Radiation therapy margin reduction for patients with localized prostate cancer: A prospective study of the dosimetric impact and quality of life.

OBJECTIVES: To investigate the impact of reducing Clinical Target Volume (CTV) to Planning Target Volume (PTV) margins on delivered radiation therapy (RT) dose and patient reported quality-of-life (QOL) for patients with localized prostate cancer. METHODS: Twenty patients were included in a single institution IRB-approved prospective study. Nine were planned with reduced margins (4 mm at prostate/rectum interface, 5 mm elsewhere), and 11 with standard margins (6/10 mm). Cumulative delivered dose was calculated using deformable dose accumulation. Each daily CBCT dataset was deformed to the planning CT (pCT), dose was computed, and accumulated on the resampled pCT using a parameter-optimized, B-spline algorithm (Elastix, ITK/VTK). EPIC-26 patient reported QOL was prospectively collected pre-treatment, post-treatment, and at 2-, 6-, 12-, 18-, 24-, 36-, 48-, and 60-month follow-ups. Post -RT QOL scores were baseline corrected and standardized to a [0-100] scale using EPIC-26 methodology. Correlations between QOL scores and dosimetric parameters were investigated, and the overall QOL differences between the two groups (QOLMargin-reduced -QOLcontrol ) were calculated. RESULTS: The median QOL follow-up length for the 20 patients was 48 months. Difference between delivered dose and planned dose did not reach statistical significance (p > 0.1) for both targets and organs at risk between the two groups. At 4 years post-RT, standardized mean QOLMargin-reduced -QOLcontrol were improved for Urinary Incontinence, Urinary Irritative/Obstructive, Bowel, and Sexual EPIC domains by 3.5, 14.8, 10.2, and 16.1, respectively (higher values better). The control group showed larger PTV/rectum and PTV/bladder intersection volumes (7.2 ± 5.8, 18.2 ± 8.1 cc) than the margin-reduced group (2.6 ± 1.8, 12.5 ± 8.3 cc), though the dose to these intersection volumes did not reach statistical significance (p > 0.1) between the groups. PTV/rectum intersection volume showed a moderate correlation (r = -0.56, p < 0.05) to Bowel EPIC domain. CONCLUSIONS: Results of this prospective study showed that margin-reduced group exhibited clinically meaningful improvement of QOL without compromising the target dose coverage.

Experimental validation of a novel method of dose accumulation for the rectum.

BACKGROUND: Dose-surface maps (DSMs) are an increasingly popular tool to evaluate spatial dose-outcome relationships for the rectum. Recently, DSM addition has been proposed as an alternative method of dose accumulation from deformable registration-based techniques. In this study, we performed the first experimental investigation of the accuracy at which DSM accumulation can capture the total dose delivered to a rectum's surface in the presence of inter-fraction motion. MATERIAL AND METHODS: A custom PVC rectum phantom capable of representing typical rectum inter-fraction motion and filling variations was constructed for this project. The phantom allowed for the placement of EBT3 film sheets on the representative rectum surface to measure rectum surface dose. A multi-fraction prostate VMAT treatment was designed and delivered to the phantom in a water tank for a variety of inter-fraction motion scenarios. DSMs for each fraction were calculated in two ways using CBCT images acquired during delivery and summed to produce accumulated DSMs. Accumulated DSMs were then compared to film measurements using gamma analysis (3%/2 mm criteria). Similarity of isodose clusters between films and DSMs was also investigated. RESULTS: Baseline agreement between film measurements and accumulated DSMs for a stationary rectum was 95.6%. Agreement between film and accumulated DSMs in the presence of different types of inter.-fraction motion was ≥92%, and isodose cluster mean distance to agreement was within 1.5 mm for most scenarios. Overall, DSM accumulation performed the best when using DSMs that accounted for changes in rectum path orientation. CONCLUSION: Dose accumulation performed with DSMs was found to accurately replicate total delivered dose to a rectum phantom in the presence of inter-fraction motion.

CBCT-based deformable dose accumulation of external beam radiotherapy in cervical cancer.

