Virtual unenhanced dual-energy computed tomography for photon radiotherapy: The effect on dose distribution and cone-beam computed tomography based position verification.

Background and Purpose: Virtual Unenhanced images (VUE) from contrast-enhanced dual-energy computed tomography (DECT) eliminate manual suppression of contrast-enhanced structures (CES) or pre-contrast scans. CT intensity decreases in high-density structures outside the CES following VUE algorithm application. This study assesses VUE's impact on the radiotherapy workflow of gynecological tumors, comparing dose distribution and cone-beam CT-based (CBCT) position verification to contrast-enhanced CT (CECT) images. Materials and Methods: A total of 14 gynecological patients with contrast-enhanced CT simulation were included. Two CT images were reconstructed: CECT and VUE. Volumetric Modulated Arc Therapy (VMAT) plans generated on CECT were recalculated on VUE using both the CECT lookup table (LUT) and a dedicated VUE LUT. Gamma analysis assessed 3D dose distributions. CECT and VUE images were retrospectively registered to daily CBCT using Chamfer matching algorithm.. Results: Planning target volume (PTV) dose agreement with CECT was within 0.35% for D2%, Dmean, and D98%. Organs at risk (OARs) D2% agreed within 0.36%. A dedicated VUE LUT lead to smaller dose differences, achieving a 100% gamma pass rate for all subjects. VUE imaging showed similar translations and rotations to CECT, with significant but minor translation differences (<0.02 cm). VUE-based registration outperformed CECT. In 24% of CBCT-CECT registrations, inadequate registration was observed due to contrast-related issues, while corresponding VUE images achieved clinically acceptable registrations. Conclusions: VUE imaging in the radiotherapy workflow is feasible, showing comparable dose distributions and improved CBCT registration results compared to CECT. VUE enables automated bone registration, limiting inter-observer variation in the Image-Guided Radiation Therapy (IGRT) process.

Stomach Motion and Deformation: Implications for Preoperative Gastric Cancer Radiation Therapy.

PURPOSE: Selection and development of image guided strategies for preoperative gastric radiation therapy requires quantitative knowledge of the various sources of anatomic changes of the stomach. This study aims to investigate the magnitude of interfractional and intrafractional stomach motion and deformation using fiducial markers and 4-dimensional (4D) imaging. METHODS AND MATERIALS: Fourteen patients who underwent preoperative gastric cancer radiation therapy received 2 to 6 fiducial markers distributed throughout the stomach (total of 54 markers) and additional imaging (ie, 1 planning 4D computed tomography [pCT], 20-25 pretreatment 4D cone beam [CB] CTs, 4-5 posttreatment 4D CBCTs). Marker coordinates on all end-exhale (EE) and end-inhale (EI) scans were obtained after a bony anatomy match. Interfractional marker displacements (ie, between EE pCT and all EE CBCTs) were evaluated for 5 anatomic regions (ie, cardia, small curvature, proximal and distal large curvature, and pylorus). Motion was defined as displacement of the center-of-mass of available markers (COMstomach), deformation as the average difference in marker-pair distances. Interfractional (ie, between EE pCT and all EE CBCTs), respiratory (between EE and EI pCT and CBCTs), and pre-post (pre- and posttreatment EE CBCTs) motion and deformation were quantified. RESULTS: The interfractional marker displacement varied per anatomic region and direction, with systematic and random errors ranging from 1.6-8.8 mm and 2.2-8.2 mm, respectively. Respiratory motion varied per patient (median, 3-dimensional [3D] amplitude 5.2-20.0 mm) and day (interquartile range, 0.8-4.2 mm). Regarding COMstomach motion, respiratory motion was larger than interfractional motion (median, 10.9 vs 8.9 mm; P < .0001; Wilcoxon rank-sum), which was larger than pre-post motion (3.6 mm; P < .0001). Interfractional deformations (median, 5.8 mm) were significantly larger than pre-post deformations (2.6 mm; P < .0001), which were larger than respiratory deformation (1.8 mm; P < .0001). CONCLUSIONS: The demonstrated sizable stomach motions and deformations during radiation therapy stress the need for generous nonuniform planning target volume margins for preoperative gastric cancer radiation therapy. These margins can be decreased by daily image guidance and adaptive radiation therapy.

Online adaptive radiotherapy for bladder cancer using a simultaneous integrated boost and fiducial markers.

