARs) doses of the original plan. Results: The mean DIL D90 was significantly increased from 134% of the prescription dose on the original plans to 154% on the re-optimized plans. The mean urethra D10 and mean bladder D1cc were significantly reduced from 123% to 117% and from 72% to 65%, respectively. Prostate D90 was reduced from 106% to 102%, and prostate V100 was reduced from 93% to 91%. Conclusions: We re-optimized HDR brachytherapy plans to escalate DILs dose to a mean D90 of > 150% while maintaining favorable prostate coverage and OARs doses. We propose DIL D90 dose of > 150% (22.5 Gy) as an achievable goal.

OpenKBP-Opt: an international and reproducible evaluation of 76 knowledge-based planning pipelines.

Objective.To establish an open framework for developing plan optimization models for knowledge-based planning (KBP).Approach.Our framework includes radiotherapy treatment data (i.e. reference plans) for 100 patients with head-and-neck cancer who were treated with intensity-modulated radiotherapy. That data also includes high-quality dose predictions from 19 KBP models that were developed by different research groups using out-of-sample data during the OpenKBP Grand Challenge. The dose predictions were input to four fluence-based dose mimicking models to form 76 unique KBP pipelines that generated 7600 plans (76 pipelines × 100 patients). The predictions and KBP-generated plans were compared to the reference plans via: the dose score, which is the average mean absolute voxel-by-voxel difference in dose; the deviation in dose-volume histogram (DVH) points; and the frequency of clinical planning criteria satisfaction. We also performed a theoretical investigation to justify our dose mimicking models.Main results.The range in rank order correlation of the dose score between predictions and their KBP pipelines was 0.50-0.62, which indicates that the quality of the predictions was generally positively correlated with the quality of the plans. Additionally, compared to the input predictions, the KBP-generated plans performed significantly better (P< 0.05; one-sided Wilcoxon test) on 18 of 23 DVH points. Similarly, each optimization model generated plans that satisfied a higher percentage of criteria than the reference plans, which satisfied 3.5% more criteria than the set of all dose predictions. Lastly, our theoretical investigation demonstrated that the dose mimicking models generated plans that are also optimal for an inverse planning model.Significance.This was the largest international effort to date for evaluating the combination of KBP prediction and optimization models. We found that the best performing models significantly outperformed the reference dose and dose predictions. In the interest of reproducibility, our data and code is freely available.

Knowledge-based quality control of organ delineations in radiation therapy.

PURPOSE: To reduce the likelihood of errors in organ delineations used for radiotherapy treatment planning, a knowledge-based quality control (KBQC) system, which discriminates between valid and anomalous delineations is developed. METHOD AND MATERIALS: The KBQC is comprised of a group-wise inference system and anomaly detection modules trained using historical priors from 296 locally advanced lung and prostate cancer patient computational tomographies (CTs). The inference system discriminates different organs based on shape, relational, and intensity features. For a given delineated image set, the inference system solves a combinatorial optimization problem that results in an organ group whose relational features follow those of the training set considering the posterior probabilities obtained from support vector machine (SVM), discriminant subspace ensemble (DSE), and artificial neural network (ANN) classifiers. These classifiers are trained on nonrelational features with a 10-fold cross-validation scheme. The anomaly detection module is a bank of ANN autoencoders, each corresponding with an organ, trained on nonrelational features. A heuristic rule detects anomalous organs that exceed predefined organ-specific tolerances for the feature reconstruction error and the classifier's posterior probabilities. Independent data sets with anomalous delineations were used to test the overall performance of the KBQC system. The anomalous delineations were manually manipulated, computer-generated, or propagated based on a transformation obtained by imperfect registrations. Both peer-review-based scoring system and shape similarity coefficient (DSC) were used to label regions of interest (ROIs) as normal or anomalous in two independent test cohorts. RESULTS: The accuracy of the classifiers was ≥ $\ge$ 99.8%, and the minimum per-class F1-scores were 0.99, 0.99, and 0.98 for SVM, DSE, and ANN, respectively. The group-wise inference system reduced the miss-classification likelihood for the test data set with anomalous delineations compared to each individual classifier and a fused classifier that used the average posterior probability of all classifiers. For 15 independent locally advanced lung patients, the system detected > $>$ 79% of the anomalous ROIs. For 1320 auto-segmented abdominopelvic organs, the anomaly detection system identified anomalous delineations, which also had low Dice similarity coefficient values with respect to manually delineated organs in the training data set. CONCLUSION: The KBQC system detected anomalous delineations with superior accuracy compared to classification methods that judge only based on posterior probabilities.