Background: Delivered radiotherapy doses do not exactly match those planned for a course of treatment, largely due to inter-fraction changes in anatomy. In this study, accumulated delivered dose was calculated for a sample of cervical cancer patients, by deformably registering daily cone beam computed tomography (CBCT) images to the planning computed tomography (CT) scan. Planned and accumulated doses were compared for the clinical target volume (CTV), bladder, and rectum.Material and Methods: For 10 patients receiving 45 Gy in 25 fractions of external beam radiotherapy, daily dose distributions were calculated on CBCT. These images were deformed onto the planning CT and the dose was accumulated using Velocity 4.1 (Varian Medical Systems, Palo Alto, USA). The quality of deformable image registration was evaluated visually and by calculating Dice similarity coefficients and mean distance to agreement.Results: V95%>99% was achieved for the primary CTV in 9/10 patients for the planned dose distribution and 7/10 patients for the accumulated dose distribution. Primary CTV coverage by 95% of the prescription dose was reduced in one patient, due to an increase in anterior-posterior separation. Comparison of planned and accumulated dose volume histograms (DVHs) for the bladder and rectum found agreement within 5% at low and intermediate doses, but differences exceeded 20% at higher doses. Direct addition of CBCT DVHs was seen to be a poor estimate for the accumulated DVH at higher doses.Conclusion: Computation of delivered radiotherapy dose that accounts for inter-fraction anatomical changes is important for establishing dose-effect relationships. Updating delivered dose distributions after each fraction would support informed clinical decision making on any potential treatment interventions.

Dosimetric impact of deformable image registration using radiophotoluminescent glass dosimeters with a physical geometric phantom.

PURPOSE: To study the dosimetry impact of deformable image registration (DIR) using radiophotoluminescent glass dosimeter (RPLD) and custom developed phantom with various inserts. METHODS: The phantom was developed to facilitate simultaneous evaluation of geometric and dosimetric accuracy of DIR. Four computed tomography (CT) images of the phantom were acquired with four different configurations. Four volumetric modulated arc therapy (VMAT) plans were computed for different phantom. Two different patterns were applied to combination of four phantom configurations. RPLD dose measurement was combined between corresponding two phantom configurations. DIR-based dose accumulation was calculated between corresponding two CT images with two commercial DIR software and various DIR parameter settings, and an open source software. Accumulated dose calculated using DIR was then compared with measured dose using RPLD. RESULTS: The mean ± standard deviation (SD) of dose difference was 2.71 ± 0.23% (range, 2.22%-3.01%) for tumor-proxy and 3.74 ± 0.79% (range, 1.56%-4.83%) for rectum-proxy. The mean ± SD of target registration error (TRE) was 1.66 ± 1.36 mm (range, 0.03-4.43 mm) for tumor-proxy and 6.87 ± 5.49 mm (range, 0.54-17.47 mm) for rectum-proxy. These results suggested that DIR accuracy had wide range among DIR parameter setting. CONCLUSIONS: The dose difference observed in our study was 3% for tumor-proxy and within 5% for rectum-proxy. The custom developed physical phantom with inserts showed potential for accurate evaluation of DIR-based dose accumulation. The prospect of simultaneous evaluation of geometric and dosimetric DIR accuracy in a single phantom may be useful for validation of DIR for clinical use.

How does CBCT reconstruction algorithm impact on deformably mapped targets and accumulated dose distributions?

PURPOSE: We performed quantitative analysis of differences in deformable image registration (DIR) and deformable dose accumulation (DDA) computed on CBCT datasets reconstructed using the standard (Feldkamp-Davis-Kress: FDK_CBCT) and a novel iterative (iterative_CBCT) CBCT reconstruction algorithms. METHODS: Both FDK_CBCT and iterative_CBCT images were reconstructed for 323 fractions of treatment for 10 prostate cancer patients. Planning CT images were deformably registered to each CBCT image data set. After daily dose distributions were computed, they were mapped to planning CT to obtain deformed doses. Dosimetric and image registration results based CBCT images reconstructed by two algorithms were compared at three levels: (A) voxel doses over entire dose calculation volume, (B) clinical constraint results on targets and sensitive structures, and (C) contours propagated to CBCT images using DIR results based on three algorithms (SmartAdapt, Velocity, and Elastix) were compared with manually delineated contours as ground truth. RESULTS: (A) Average daily dose differences and average normalized DDA differences between FDK_CBCT and iterative_CBCT were ≤1 cGy. Maximum daily point dose differences increased from 0.22 ± 0.06 Gy (before the deformable dose mapping operation) to 1.33 ± 0.38 Gy after the deformable dose mapping. Maximum differences of normalized DDA per fraction were up to 0.80 Gy (0.42 ± 0.19 Gy). (B) Differences in target minimum doses were up to 8.31 Gy (-0.62 ± 4.60 Gy) and differences in critical structure doses were 0.70 ± 1.49 Gy. (C) For mapped prostate contours based on iterative_CBCT (relative to standard FDK_CBCT), dice similarity coefficient increased by 0.10 ± 0.09 (p < 0.0001), mass center distances decreased by 2.5 ± 3.0 mm (p < 0.00005), and Hausdorff distances decreased by 3.3 ± 4.4 mm (p < 0.00015). CONCLUSIONS: The new iterative CBCT reconstruction algorithm leads to different mapped volumes of interest, deformed and cumulative doses than results based on conventional FDK_CBCT.