PURPOSE: The aim was to assess the feasibility of online adaptive radiotherapy (oART) for bladder cancer using a focal boost by focusing on the quality of the online treatment plan and automatic target delineation, duration of the workflow and performance in the presence of fiducial markers for tumor bed localization. METHODS: Fifteen patients with muscle invasive bladder cancer received daily oART with Cone Beam CT (CBCT), artificial intelligence (AI)-assisted automatic delineation of the daily anatomy and online plan reoptimization. The bladder and pelvic lymph nodes received a total dose of 40 Gy in 20 fractions, the tumor received an additional simultaneously integrated boost (SIB) of 15 Gy. The dose distribution of the reference plan was calculated for the daily anatomy, i.e. the scheduled plan. Simultaneously, a reoptimization of the plan was performed i.e. the adaptive plan. The target coverage and V95% outside the target were evaluated for both plans. The need for manual adjustments of the GTV delineation, the duration of the workflow and the influence of fiducial markers were assessed. RESULTS: All 300 adaptive plans met the requirement of the CTV-coverage V95%≥98% for both the boost (55 Gy) and elective volume (40 Gy). For the scheduled plans the CTV-coverage was 53.5% and 98.5%, respectively. Significantly less tissue outside the targets received 55 Gy in case of the adaptive plans as compared to the scheduled plans. Manual corrections of the GTV were performed in 67% of the sessions. In 96% of these corrections the GTV was enlarged and resulted in a median improvement of 1% for the target coverage. The median on-couch time was 22 min. A third of the session time consisted of reoptimization of the treatment plan. Fiducial markers were visible on the CBCTs and aided the tumor localization. CONCLUSIONS: AI-driven CBCT-guided oART aided by fiducial markers is feasible for bladder cancer radiotherapy treatment including a SIB. The quality of the adaptive plans met the clinical requirements and fiducial markers were visible enabling consistent daily tumor localization. Improved automatic delineation to lower the need for manual corrections and faster reoptimization would result in shorter session time.

Endoscopically placed fiducial markers for image-guided radiotherapy in preoperative gastric cancer: Technical feasibility and potential benefit.

Background and study aims Fiducial markers have demonstrated clinical value in radiotherapy in several organs, but little is known about markers in the stomach. Here, we assess the technical feasibility of endoscopic placement of markers in gastric cancer patients and their potential benefit for image-guided radiotherapy (IGRT). Patients and methods In this prospective feasibility study, 14 gastric cancer patients underwent endoscopy-guided gold (all patients) and liquid (7 patients) marker placements distributed throughout the stomach. Technical feasibility, procedure duration, and potential complications were evaluated. Assessed benefit for IGRT comprised marker visibility on acquired imaging (3-4 computed tomography [CT] scans and 19-25 cone-beam CTs [CBCTs] per patient) and lack of migration. Marker visibility was compared per marker type and location (gastroesophageal junction (i.e., junction/cardia), corpus (corpus/antrum/fundus), and pylorus). Results Of the 93 marker implantation attempts, 59 were successful, i.e., marker in stomach wall and present during entire 5-week radiotherapy course (2-6 successfully placed markers per patient), with no significant difference (Fisher's exact test; P >0.05) in success rate between gold (39/66=59%) and liquid (20/27=74%). Average procedure duration was 24.4 min (range 16-38). No procedure-related complications were reported. All successfully placed markers were visible on all CTs, with 81% visible on ≥95% of CBCTs. Five markers were poorly visible (on <75% of CBCTs), possibly due to small marker volume and peristaltic motion since all five were liquid markers located in the corpus. No migration was observed. Conclusions Endoscopic placement of fiducial markers in the stomach is technically feasible and safe. Being well visible and positionally stable, markers provide a potential benefit for IGRT.

Diaphragm and abdominal organ motion during radiotherapy: a comprehensive multicenter study in 189 children.

BACKGROUND: For accurate thoracic and abdominal radiotherapy, inter- and intrafractional geometrical uncertainties need to be considered to enable accurate margin sizes. We aim to quantify interfractional diaphragm and abdominal organ position variations, and intrafractional diaphragm motion in a large multicenter cohort of pediatric cancer patients (< 18 years). We investigated the correlation of interfractional position variations and intrafractional motion with age, and with general anesthesia (GA). METHODS: In 189 children (mean age 8.1; range 0.4-17.9 years) from six institutes, interfractional position variation of both hemidiaphragms, spleen, liver, left and right kidneys was quantified using a two-step registration. CBCTs were registered to the reference CT relative to the bony anatomy, followed by organ registration. We calculated the group mean, systematic and random errors (standard deviations Σ and σ, respectively) in cranial-caudal (CC), left-right and anterior-posterior directions. Intrafractional right hemidiaphragm motion was quantified using CBCTs on which the breathing amplitude, defined as the difference between end-inspiration and end-expiration peaks, was assessed (N = 79). We investigated correlations with age (Spearman's ρ), and differences in motion between patients treated with and without GA (N = 75; all < 5.5 years). RESULTS: Interfractional group means were largest in CC direction and varied widely between patients, with largest variations in the right hemidiaphragm (range -13.0-17.5 mm). Interfractional group mean of the left kidney showed a borderline significant correlation with age (p = 0.047; ρ = 0.17). Intrafractional right hemidiaphragm motion in patients ≥ 5.5 years (mean 10.3 mm) was significantly larger compared to patients < 5.5 years treated without GA (mean 8.3 mm) (p = 0.02), with smaller Σ and σ values. We found a significant correlation between breathing amplitude and age (p < 0.001; ρ = 0.43). Interfractional right hemidiaphragm position variations were significantly smaller in patients < 5.5 years treated with GA than without GA (p = 0.004), but intrafractional motion showed no significant difference. CONCLUSION: In this large multicenter cohort of children undergoing thoracic and abdominal radiotherapy, we found that interfractional position variation does not depend on age, but the use of GA in patients < 5.5 years showed smaller systematic and random errors. Furthermore, our results showed that breathing amplitude increases with age. Moreover, variations between patients advocate the need for a patient-specific margin approach.