A regression-based approach to compute the pixels sensitivity map of linear accelerator portal imaging devices.

PURPOSE: To determine the pixel sensitivity map (PSM) for amorphous silicon electronic portal imaging devices (EPIDs) using a single flood field signal. METHOD AND MATERIALS: A raw EPID signal results from the incident particle energy fluence, the inherent pixels response, and the background signal. In large open fields, particle energy fluence is a slow-varying signal that is locally considered spatially constant. Pixels response is a fast and abrupt varying behavior. The background signal is due to the EPID panel electronics, which is determined during radiation absence. To determine the PSM, after correcting for the background signal, we apply a model that captures the underlying smooth particle energy fluence-induced signal. This fluence signal-fitted model is then used to determine the PSM. Here, we use a polynomial-based regression surface model in both x and y dimensions. To validate the generated PSM, we measure beams and compute PSMs for multiple beam energies with and without flattening filters and for multiple source-to-imager distances. Since the PSM is a detector characteristic, it should be independent of those variables. We also intercompare measurements of fixed slit fields with the EPID being shifted between measurements. RESULTS: The fluence signal of the flattening filter-free (FFF) beams was optimally modeled as a 12th degree polynomial surfaces, which had ≤ 0.1% residuals near the central axis. The 6 and 10 MV FFF PSMs were within ˜0.1%, and independent of the EPID SID, suggesting that the PSM is energy independent. The 6, 10, and 15 MV flattened-beam PSMs were well modeled as 12th degree polynomial surfaces, which were equivalent within ˜0.24% but differed from the FFF PSM by up to 0.5% near the beam central axis. Applying the FFF PSMs to the flattened-beam measurements reduced the central-axis deviation between the raw and corrected signal to < 0.1%, confirming the PSM energy independence hypothesis. When the FFF PSM is utilized, output verification with shifted slit deliveries agreed within ˜0.5% for all beam energies, which is within the radiation delivery uncertainty of ˜0.57%. CONCLUSION: PSM for MV EPIDs can be determined by separating out the slowly varying, well-behaved fluence signal from the pixel-to-pixel sensitivity variations. The quality of the PSM is found to be dependent on the quality of the surface fit, which is best for the 6 MV FFF beam measured at SID equal to 180 cm. Within fitting errors, the PSM is independent of beam energy for 6, 10, and 15 MV beams with and without flattening filters. The PSM generation does not require shifting the EPID panel nor multiple EPID panel irradiations and should be usable for linacs with fixed geometry EPIDs.

Extracting diffusion tensor fractional anisotropy and mean diffusivity from 3-direction DWI scans using deep learning.

PURPOSE: To develop and evaluate machine-learning methods that reconstruct fractional anisotropy (FA) values and mean diffusivities (MD) from 3-direction diffusion MRI (dMRI) acquisitions. METHODS: Two machine-learning models were implemented to map undersampled dMRI signals with high-quality FA and MD maps that were reconstructed from fully sampled DTI scans. The first model was a previously described multilayer perceptron (MLP), which maps signals and FA/MD values from a single voxel. The second was a convolutional neural network U-Net model, which maps dMRI slices to full FA/MD maps. Each method was trained on dMRI brain scans (N = 46), and reconstruction accuracies were compared with conventional linear-least-squares (LLS) reconstructions. RESULTS: In an independent testing cohort (N = 20), 3-direction U-Net reconstructions had significantly lower absolute FA error than both 3-direction MLP (U-Net3-dir : 0.06 ± 0.01 vs. MLP3-dir : 0.08 ± 0.01, P < 1 × 10-5 ) and 6-direction LLS (LLS6-dir : 0.09 ± 0.03, P = 1 × 10-5 ). The MD errors were not significantly different among 3-direction MLP (0.06 ± 0.01 × 10-3 mm2 /s), 3-direction U-Net (0.06 ± 0.01 × 10-3 mm2 /s), and 6-direction LLS (0.07 ± 0.02 × 10-3 mm2 /s, P > .1). CONCLUSION: The proposed U-Net model reconstructed FA from 3-direction dMRI scans with improved accuracy compared with both a previously described MLP approach and LLS fitting from 6-direction scans. The MD reconstruction accuracies did not differ significantly between reconstructions.

An Automated Workflow to Improve Efficiency in Radiation Therapy Treatment Planning by Prioritizing Organs at Risk.