[Database of Radiotherapy Plan Image for Deformable Image Registration].

Guidelines require commissioning for deformable image registration (DIR) software before clinical use. The accuracy of DIR software depends upon data used. If common datasets for the DIR commissioning are available, the DIR results using the common datasets would be useful as an accuracy benchmark. Thus, the DIR-database (DIR-DB) was developed for DIR accuracy check and was open to access, which included radiotherapy plan data. This study was approved by Institutional Review Board (IRB). The DIR-DB recorded radiotherapy plans which had been finished on June 2017 and which at least two radiotherapy plans were built for a case in a treatment course. Cone-beam computed tomography (CBCT) images for patient setup were also collected and recorded in the DIR-DB, if it is available. All recorded data were anonymized and were allowed to access by users in Japan with the IRB approval. The accuracy metrics of DIR; Hausdorff distance, mean distance to agreement, Dice similarity coefficient, Jaccard were put up on the DIR-DB web site. The number of recorded cases were 11 cases for head and neck, 16 cases for thorax, 7 cases for abdomen, 8 cases for pelvis and 6 cases for prostate treated with brachytherapy. The number of case for CBCT was 17 cases. It was meaningful for DIR accuracy check in Japan that the DIR-DB and DIR results using the data in the database were released.

Deformable abdominal phantom for the validation of real-time image guidance and deformable dose accumulation.

PURPOSE: End-to-end testing with quality assurance (QA) phantoms for deformable dose accumulation and real-time image-guided radiotherapy (IGRT) has recently been recommended by American Association of Physicists in Medicine (AAPM) Task Groups 132 and 76. The goal of this work was to develop a deformable abdominal phantom containing a deformable three-dimensional dosimeter that could provide robust testing of these systems. METHODS: The deformable abdominal phantom was fabricated from polyvinyl chloride plastisol and phantom motion was simulated with a programmable motion stage and plunger. A deformable normoxic polyacrylamide gel (nPAG) dosimeter was incorporated into the phantom apparatus to represent a liver tumor. Dosimeter data were acquired using magnetic resonance imaging (MRI). Static measurements were compared to planned dose distributions. Static and dynamic deformations were used to simulate inter- and intrafractional motion in the phantom and measurements were compared to baseline measurements. RESULTS: The statically irradiated dosimeters matched the planned dose distribution with an average γ pass rates of 97.0 ± 0.5% and 97.5 ± 0.2% for 3%/5 mm and 5%/5 mm criteria, respectively. Static deformations caused measured dose distribution shifts toward the phantom plunger. During the dynamic deformation experiment, the dosimeter that utilized beam gating showed an improvement in the γ pass rate compared to the dosimeter that did not. CONCLUSIONS: A deformable abdominal phantom apparatus which incorporates a deformable nPAG dosimeter was developed to test real-time IGRT systems and deformable dose accumulation algorithms. This apparatus was used to benchmark simple static irradiations in which it was found that measurements match well to the planned distributions. Deformable dose accumulation could be tested by directly measuring the shifts and blurring of the target dose due to interfractional organ deformation and motion. Dosimetric improvements were achieved from the motion management during intrafractional motion.

The impact of robustness of deformable image registration on contour propagation and dose accumulation for head and neck adaptive radiotherapy.