Accuracy of abdominal organ motion estimation in radiotherapy using the right hemidiaphragm top as a surrogate during prolonged breath-holds quantified with MRI.

BACKGROUND: Respiratory motion presents a challenge in radiotherapy of thoracic and upper abdominal tumors. Techniques to account for respiratory motion include tracking. Using magnetic resonance imaging (MRI) guided radiotherapy systems, tumors can be tracked continuously. Using conventional linear accelerators, tracking of lung tumors is possible by determining tumor motion on kilo voltage (kV) imaging. But tracking of abdominal tumors with kV imaging is hampered by limited contrast. Therefore, surrogates for the tumor are used. One of the possible surrogates is the diaphragm. However, there is no universal method for establishing the error when using a surrogate and there are particular challenges in establishing such errors during free breathing (FB). Prolonged breath-holding might address these challenges. PURPOSE: The aim of this study was to quantify the error when using the right hemidiaphragm top (RHT) as surrogate for abdominal organ motion during prolonged breath-holds (PBH) for possible application in radiation treatments. METHODS: Fifteen healthy volunteers were trained to perform PBHs in two subsequent MRI sessions (PBH-MRI1 and PBH-MRI2). From each MRI acquisition, we selected seven images (dynamics) to determine organ displacement during PBH by using deformable image registration (DIR). On the first dynamic, the RHT, right and left hemidiaphragm, liver, spleen and right and left kidney were segmented. We used the deformation vector fields (DVF), generated by DIR, to determine the displacement of each organ between two dynamics in inferior-superior (IS), anterior-posterior (AP), left-right (LR) direction and we calculated the 3D vector magnitude (|d|). The displacements of the RHT, both hemidiaphragms and the abdominal organs were compared using a linear fit to determine the correlation (R2 of the fit) and the displacement ratio (DR, slope of the fit) between displacements of the RHT and each organ. We quantified the median difference between the DRs of PBH-MRI1 and PBH-MRI2 for each organ. Additionally, we estimated organ displacement in the second PBH by applying the DR from the first PBH to the displacement of the RHT measured during the second PBH. We compared the estimated organ displacement to the measured organ displacement during the second PBH. The difference between the two values was defined as the estimation error of using the RHT as a surrogate and assuming a constant DR over MRI sessions. RESULTS: The linear relationships were confirmed by the high R2 values of the linear fit between the displacements of the RHT and the abdominal organs (R2 > 0.96) in the IS and AP direction and |d|, and high to moderate correlations in the LR direction (0.93 > R2 > 0.64). The median DR difference between PBH-MRI1 and PBH-MRI2 varied between 0.13 and 0.31 for all organs. The median estimation error of the RHT as a surrogate varied between 0.4 and 0.8 mm/min for all organs. CONCLUSION: The RHT could serve as an accurate surrogate for abdominal organ motion during radiation treatments, for example, in tracking, provided the error of the RHT as motion surrogate is taken into account in the margins. TRIAL REGISTRATION: The study was registered in the Netherlands Trial Register (NL7603).

Dosimetric benefit of a library of plans versus single-plan strategy for pre-operative gastric cancer radiotherapy.

BACKGROUND AND PURPOSE: The stomach experiences large volume and shape changes during pre-operative gastric radiotherapy. This study evaluates the dosimetric benefit for organs-at-risk (OARs) of a library of plans (LoP) compared to the traditional single-plan (SP) strategy. MATERIALS AND METHODS: Twelve patients who received SP CBCT-guided pre-operative gastric radiotherapy (45 Gy; 25 fractions) were included. Clinical target volume (CTV) consisted of CTVstomach (i.e., stomach + 10 mm uniform margin minus OARs) and CTVLN (i.e., regional lymph node stations). For LoP, five stomach volumes (approximately equidistant with fixed volumes) were created using a previously developed stomach deformation model (volume = 150-750 mL). Appropriate planning target volume (PTV) margins were calculated for CTVstomach (SP and LoP, separately) and CTVLN. Treatment plans were automatically generated/optimized and the best-fitting library plan was manually selected for each daily CBCT. OARs (i.e., liver, kidneys, heart, spleen, spinal canal) doses were accumulated and dose-volume histogram (DVH) parameters were evaluated. RESULTS: The non-isotropic PTVstomach margins were significantly (p < 0.05) smaller for LoP than SP (median = 13.1 vs 19.8 mm). For each patient, the average PTV was smaller using a LoP (difference range 134-1151 mL). For all OARs except the kidneys, DVH parameters were significantly reduced using a LoP. Differences in mean dose (Dmean) for liver, heart and spleen ranged between -1.8 to 5.7 Gy. For LoP, a benefit of heart Dmean > 4 Gy and spleen Dmean > 2 Gy was found in 4 and 5 patients, respectively. CONCLUSION: A LoP strategy for pre-operative gastric cancer reduced average PTV and reduced OAR dose compared to a SP strategy, thereby potentially reducing risks for radiation-induced toxicities.