PURPOSE: Manual delineation (MD) of organs at risk (OAR) is time and labor intensive. Auto-delineation (AD) can reduce the need for MD, but because current algorithms are imperfect, manual review and modification is still typically used. Recognizing that many OARs are sufficiently far from important dose levels that they do not pose a realistic risk, we hypothesize that some OARs can be excluded from MD and manual review with no clinical effect. The purpose of this study was to develop a method that automatically identifies these OARs and enables more efficient workflows that incorporate AD without degrading clinical quality. METHODS AND MATERIALS: Preliminary dose map estimates were generated for n = 10 patients with head and neck cancers using only prescription and target-volume information. Conservative estimates of clinical OAR objectives were computed using AD structures with spatial expansion buffers to account for potential delineation uncertainties. OARs with estimated dose metrics below clinical tolerances were deemed low priority and excluded from MD and/or manual review. Final plans were then optimized using high-priority MD OARs and low-priority AD OARs and compared with reference plans generated using all MD OARs. Multiple different spatial buffers were used to accommodate different potential delineation uncertainties. RESULTS: Sixty-seven out of 201 total OARs were identified as low-priority using the proposed methodology, which permitted a 33% reduction in structures requiring manual delineation/review. Plans optimized using low-priority AD OARs without review or modification met all planning objectives that were met when all MD OARs were used, indicating clinical equivalence. CONCLUSIONS: Prioritizing OARs using estimated dose distributions allowed a substantial reduction in required MD and review without affecting clinically relevant dosimetry.

Multiobjective, Multidelivery Optimization for Radiation Therapy Treatment Planning.

PURPOSE: To introduce multiobjective, multidelivery optimization (MODO), which generates alternative patient-specific plans emphasizing dosimetric trade-offs and conformance to quasi-constrained (QC) conditions for multiple delivery techniques. METHODS AND MATERIALS: For M delivery techniques and N organs at risk (OARs), MODO generates M (N + 1) alternative treatment plans per patient. For 30 locally advanced lung cancer cases, the algorithm was investigated based on dosimetric trade-offs to 4 OARs: each lung, heart, and esophagus (N = 4) and 4 delivery techniques (4-field coplanar intensity modulated radiation therapy [IMRT], 9-field coplanar IMRT, 27-field noncoplanar IMRT, and noncoplanar arc IMRT) and conformance to QC conditions, including dose to 95% (D95) of the planning target volume (PTV), maximum dose (Dmax) to PTV (PTV-Dmax), and spinal cord Dmax. The MODO plan set was evaluated for conformance to QC conditions while simultaneously revealing dosimetric trade-offs. Statistically significant dosimetric trade-offs were defined such that the coefficient of determination was >0.8 with dosimetric indices that varied by at least 5 Gy. RESULTS: Plans varied mean dose by >5 Gy to ipsilateral lung for 24 of 30 patients, contralateral lung for 29 of 30 patients, esophagus for 29 of 30 patients, and heart for 19 of 30 patients. In the 600 plans, average PTV-D95 = 67.6 ± 2.1 Gy, PTV-Dmax = 79.8 ± 5.2 Gy, and spinal cord Dmax among all plans was 51.4 Gy. Statistically significant dosimetric trade-offs reducing OAR mean dose by >5 Gy were evident in 19 of 30 patients, including multiple OAR trade-offs of at least 5 Gy in 7 of 30 cases. The most common statistically significant trade-off was increasing PTV-Dmax to reduce dose to OARs (15 of 30). The average 4-field plan reduced total lung V20 by 10.4% ± 8.3% compared with 9-field plans, 7.7% ± 7.9% compared with 27-field noncoplanar plans, and 11.7% ± 10.3% compared with 2-arc noncoplanar plans, with corresponding increases in PTV-Dmax of 5.3 ± 5.9 Gy, 4.6 ± 5.6 Gy, and 9.3 ± 7.3 Gy. CONCLUSIONS: The proposed optimization method produces clinically relevant treatment plans that meet QC conditions and demonstrate variations in OAR doses.

Dose escalation in the definite target volume.