Deformable image registration (DIR) is the key process for contour propagation and dose accumulation in adaptive radiation therapy (ART). However, currently, ART suffers from a lack of understanding of "robustness" of the process involving the image contour based on DIR and subsequent dose variations caused by algorithm itself and the presetting parameters. The purpose of this research is to evaluate the DIR caused variations for contour propagation and dose accumulation during ART using the RayStation treatment planning system. Ten head and neck cancer patients were selected for retrospective studies. Contours were performed by a single radiation oncologist and new treatment plans were generated on the weekly CT scans for all patients. For each DIR process, four deformation vector fields (DVFs) were generated to propagate contours and accumulate weekly dose by the following algorithms: (a) ANACONDA with simple presetting parameters, (b) ANACONDA with detailed presetting parameters, (c) MORFEUS with simple presetting parameters, and (d) MORFEUS with detailed presetting parameters. The geometric evaluation considered DICE coefficient and Hausdorff distance. The dosimetric evaluation included D95 , Dmax , Dmean , Dmin , and Homogeneity Index. For geometric evaluation, the DICE coefficient variations of the GTV were found to be 0.78 ± 0.11, 0.96 ± 0.02, 0.64 ± 0.15, and 0.91 ± 0.03 for simple ANACONDA, detailed ANACONDA, simple MORFEUS, and detailed MORFEUS, respectively. For dosimetric evaluation, the corresponding Homogeneity Index variations were found to be 0.137 ± 0.115, 0.006 ± 0.032, 0.197 ± 0.096, and 0.006 ± 0.033, respectively. The coherent geometric and dosimetric variations also consisted in large organs and small organs. Overall, the results demonstrated that the contour propagation and dose accumulation in clinical ART were influenced by the DIR algorithm, and to a greater extent by the presetting parameters. A quality assurance procedure should be established for the proper use of a commercial DIR for adaptive radiation therapy.

Dosimetric effects of anatomical changes during fractionated photon radiation therapy in pancreatic cancer patients.

Pancreatic tumors show large interfractional position variation. In addition, changes in gastrointestinal gas volumes and body contour take place over the course of radiation therapy. We aimed to quantify the effect of these anatomical changes on target dose coverage, for the clinically used fiducial marker-based patient position verification and, for comparison, also for simulated bony anatomy-based position verification. Nine consecutive patients were included in this retrospective study. To enable fraction dose calculations on cone-beam CT (CBCT), the planning CT was deformably registered to each CBCT (13-15 per patient); gas volumes visible on CBCT were copied to the deformed CT. Fraction doses were calculated for the clinically used 10 MV VMAT treatment plan (with for the planning target volume (PTV): D98% = 95%), according to fiducial marker-based and bony anatomy-based image registrations. Dose distributions were rigidly summed to yield the accumulated dose. To evaluate target dose coverage, we defined an iCTV+5 mm volume, i.e., the internal clinical target volume (iCTV) expanded with a 5 mm margin to account for remaining uncertainties including delineation uncertainties. We analyzed D98% , Dmean , and D2% for iCTV+5 mm and PTV (i.e., iCTV plus 10 mm margin). We found that for fiducial marker-based registration, differences between fraction doses and planned dose were minimal. For bony anatomy-based registration, fraction doses differed considerably, resulting in large differences between planned and accumulated dose for some patients, up to a decrease in D98% of the iCTV+5 mm from 95.9% to 85.8%. Our study shows that fractionated photon irradiation of pancreatic tumors is robust against variations in body contour and gastrointestinal gas, with dose coverage only mildly affected. However, as a result of interfractional tumor position variations, target dose coverage can severely decline when using bony anatomy for patient position verification. Therefore, the use of intratumoral fiducial marker-based daily position verification is essential in pancreatic cancer patients.

Evaluation of Deformable Image Registration (DIR) Methods for Dose Accumulation in Nasopharyngeal Cancer Patients during Radiotherapy.