Towards artificial intelligence-based automated treatment planning in clinical practice: A prospective study of the first clinical experiences in high-dose-rate prostate brachytherapy.

PURPOSE: This prospective study evaluates our first clinical experiences with the novel ``BRachytherapy via artificial Intelligent GOMEA-Heuristic based Treatment planning'' (BRIGHT) applied to high-dose-rate prostate brachytherapy. METHODS AND MATERIALS: Between March 2020 and October 2021, 14 prostate cancer patients were treated in our center with a 15Gy HDR-brachytherapy boost. BRIGHT was used for bi-objective treatment plan optimization and selection of the most desirable plans from a coverage-sparing trade-off curve. Selected BRIGHT plans were imported into the commercial treatment planning system Oncentra Brachy . In Oncentra Brachy a dose distribution comparison was performed for clinical plan choice, followed by manual fine-tuning of the preferred BRIGHT plan when deemed necessary. The reasons for plan selection, clinical plan choice, and fine-tuning, as well as process speed were monitored. For each patient, the dose-volume parameters of the (fine-tuned) clinical plan were evaluated. RESULTS: In all patients, BRIGHT provided solutions satisfying all protocol values for coverage and sparing. In four patients not all dose-volume criteria of the clinical plan were satisfied after manual fine-tuning. Detailed information on tumour coverage, dose-distribution, dwell time pattern, and insight provided by the patient-specific trade-off curve, were used for clinical plan choice. Median time spent on treatment planning was 42 min, consisting of 16 min plan optimization and selection, and 26 min undesirable process steps. CONCLUSIONS: BRIGHT is implemented in our clinic and provides automated prostate high-dose-rate brachytherapy planning with trade-off based plan selection. Based on our experience, additional optimization aims need to be implemented to further improve direct clinical applicability of treatment plans and process efficiency.

Adverse late health outcomes among children treated with 3D radiotherapy techniques: Study design of the Dutch pediatric 3D-RT study.

BACKGROUND: Adverse late health outcomes after multimodal treatment for pediatric cancer are diverse and of prime interest. Currently available evidence and survivorship care guidelines are largely based on studies addressing side-effects of two dimensional planned radiotherapy. AIMS: The Dutch pediatric 3D-planned radiotherapy (3D-RT) study aims to gain insight in the long-term health outcomes among children who had radiotherapy in the 3D era. Here, we describe the study design, data-collection methods, and baseline cohort characteristics. METHODS AND RESULTS: The 3D-RT study represents an expansion of the Dutch Childhood Cancer Survivor study (DCCSS) LATER cohort, including pediatric cancer patients diagnosed during 2000-2012, who survived at least 5 years after initial diagnosis and 2 years post external beam radiotherapy. Individual cancer treatment parameters were obtained from medical files. A national infrastructure for uniform collection and archival of digital radiotherapy files (Computed Tomography [CT]-scans, delineations, plan, and dose files) was established. Health outcome information, including subsequent tumors, originated from medical records at the LATER outpatient clinics, and national registry-linkage. With a median follow-up of 10.9 (interquartile range [IQR]: 7.9-14.3) years after childhood cancer diagnosis, 711 eligible survivors were identified. The most common cancer types were Hodgkin lymphoma, medulloblastoma, and nephroblastoma. Most survivors received radiotherapy directed to the head/cranium only, the craniospinal axis, or the abdominopelvic region. CONCLUSION: The 3D-RT study will provide knowledge on the risk of adverse late health outcomes and radiation-associated dose-effect relationships. This information is valuable to guide follow-up care of childhood cancer survivors and to refine future treatment protocols.

Quantifying intrafractional gastric motion using auto-segmentation on MRI: Deformation and respiratory-induced displacement compared.

BACKGROUND AND PURPOSE: For accurate pre-operative gastric radiotherapy, intrafractional changes must be taken into account. The aim of this study is to quantify local gastric deformations and compare these deformations with respiratory-induced displacement. MATERIALS AND METHODS: Coronal 2D MRI scans (15-16 min; 120 repetitions of 25-27 interleaved slices) were obtained for 18 healthy volunteers. A deep-learning network was used to auto-segment the stomach. To separate out respiratory-induced displacements, auto-segmentations were rigidly shifted in superior-inferior (SI) direction to align the centre of mass (CoM) within every slice. From these shifted auto-segmentations, 3D iso-probability surfaces (isosurfaces) were established: a reference surface for POcc  = 0.50 and 50 other isosurfaces (from POcc  = 0.01 to 0.99), with POcc indicating the probability of occupation by the stomach. For each point on the reference surface, distances to all isosurfaces were determined and a cumulative Gaussian was fitted to this probability-distance dataset to obtain a standard deviation (SDdeform ) expressing local deformation. For each volunteer, we determined median and 98th percentile of SDdeform over the reference surface and compared these with the respiratory-induced displacement SDresp , that is, the SD of all CoM shifts (paired Wilcoxon signed-rank, α = 0.05). RESULTS: Larger deformations were mostly seen in the antrum and pyloric region. Median SDdeform (range, 2.0-2.9 mm) was smaller than SDresp (2.7-8.8 mm) for each volunteer (p < 0.00001); 98th percentile of SDdeform (3.2-7.3 mm) did not significantly differ from SDresp (p = 0.13). CONCLUSION: Locally, gastric deformations can be large. Overall, however, these deformations are limited compared to respiratory-induced displacement. Therefore, unless respiratory motion is considerably reduced, the need to separately include these deformation uncertainties in the treatment margins may be limited.