PURPOSE: To introduce the definite target volume (DTV) and evaluate dosimetric consequences of boosting dose to this region of high clinical target volume (CTV)- and low organs at risk (OAR)-probability. METHODS: This work defines the DTV via occupancy probability and via contraction of the CTV by margin M less any planning risk volume (PRV) volumes. The equivalence to within varying occupancy probability of the two methods is established for spherical target volumes. We estimate a margin for four radiation treatment sites based on modern images guided radiation therapy-literature utilizing repeat volumetric imaging. Based on margins and patient-specific DTV targets, the ability to dose escalate the DTV including the effects of spatial uncertainty was evaluated. We simulate delivery assuming violation of the underlying spatial uncertainty of 130%. RESULTS: Contracting the planning target volume (PTV) by M and excluding PRV volumes, the DTV ranged from 7.3 to 93.6 cc. In a brain treatment, DTV-Dmax increased to 66.8 Gy (145% of prescription isodose); in advanced lung DTV-Dmax increased to 122.2 Gy (204% of prescription isodose), in a pancreatic case DTV-Dmax was boosted up to 87.3 Gy (173% or prescription isodose), and in retroperitoneal sarcoma to 74.6 Gy (249% of prescription isodose). The high point doses were not associated with increased dose to OARs, even when considering the effects of spatial uncertainty. Simulated delivery at 130% of assumed spatial uncertainties revealed DTV-based planning can result in minor increases in OAR Dmean/Dmax of 2.7 ± 2.1 Gy/1.8 ± 2.2 Gy with duodenum Dmax > 110% of prescription isodose in the pancreatic case. These dose increases were consistent with simulation of clinical, homogenous PTV-dose distributions. CONCLUSION: We have proposed and tested a method to deliver extremely high doses to subvolumes of target volumes in multiple treatment sites by defining a new target volume, the DTV. Based on simulated delivery, the method does not result in significant increases in dose to OARs if spatial uncertainty can be estimated.

Quantifying the dosimetric impact of organ-at-risk delineation variability in head and neck radiation therapy in the context of patient setup uncertainty.

The purpose of this study was to quantify the potential dosimetric impact of delineation variability (DV) in head and neck radiation therapy (RT) when inherent patient setup variability (SV) is also considered. The impact of DV was assessed by generating plans with multiple structure sets, cross-evaluating them, including SV, across sets, and determining P PQM: the probability of achieving organ-specific plan quality metrics (PQM). DV was incorporated by: (1) using multiple organ at risk (OAR) structure sets delineated by independent manual observers; and (2) randomly perturbing manually generated OARs to generate alternatives with varying levels of uncertainty (low, medium, and high DV). For each structure set, independent VMAT plans were auto-generated to meet clinical PQMs. Each plan was cross-evaluated using OARs from multiple structure sets with simulated SV including per-fraction random (σ s) and per-treatment-course systematic (Σs) setup errors. The dosimetric impact of DV was assessed by examining P PQM with and without SV/DV. Clinically significant differences were defined by those that exceeded differences caused by a +2% output variation. Without including SV, simulated DV at the medium level reduced P PQM by an average of 5.5% for all OARs with D max PQMs. This reduction decreased to 2.8% for SV = 2 mm and 2.4% for SV = 4 mm (the average P PQM reduction due to 2% output errors was 2.7%). For OARs with D mean PQMs, the average P PQM reduction was 0.9% for SV = 0 and ⩽0.1% for SV ⩾ 2 mm. The effect of DV was larger for OARs that directly abutted a target volume than for those that did not. These trends were also observed with real DV from multi-observer delineations. The dosimetric impact of DV appeared to decrease when random and systematic SV was considered. Sensitivity to DV was affected by OAR objective type (i.e. D mean versus D max objectives) as well as distance from the target volume.

Highly accelerated, model-free diffusion tensor MRI reconstruction using neural networks.

PURPOSE: The purpose of this study was to develop a neural network that accurately performs diffusion tensor imaging (DTI) reconstruction from highly accelerated scans. MATERIALS AND METHODS: This retrospective study was conducted using data acquired between 2013 and 2018 and was approved by the local institutional review board. DTI acquired in healthy volunteers (N = 10) was used to train a neural network, DiffNet, to reconstruct fractional anisotropy (FA) and mean diffusivity (MD) maps from small subsets of acquired DTI data with between 3 and 20 diffusion-encoding directions. FA and MD maps were then reconstructed in volunteers and in patients with glioblastoma multiforme (GBM, N = 12) using both DiffNet and conventional reconstructions. Accuracy and precision were quantified in volunteer scans and compared between reconstructions. The accuracy of tumor delineation was compared between reconstructed patient data by evaluating agreement between DTI-derived tumor volumes and volumes defined by contrast-enhanced T1-weighted MRI. Comparisons were performed using areas under the receiver operating characteristic curves (AUC). RESULTS: DiffNet FA reconstructions were more accurate and precise compared with conventional reconstructions for all acceleration factors. DiffNet permitted reconstruction with only three diffusion-encoding directions with significantly lower bias than the conventional method using six directions (0.01 ± 0.01 vs 0.06 ± 0.01, P < 0.001). While MD-based tumor delineation was not substantially different with DiffNet (AUC range: 0.888-0.902), DiffNet FA had higher AUC than conventional reconstructions for fixed scan time and achieved similar performance with shorter scans (conventional, six directions: AUC = 0.926, DiffNet, three directions: AUC = 0.920). CONCLUSION: DiffNet improved DTI reconstruction accuracy, precision, and tumor delineation performance in GBM while permitting reconstruction from only three diffusion-encoding directions.&!#6.