INTRODUCTION: Deformable image registration (DIR) is used to modify structures according to anatomical changes for observing the dosimetric effect. In this study, megavoltage computed tomography (MVCT) images were used to generate cumulative doses for nasopharyngeal cancer (NPC) patients by various DIR methods. The performance of the multiple DIR methods was analysed, and the impact of dose accumulation was assessed. PATIENTS AND METHODS: The study consisted of five NPC patients treated with a helical tomotherapy unit. The weekly MVCT images at the 1st, 6th, 11th, 16th, 21st, 26th, and 31st fractions were used to assess the dose accumulation by the four DIR methods. The cumulative dose deviations from the initial treatment plan were analysed, and correlations of these variations with the anatomic changes and DIR methods were explored. RESULTS: The target dose received a slightly different result from the initial plan at the end of the treatment. The organ dose differences increased as the treatment progressed to 6.8% (range: 2.2 to 10.9%), 15.2% (range: -1.7 to 36.3%), and 6.4% (range: -1.6 to 13.2%) for the right parotid, the left parotid, and the spinal cord, respectively. The mean uncertainty values to estimate the accumulated doses for all the DIR methods were 0.21 ± 0.11 Gy (target dose), 1.99 ± 0.76 Gy (right parotid), 1.19 ± 0.24 Gy (left parotid), and 0.41 ± 0.04 Gy (spinal cord). CONCLUSIONS: Accuracy of the DIR methods affects the estimation of dose accumulation on both the target dose and the organ dose. The DIR methods provide an adequate dose estimation technique for observation as a result of inter-fractional anatomic changes and are beneficial for adaptive treatment strategies.

Multi-centre evaluation of variation in cumulative dose assessment in reirradiation scenarios.

BACKGROUND AND PURPOSE: Safe reirradiation relies on assessment of cumulative doses to organs at risk (OARs) across multiple treatments. Different clinical pathways can result in inconsistent estimates. Here, we quantified the consistency of cumulative dose to OARs across multi-centre clinical pathways. MATERIAL AND METHODS: We provided DICOM planning CT, structures and doses for two reirradiation cases: head & neck (HN) and lung. Participants followed their standard pathway to assess the cumulative physical and EQD2 doses (with provided α/ß values), and submitted DVH metrics and a description of their pathways. Participants could also submit physical dose distributions from Course 1 mapped onto the CT of Course 2 using their best available tools. To assess isolated impact of image registrations, a single observer accumulated each submitted spatially mapped physical dose for every participating centre. RESULTS: Cumulative dose assessment was performed by 24 participants. Pathways included rigid (n = 15), or deformable (n = 5) image registration-based 3D dose summation, visual inspection of isodose line contours (n = 1), or summation of dose metrics extracted from each course (n = 3). Largest variations were observed in near-maximum cumulative doses (25.4 - 41.8 Gy for HN, 2.4 - 33.8 Gy for lung OARs), with lower variations in volume/dose metrics to large organs. A standardised process involving spatial mapping of the first course dose to the second course CT followed by summation improved consistency for most near-maximum dose metrics in both cases. CONCLUSION: Large variations highlight the uncertainty in reporting cumulative doses in reirradiation scenarios, with implications for outcome analysis and understanding of published doses. Using a standardised workflow potentially including spatially mapped doses improves consistency in determination of accumulated dose in reirradiation scenarios.

Impact of daily plan adaptation on accumulated doses in ultra-hypofractionated magnetic resonance-guided radiation therapy of prostate cancer.

Background and purpose: Ultra-hypofractionated online adaptive magnetic resonance-guided radiotherapy (MRgRT) is promising for prostate cancer. However, the impact of online adaptation on target coverage and organ-at-risk (OAR) sparing at the level of accumulated dose has not yet been reported. Using deformable image registration (DIR)-based accumulation, we compared the delivered adapted dose with the simulated non-adapted dose. Materials and methods: Twenty-three prostate cancer patients treated at two clinics with 0.35 T magnetic resonance-guided linear accelerator (MR-linac) following the same treatment protocol (5 × 7.5 Gy with urethral sparing and daily adaptation) were included. The fraction MR images were deformably registered to the planning MR image. Both non-adapted and adapted fraction doses were accumulated with the corresponding vector fields. Two DIR approaches were implemented. PTV* (planning target volume minus urethra+2mm) D95%, CTV* (clinical target volume minus urethra) D98%, and OARs (urethra+2mm, bladder, and rectum) D0.2cc, were evaluated. Statistical significance was inferred from a two-tailed Wilcoxon signed-rank test (p < 0.05). Results: Normalized to the baseline, the accumulated PTV* D95% increased significantly by 2.7 % ([1.5, 4.3]%) through adaptation, and the CTV* D98% by 1.2 % ([0.1, 1.7]%). For the OARs after adaptation, accumulated bladder D0.2cc decreased by 0.4 % ([-1.2, 0.4]%), urethra+2mmD0.2cc by 0.8 % ([-1.6, -0.1]%), while rectum D0.2cc increased by 2.6 % ([1.2, 4.9]%). For all patients, rectum D0.2cc was still below the clinical constraint. Results of both DIR approaches differed on average by less than 0.2 %. Conclusions: Online adaptation in MRgRT improved target coverage and OARs sparing at the level of accumulated dose.