Patterns of Hearing Loss in Irradiated Survivors of Head and Neck Rhabdomyosarcoma.

PURPOSE: The frequency and patterns of HL in a HNRMS survivor cohort were investigated. A dose-effect relationship between the dose to the cochlea and HL was explored. METHODS: Dutch survivors treated for HNRMS between 1993 and 2017 with no relapse and at least two years after the end of treatment were eligible for inclusion. The survivors were evaluated for HL with pure-tone audiometry. HL was graded according to the Muenster, Common Terminology Criteria for Adverse Events (CTCAE) v4.03 and International Society for Paediatric Oncology (SIOP) classification. We defined deleterious HL as Muenster ≥ 2b, CTCAE ≥ 2, and SIOP ≥ 2. Mixed-effects logistic regression was used to search for the dose-effect relationship between the irradiation dose to the cochlea and the occurrence of HL. RESULTS: Forty-two HNRMS survivors underwent pure-tone audiometry. The Muenster, CTCAE and SIOP classification showed that 19.0% (n = 8), 14.2% (n = 6) and 11.9% (n = 5) of survivors suffered from HL, respectively. A low-frequency HL pattern with normal hearing or milder hearing loss in the higher frequencies was seen in four survivors. The maximum cochlear irradiation dose was significantly associated with HL (≥Muenster 2b) (p = 0.047). In our series, HL (≥Muenster 2b) was especially observed when the maximum dose to the cochlea exceeded 19 Gy. CONCLUSION: HL occurred in up to 19% of survivors of HNRMS. More research is needed on HL patterns in HNRMS survivors and on radiotherapy dose-effect relationships.

Validation and Comparison of Radiograph-Based Organ Dose Reconstruction Approaches for Wilms Tumor Radiation Treatment Plans.

Purpose: Our purpose was to validate and compare the performance of 4 organ dose reconstruction approaches for historical radiation treatment planning based on 2-dimensional radiographs. Methods and Materials: We considered 10 patients with Wilms tumor with planning computed tomography images for whom we developed typical historic Wilms tumor radiation treatment plans, using anteroposterior and posteroanterior parallel-opposed 6 MV flank fields, normalized to 14.4 Gy. Two plans were created for each patient, with and without corner blocking. Regions of interest (lungs, heart, nipples, liver, spleen, contralateral kidney, and spinal cord) were delineated, and dose-volume metrics including organ mean and minimum dose (Dmean and Dmin) were computed as the reference baseline for comparison. Dosimetry for the 20 plans was then independently reconstructed using 4 different approaches. Three approaches involved surrogate anatomy, among which 2 used demographic-matching criteria for phantom selection/building, and 1 used machine learning. The fourth approach was also machine learning-based, but used no surrogate anatomies. Absolute differences in organ dose-volume metrics between the reconstructed and the reference values were calculated. Results: For Dmean and Dmin (average and minimum point dose) all 4 dose reconstruction approaches performed within 10% of the prescribed dose (≤1.4 Gy). The machine learning-based approaches showed a slight advantage for several of the considered regions of interest. For Dmax (maximum point dose), the absolute differences were much higher, that is, exceeding 14% (2 Gy), with the poorest agreement observed for near-beam and out-of-beam organs for all approaches. Conclusions: The studied approaches give comparable dose reconstruction results, and the choice of approach for cohort dosimetry for late effects studies should still be largely driven by the available resources (data, time, expertise, and funding).

Pediatric radiotherapy for thoracic and abdominal targets: Organ motion, reported margin sizes, and delineation variations - A systematic review.

For radiotherapy of thoracic and abdominal tumors safety margins are applied to address geometrical uncertainties caused by e.g. set-up errors, organ motion and delineation variability. For pediatric patients no standardized margins are defined. Moreover, studies on these geometrical uncertainties are relatively scarce. Therefore, this systematic review presents an overview of organ motion, applied margin sizes and delineation variability in patients <18 years. A search from January 2000 to March 2021 in Medline, Embase, Web of Science, ClinicalTrials.gov and the International Trials Registry Platform resulted in the inclusion of 117 studies reporting on organ motion, margin sizes and/or delineation variability. Studies were heterogeneous concerning age, tumor types, the use of general anesthesia, imaging modalities; image guidance techniques were reported in 39% of the studies. Inter- and intrafractional motion as reported for different organs was largest in cranio-caudal direction and ranged from -9.1 to 10.0 mm and -4.4 to 19.5 mm, respectively. Motion quantification methodologies differed between studies regarding measures of displacement and definitions of motion direction. Reported CTV-PTV margins varied from 3 to 20 mm for both thoracic and abdominal targets, and for spinal and pelvic from 3to 15 mm and 3 to 10 mm, respectively. Studies reported wide variation in interobserver variability of target volume delineation, which may affect dose distributions to both target volumes and organs at risk. Results of this review indicate possible reduction of margin sizes for children, however, wide variation in organ motion and delineation variability caused by differences in methodologies and outcomes hamper the use of standardized margins.