Quality assurance tool for organ at risk delineation in radiation therapy using a parametric statistical approach.

PURPOSE: To develop a quality assurance (QA) tool that identifies inaccurate organ at risk (OAR) delineations. METHODS: The QA tool computed volumetric features from prior OAR delineation data from 73 thoracic patients to construct a reference database. All volumetric features of the OAR delineation are computed in three-dimensional space. Volumetric features of a new OAR are compared with respect to those in the reference database to discern delineation outliers. A multicriteria outlier detection system warns users of specific delineation outliers based on combinations of deviant features. Fifteen independent experimental sets including automatic, propagated, and clinically approved manual delineation sets were used for verification. The verification OARs included manipulations to mimic common errors. Three experts reviewed the experimental sets to identify and classify errors, first without; and then 1 week after with the QA tool. RESULTS: In the cohort of manual delineations with manual manipulations, the QA tool detected 94% of the mimicked errors. Overall, it detected 37% of the minor and 85% of the major errors. The QA tool improved reviewer error detection sensitivity from 61% to 68% for minor errors (P = 0.17), and from 78% to 87% for major errors (P = 0.02). CONCLUSIONS: The QA tool assists users to detect potential delineation errors. QA tool integration into clinical procedures may reduce the frequency of inaccurate OAR delineation, and potentially improve safety and quality of radiation treatment planning.

Clinical adequacy assessment of autocontours for prostate IMRT with meaningful endpoints.

PURPOSE: To determine if radiation treatment plans created based on autosegmented (AS) regions-of-interest (ROI)s are clinically equivalent to plans created based on manually segmented ROIs, where equivalence is evaluated using probabilistic dosimetric metrics and probabilistic biological endpoints for prostate IMRT. METHOD AND MATERIALS: Manually drawn contours and autosegmented ROIs were created for 167 CT image sets acquired from 19 prostate patients. Autosegmentation was performed utilizing Pinnacle's Smart Probabilistic Image Contouring Engine. For each CT set, 78 Gy/39 fraction 7-beam IMRT treatment plans with 1 cm CTV-to-PTV margins were created for each of the three contour scenarios; PMD using manually delineated (MD) ROIs, PAS using autosegmented ROIs, and PAM using autosegmented organ-at-risks (OAR)s and the manually drawn target. For each plan, 1000 virtual treatment simulations with different systematic errors for each simulation and a different random error for each fraction were performed. The statistical probability of achieving dose-volume metrics (coverage probability (CP)), expectation values for normal tissue complication probability (NTCP), and tumor control probability (TCP) metrics for all possible cross-evaluation pairs of ROI types and planning scenarios were reported. In evaluation scenarios, the root mean square loss (RMSL) and maximum absolute loss (MAL) of coverage probability of dose-volume objectives, E[TCP], and E[NTCP] were compared with respect to the base plan created and evaluated with manually drawn contours. RESULTS: Femoral head dose objectives were satisfied in all situations, as well as the maximum dose objectives for all ROIs. Bladder metrics were within the clinical coverage tolerances except D35Gy for the autosegmented plan evaluated with the manual contours. Dosimetric indices for CTV and rectum could be highly compromised when the definition of the ROIs switched from manually delineated to autosegmented. Seventy-two percent of CT image sets satisfied the worst-case CP thresholds for all dosimetric objectives in all scenarios, the percentage dropped to 50% if biological indices were taken into account. Among evaluation scenarios, (MD,PAM ) bore the highest resemblance to (MD,PMD ) where 99% and 88% of cases met all CP thresholds for bladder and rectum, respectively. CONCLUSIONS: When including daily setup variations in prostate IMRT, the dose-volume metric CP, and biological indices of ROIs were approximately equivalent for the plans created based on manually drawn targets and autosegmented OARs in 88% of cases. The accuracy of autosegmented prostates and rectums are impediment to attain statistically equivalent plans created based on manually drawn ROIs.