Dose tracking assessment for magnetic resonance guided adaptive radiotherapy of rectal cancers.

BACKGROUND: Magnetic resonance-guided adaptive radiotherapy (MRgART) at MR-Linac allows for plan optimisation on the MR-based synthetic CT (sCT) images, adjusting the target and organs at risk according to the patient's daily anatomy. Conversely, conventional linac image-guided radiotherapy (IGRT) involves rigid realignment of regions of interest to the daily anatomy, followed by the delivery of the reference computed tomography (CT) plan. This study aims to evaluate the effectiveness of MRgART versus IGRT for rectal cancer patients undergoing short-course radiotherapy, while also assessing the dose accumulation process to support the findings and determine its usefulness in enhancing treatment accuracy. METHODS: Nineteen rectal cancer patients treated with a 1.5 Tesla MR-Linac with a prescription dose of 25 Gy (5 Gy x 5) and undergoing daily adapted radiotherapy by plan optimization based on online MR-based sCT images, were included in this retrospective study. For each adapted plan ([Formula: see text]), a second plan ([Formula: see text]) was generated by recalculating the reference CT plan on the daily MR-based sCT images after rigid registration with the reference CT images to simulate the IGRT workflow. Dosimetry of [Formula: see text] and[Formula: see text]was compared for each fraction. Cumulative doses on the first and last fractions were evaluated for both workflows. The dosimetry per single fraction and the cumulative doses were compared using dose-volume histogram parameters. RESULTS: Ninety-five fractions delivered with MRgART were compared to corresponding simulated IGRT fractions. All MRgART fractions fulfilled the target clinical requirements. IGRT treatments did not meet the expected target coverage for 63 out of 94 fractions (67.0%), with 13 fractions showing a V95 median point percentage decrease of 2.78% (range, 1.65-4.16%), and 55 fractions exceeding the V107% threshold with a median value of 15.4 cc (range, 6.0-43.8 cc). For the bladder, the median [Formula: see text] values were 18.18 Gy for the adaptive fractions and 19.60 Gy for the IGRT fractions. Similarly the median [Formula: see text] values for the small bowel were 23.40 Gy and 25.69 Gy, respectively. No statistically significant differences were observed in the doses accumulated on the first or last fraction for the adaptive workflow, with results consistent with the single adaptive fractions. In contrast, accumulated doses in the IGRT workflow showed significant variations mitigating the high dose constraint, nevertheless, more than half of the patients still did not meet clinical requirements. CONCLUSIONS: MRgART for short-course rectal cancer treatments ensures that the dose delivered matches each fraction of the planned dose and the results are confirmed by the dose accumulation process, which therefore seems redundant. In contrast, IGRT may lead to target dose discrepancies and non-compliance with organs at risk constraints and dose accumulation can still highlight notable dosimetric differences.

Quantification of deformable image registration uncertainties for dose accumulation on head and neck cancer proton treatments.

PURPOSE: Head and neck cancer (HNC) patients in radiotherapy require adaptive treatment plans due to anatomical changes. Deformable image registration (DIR) is used in adaptive radiotherapy, e.g. for deformable dose accumulation (DDA). However, DIR's ill-posedness necessitates addressing uncertainties, often overlooked in clinical implementations. DIR's further clinical implementation is hindered by missing quantitative commissioning and quality assurance tools. This study evaluates one pathway for more quantitative DDA uncertainties. METHODS: For five HNC patients, each with multiple repeated CTs acquired during treatment, a simultaneous-integrated boost (SIB) plan was optimized. Recalculated doses were warped individually using multiple DIRs from repeated to reference CTs, and voxel-by-voxel dose ranges determined an error-bar for DDA. Followed by evaluating, a previously proposed early-stage DDA uncertainty estimation method tested for lung cancer, which combines geometric DIR uncertainties, dose gradients and their directional dependence, in the context of HNC. RESULTS: Applying multiple DIRs show dose differences, pronounced in high dose gradient regions. The patient with largest anatomical changes (-13.1 % in ROI body volume), exhibited 33 % maximum uncertainty in contralateral parotid, with 54 % of voxels presenting an uncertainty >5 %. Accumulation over multiple CTs partially mitigated uncertainties. The estimation approach predicted 92.6 % of voxels within ±5 % to the reference dose uncertainty across all patients. CONCLUSIONS: DIR variations impact accumulated doses, emphasizing DDA uncertainty quantification's importance for HNC patients. Multiple DIR dose warping aids in quantifying DDA uncertainties. An estimation approach previously described for lung cancer was successfully validated for HNC, for SIB plans, presenting different dose gradients, and for accumulated treatments.