Gastric deformation models for adaptive radiotherapy: Personalized vs population-based strategy.

BACKGROUND AND PURPOSE: To create a library of plans (LoP) for gastric cancer adaptive radiotherapy, accurate predictions of shape changes due to filling variations are essential. The ability of two strategies (personalized and population-based) to predict stomach shape based on filling was evaluated for volunteer and patient data to explore the potential for use in a LoP. MATERIALS AND METHODS: For 19 healthy volunteers, stomachs were delineated on MRIs with empty (ES), half-full (HFS) and full stomach (FS). For the personalized strategy, a deformation vector field from HFS to corresponding ES was acquired and extrapolated to predict FS. For the population-based strategy, the average deformation vectors from HFS to FS of 18 volunteers were applied to the HFS of the remaining volunteer to predict FS (leave-one-out principle); thus, predictions were made for each volunteer. Reversed processes were performed to predict ES. To validate, for seven gastric cancer patients, the volunteer population-based model was applied to their pre-treatment CT to predict stomach shape on 2-3 repeat CTs. For all predictions, volume was made equal to true stomach volume. RESULTS: FS predictions were satisfactory, with median Dice similarity coefficient (mDSC) of 0.91 (population-based) and 0.89 (personalized). ES predictions were poorer: mDSC = 0.82 for population-based; personalized strategy yielded unachievable volumes. Population-based shape predictions (both ES and FS) were comparable between patients (mDSC = 0.87) and volunteers (0.88). CONCLUSION: The population-based model outperformed the personalized model and demonstrated its ability in predicting filling-dependent stomach shape changes and, therefore, its potential for use in a gastric cancer LoP.

Evaluating differences in respiratory motion estimates during radiotherapy: a single planning 4DMRI versus daily 4DMRI.

BACKGROUND: In radiotherapy, respiratory-induced tumor motion is typically measured using a single four-dimensional computed tomography acquisition (4DCT). Irregular breathing leads to inaccurate motion estimates, potentially resulting in undertreatment of the tumor and unnecessary dose to healthy tissue. The aim of the research was to determine if a daily pre-treatment 4DMRI-strategy led to a significantly improved motion estimate compared to single planning 4DMRI (with or without outlier rejection). METHODS: 4DMRI data sets from 10 healthy volunteers were acquired. The first acquisition simulated a planning MRI, the respiratory motion estimate (constructed from the respiratory signal, i.e. the 1D navigator) was compared to the respiratory signal in the subsequent scans (simulating 5-29 treatment fractions). The same procedure was performed using the first acquisition of each day as an estimate for the subsequent acquisitions that day (2 per day, 4-20 per volunteer), simulating a daily MRI strategy. This was done for three outlier strategies: no outlier rejection (NoOR); excluding 5% of the respiratory signal whilst minimizing the range (Min95) and excluding the datapoints outside the mean end-inhalation and end-exhalation positions (MeanIE). RESULTS: The planning MRI median motion estimates were 27 mm for NoOR, 18 mm for Min95, and 13 mm for MeanIE. The daily MRI median motion estimates were 29 mm for NoOR, 19 mm for Min95 and 15 mm for MeanIE. The percentage of time outside the motion estimate were for the planning MRI: 2%, 10% and 32% for NoOR, Min95 and MeanIE respectively. These values were reduced with the daily MRI strategy: 0%, 6% and 17%. Applying Min95 accounted for a 30% decrease in motion estimate compared to NoOR. CONCLUSION: A daily MRI improved the estimation of respiratory motion as compared to a single 4D (planning) MRI significantly. Combining the Min95 technique with a daily 4DMRI resulted in a decrease of inclusion time of 6% with a 30% decrease of motion. Outlier rejection alone on a planning MRI often led to underestimation of the movement and could potentially lead to an underdosage. TRIAL REGISTRATION: protocol W15_373#16.007.

Low dose cone beam CT for paediatric image-guided radiotherapy: Image quality and practical recommendations.