Adaptive intensity modulated proton therapy using 4D robust planning: a proof-of-concept for the application of dose mimicking approach.

Objective.A four-dimensional robust optimisation (4DRO) is usually employed when the tumour respiratory motion needs to be addressed. However, it is computationally demanding, and an automated method is preferable for adaptive planning to avoid manual trial-and-error. This study proposes a 4DRO technique based on dose mimicking for automated adaptive planning.Approach.Initial plans for 4DRO intensity modulated proton therapy were created on an average CT for four patients with clinical target volume (CTV) in the lung, oesophagus, or pancreas, respectively. These plans were robustly optimised using three phases of four-dimensional computed tomography (4DCT) and accounting for setup and density uncertainties. Weekly 4DCTs were used for adaptive replanning, using a constant relative biological effectiveness (cRBE) of 1.1. Two methods were used: (1) template-based adaptive (TA) planning and (2) dose-mimicking-based adaptive (MA) planning. The plans were evaluated using variable RBE (vRBE) weighted doses and biologically consistent dose accumulation (BCDA).Main results.MA and TA plans had comparable CTV coverage except for one patient where the MA plan had a higher D98 and lower D2 but with an increased D2 in few organs at risk (OARs). CTV D98 deviations in non-adaptive plans from the initial plans were up to -7.2 percentage points (p.p.) in individual cases and -1.8 p.p. when using BCDA. For the OARs, MA plans showed a reduced mean dose and D2 compared to the TA plans, with few exceptions. The vRBE-weighted accumulated doses had a mean dose and D2 difference of up to 0.3 Gy and 0.5 Gy, respectively, in the OARs with respect to cRBE-weighted doses.Significance.MA plans indicate better performance in target coverage and OAR dose sparing compared to the TA plans in 4DRO adaptive planning. Moreover, MA method is capable of handling both forms of anatomical variation, namely, changes in density and relative shifts in the position of OARs.

A multi-institutional comparison of retrospective deformable dose accumulation for online adaptive magnetic resonance-guided radiotherapy.

Background and Purpose: Application of different deformable dose accumulation (DDA) solutions makes institutional comparisons after online-adaptive magnetic resonance-guided radiotherapy (OA-MRgRT) challenging. The aim of this multi-institutional study was to analyze accuracy and agreement of DDA-implementations in OA-MRgRT. Material and Methods: One gold standard (GS) case deformed with a biomechanical-model and five clinical cases consisting of prostate (2x), cervix, liver, and lymph node cancer, treated with OA-MRgRT, were analyzed. Six centers conducted DDA using institutional implementations. Deformable image registration (DIR) and DDA results were compared using the contour metrics Dice Similarity Coefficient (DSC), surface-DSC, Hausdorff-distance (HD95%), and accumulated dose-volume histograms (DVHs) analyzed via intraclass correlation coefficient (ICC) and clinical dosimetric criteria (CDC). Results: For the GS, median DDA errors ranged from 0.0 to 2.8 Gy across contours and implementations. DIR of clinical cases resulted in DSC > 0.8 for up to 81.3% of contours and a variability of surface-DSC values depending on the implementation. Maximum HD95%=73.3 mm was found for duodenum in the liver case. Although DVH ICC > 0.90 was found after DDA for all but two contours, relevant absolute CDC differences were observed in clinical cases: Prostate I/II showed maximum differences in bladder V28Gy (10.2/7.6%), while for cervix, liver, and lymph node the highest differences were found for rectum D2cm3 (2.8 Gy), duodenum Dmax (7.1 Gy), and rectum D0.5cm3 (4.6 Gy). Conclusion: Overall, high agreement was found between the different DIR and DDA implementations. Case- and algorithm-dependent differences were observed, leading to potentially clinically relevant results. Larger studies are needed to define future DDA-guidelines.