PURPOSE: Cone beam CT (CBCT) is used in paediatric image-guided radiotherapy (IGRT) for patient setup and internal anatomy assessment. Adult CBCT protocols lead to excessive doses in children, increasing the risk of radiation-induced malignancies. Reducing imaging dose increases quantum noise, degrading image quality. Patient CBCTs also include 'anatomical noise' (e.g. motion artefacts), further degrading quality. We determine noise contributions in paediatric CBCT, recommending practical imaging protocols and thresholds above which increasing dose yields no improvement in image quality. METHODS AND MATERIALS: Sixty CBCTs including the thorax or abdomen/pelvis from 7 paediatric patients (aged 6-13 years) were acquired at a range of doses and used to simulate lower dose scans, totalling 192 scans (0.5-12.8 mGy). Noise measured in corresponding regions of each patient and a 10-year-old phantom were compared, modelling total (including anatomical) noise, and quantum noise contributions as a function of dose. Contrast-to-noise ratio (CNR) was measured between fat/muscle. Soft tissue registration was performed on the kidneys, comparing accuracy to the highest dose scans. RESULTS: Quantum noise contributed <20% to total noise in all cases, suggesting anatomical noise is the largest determinant of image quality in the abdominal/pelvic region. CNR exceeded 3 in over 90% of cases ≥ 1 mGy, and 57% of cases at 0.5 mGy. Soft tissue registration was accurate for doses > 1 mGy. CONCLUSION: Anatomical noise dominates quantum noise in paediatric CBCT. Appropriate soft tissue contrast and registration accuracy can be achieved for doses as low as 1 mGy. Increasing dose above 1 mGy holds no benefit in improving image quality or registration accuracy due to the presence of anatomical noise.

Feasibility of Conebeam CT-based online adaptive radiotherapy for neoadjuvant treatment of rectal cancer.

BACKGROUND: Online adaptive radiotherapy has the potential to reduce toxicity for patients treated for rectal cancer because smaller planning target volumes (PTV) margins around the entire clinical target volume (CTV) are required. The aim of this study is to describe the first clinical experience of a Conebeam CT (CBCT)-based online adaptive workflow for rectal cancer, evaluating timing of different steps in the workflow, plan quality, target coverage and patient compliance. METHODS: Twelve consecutive patients eligible for 5 × 5 Gy pre-operative radiotherapy were treated on a ring-based linear accelerator with a multidisciplinary team present at the treatment machine for each fraction. The accelerator is operated using an integrated software platform for both treatment planning and delivery. In all directions for all CTVs a PTV margin of 5 mm was used, except for the cranial/caudal borders of the total CTV where a margin of 8 mm was applied. A reference plan was generated based on a single planning CT. After aligning the patient the online adaptive procedure started with acquisition of a CBCT. The planning CT scan was registered to the CBCT using deformable registration and a synthetic CT scan was generated. With the support of artificial intelligence, structure guided deformation and the synthetic CT scan contours were adapted by the system to match the anatomy on the CBCT. If necessary, these contours were adjusted before a new plan was generated. A second and third CBCT were acquired to validate the new plan with respect to CTV coverage just before and after treatment delivery, respectively. Treatment was delivered using volumetric modulated arc treatment (VMAT). All steps in this process were defined and timed. RESULTS: On average the timeslot needed at the treatment machine was 34 min. The process of acquiring a CBCT, evaluating and adjusting the contours, creating the new plan and verifying the CTV on the CBCT scan took on average 20 min. Including delivery and post treatment verification this was 26 min. Manual adjustments of the target volumes were necessary in 50% of fractions. Plan quality, target coverage and patient compliance were excellent. CONCLUSIONS: First clinical experience with CBCT-based online adaptive radiotherapy shows it is feasible for rectal cancer. Trial registration Medical Research Involving Human Subjects Act (WMO) does not apply to this study and was retrospectively approved by the Medical Ethics review Committee of the Academic Medical Center (W21_087 # 21.097; Amsterdam University Medical Centers, Location Academic Medical Center, Amsterdam, The Netherlands).

A 3D cine-MRI acquisition technique and image analysis framework to quantify bowel motion demonstrated in gynecological cancer patients.

PURPOSE: Magnetic resonance imaging (MRI) is increasingly used in radiation oncology for target delineation and radiotherapy treatment planning, for example, in patients with gynecological cancers. As a consequence of pelvic radiotherapy, a part of the bowel is irradiated, yielding risk of bowel toxicity. Existing dose-effect models predicting bowel toxicity are inconclusive and bowel motion might be an important confounding factor. The exact motion of the bowel and dosimetric effects of its motion are yet uncharted territories in radiotherapy. In diagnostic radiology methods on the acquisition of dynamic MRI sequences were developed for bowel motility visualization and quantification. Our study aim was to develop an imaging technique based on three-dimensional (3D) cine-MRI to visualize and quantify bowel motion and demonstrate it in a cohort of gynecological cancer patients. METHODS: We developed an MRI acquisition suitable for 3D bowel motion quantification, namely a balanced turbo field echo sequence (TE = 1.39 ms, TR = 2.8 ms), acquiring images in 3.7 s (dynamic) with a 1.25 × 1.25 × 2.5 mm3 resolution, yielding a field of view of 200 × 200 × 125 mm3 . These MRI bowel motion sequences were acquired in 22 gynecological patients. During a 10-min scan, 160 dynamics were acquired. Subsequent dynamics were deformably registered using a B-spline transformation model, resulting in 159 3D deformation vector fields (DVFs) per MRI set. From the 159 DVFs, the average vector length was calculated per voxel to generate bowel motion maps. Quality assurance was performed on all 159 DVFs per MRI, using the Jacobian Determinant and the Harmonic Energy as deformable image registration error metrics. In order to quantify bowel motion, we introduced the concept of cumulative motion-volume histogram (MVH) of the bowel bag volume. Finally, interpatient variation of bowel motion was analyzed using the MVH parameters M10%, M50%, and M90%. The M10%/M50%/M90% represents the minimum bowel motion per frame of 10%/50%/90% of the bowel bag volume. RESULTS: The motion maps resulted in a visualization of areas with small and large movements within the bowel bag. After applying quality assurance, the M10%, M50%, and M90% were 4.4 (range 2.2-7.6) mm, 2.2 (range 0.9-4.1) mm, and 0.5 (range 0.2-1.4) mm per frame, on average over all patients, respectively. CONCLUSION: We have developed a method to visualize and quantify 3D bowel motion with the use of bowel motion specific MRI sequences in 22 gynecological cancer patients. This 3D cine-MRI-based quantification tool and the concept of MVHs can be used in further studies to determine the effect of radiotherapy on bowel motion and to find the relation with dose effects to the small bowel. In addition, the developed technique can be a very interesting application for bowel motility assessment in diagnostic radiology.

Robust optimization for HDR prostate brachytherapy applied to organ reconstruction uncertainty.

PURPOSE: Recently, we introduced a bi-objective optimization approach based on dose-volume indices to automatically create clinically good HDR prostate brachytherapy plans. To calculate dose-volume indices, a reconstruction algorithm is used to determine the 3D organ shape from 2D contours, inevitably containing settings that influence the result. We augment the optimization approach to quickly find plans that are robust to differences in 3D reconstruction. METHODS: Studied reconstruction settings were: interpolation between delineated organ contours, overlap between contours, and organ shape at the top and bottom contour. Two options for each setting yields 8 possible 3D organ reconstructions per patient, over which the robust model defines minimax optimization. For the original model, settings were based on our treatment planning system. Both models were tested on data of 26 patients and compared by re-evaluating selected optimized plans both in the original model (1 organ reconstruction, the difference determines the cost), and in the robust model (8 organ reconstructions, the difference determines the benefit). RESULTS: Robust optimization increased the run time from 3 to 6 min. The median cost for robust optimization as observed in the original model was -0.25% in the dose-volume indices with a range of [-0.01%, -1.03%]. The median benefit of robust optimization as observed in the robust model was 0.93% with a range of [0.19%, 4.16%]. For 4 patients, selected plans that appeared good when optimized in the original model, violated the clinical protocol with more than 1% when considering different settings. This was not the case for robustly optimized plans. CONCLUSIONS: Plans of high quality, irrespective of 3D organ reconstruction settings, can be obtained using our robust optimization approach. With its limited effect on total runtime, our approach therefore offers a way to account for dosimetry uncertainties that result from choices in organ reconstruction settings that is viable in clinical practice.

Bi-objective optimization of catheter positions for high-dose-rate prostate brachytherapy.

PURPOSE: Bi-objective simultaneous optimization of catheter positions and dwell times for high-dose-rate (HDR) prostate brachytherapy, based directly on dose-volume indices, has shown promising results. However, optimization with the state-of-the-art evolutionary algorithm MO-RV-GOMEA so far required several hours of runtime, and resulting catheter positions were not always clinically feasible. The aim of this study is to extend the optimization model and apply GPU parallelization to achieve clinically acceptable computation times. The resulting optimization procedure is compared with a previously introduced method based solely on geometric criteria, the adapted Centroidal Voronoi Tessellations (CVT) algorithm. METHODS: Bi-objective simultaneous optimization was performed with a GPU-parallelized version of MO-RV-GOMEA. This optimization of catheter positions and dwell times was retrospectively applied to the data of 26 patients previously treated with HDR prostate brachytherapy for 8-16 catheters (steps of 2). Optimization of catheter positions using CVT was performed in seconds, after which optimization of only the dwell times using MO-RV-GOMEA was performed in 1 min. RESULTS: Simultaneous optimization of catheter positions and dwell times using MO-RV-GOMEA was performed in 5 min. For 16 down to 8 catheters (steps of 2), MO-RV-GOMEA found plans satisfying the planning-aims for 20, 20, 18, 14, and 11 out of the 26 patients, respectively. CVT achieved this for 19, 17, 13, 9, and 2 patients, respectively. The P-value for the difference between MO-RV-GOMEA and CVT was 0.023 for 16 catheters, 0.005 for 14 catheters, and <0.001 for 12, 10, and 8 catheters. CONCLUSIONS: With bi-objective simultaneous optimization on a GPU, high-quality catheter positions can now be obtained within 5 min, which is clinically acceptable, but slower than CVT. For 16 catheters, the difference between MO-RV-GOMEA and CVT is clinically irrelevant. For 14 catheters and less, MO-RV-GOMEA outperforms CVT in finding plans satisfying all planning-aims.