Deformable anthropomorphic pelvis phantom for dose accumulation verification.

Objective.The validation of deformable image registration (DIR) for contour propagation is often done using contour-based metrics. Meanwhile, dose accumulation requires evaluation of voxel mapping accuracy, which might not be accurately represented by contour-based metrics. By fabricating a deformable anthropomorphic pelvis phantom, we aim to (1) quantify the voxel mapping accuracy for various deformation scenarios, in high- and low-contrast regions, and (2) identify any correlation between dice similarity coefficient (DSC), a commonly used contour-based metric, and the voxel mapping accuracy for each organ.Approach. Four organs, i.e. pelvic bone, prostate, bladder and rectum (PBR), were 3D printed using PLA and a Polyjet digital material, and assembled. The latter three were implanted with glass bead and CT markers within or on their surfaces. Four deformation scenarios were simulated by varying the bladder and rectum volumes. For each scenario, nine DIRs with different parameters were performed on RayStation v10B. The voxel mapping accuracy was quantified by finding the discrepancy between true and mapped marker positions, termed the target registration error (TRE). Pearson correlation test was done between the DSC and mean TRE for each organ.Main results. For the first time, we fabricated a deformable phantom purely from 3D printing, which successfully reproduced realistic anatomical deformations. Overall, the voxel mapping accuracy dropped with increasing deformation magnitude, but improved when more organs were used to guide the DIR or limit the registration region. DSC was found to be a good indicator of voxel mapping accuracy for prostate and rectum, but a comparatively poorer one for bladder. DSC > 0.85/0.90 was established as the threshold of mean TRE ⩽ 0.3 cm for rectum/prostate. For bladder, extra metrics in addition to DSC should be considered.Significance. This work presented a 3D printed phantom, which enabled quantification of voxel mapping accuracy and evaluation of correlation between DSC and voxel mapping accuracy.

Development of a multi-layer quality assurance program to evaluate the uncertainty of deformable dose accumulation in adaptive radiotherapy.

PURPOSE: Deformable dose accumulation (DDA) has uncertainties which impede the implementation of DDA-based adaptive radiotherapy (ART) in clinic. The purpose of this study is to develop a multi-layer quality assurance (MLQA) program to evaluate uncertainties in DDA. METHODS: A computer program is developed to generate a pseudo-inverse displacement vector field (DVF) for each deformable image registration (DIR) performed in Accuray's PreciseART. The pseudo-inverse DVF is first used to calculate a pseudo-inverse consistency error (PICE) and then implemented in an energy and mass congruent mapping (EMCM) method to reconstruct a deformed dose. The PICE is taken as a metric to estimate DIR uncertainties. A pseudo-inverse dose agreement rate (PIDAR) is used to evaluate the consequence of the DIR uncertainties in DDA and the principle of energy conservation is used to validate the integrity of dose mappings. The developed MLQA program was tested using the data collected from five representative cancer patients treated with tomotherapy. RESULTS: DIRs were performed in PreciseART to generate primary DVFs for the five patients. The fidelity index and PICE of these DVFs on average are equal to 0.028 mm and 0.169 mm, respectively. With the criteria of 3 mm/3% and 5 mm/5%, the PIDARs of the PreciseART-reconstructed doses are 73.9 ± 4.4% and 87.2 ± 3.3%, respectively. The PreciseART and EMCM-based dose reconstructions have their deposited energy changed by 5.6 ± 3.9% and 2.6 ± 1.5% in five GTVs, and by 9.2 ± 7.8% and 4.7 ± 3.6% in 30 OARs, respectively. CONCLUSIONS: A pseudo-inverse map-based EMCM program has been developed to evaluate DIR and dose mapping uncertainties. This program could also be used as a sanity check tool for DDA-based ART.

Liver SBRT dose accumulation to assess the impact of anatomic variations on normal tissue doses and toxicity in patients treated with concurrent sorafenib.

BACKGROUND AND PURPOSE: Unexpected liver volume reductions occurred during trials of liver SBRT and concurrent sorafenib. The aims were to accumulate liver SBRT doses to assess the impact of these anatomic variations on normal tissue dose parameters and toxicity. MATERIALS AND METHODS: Thirty-two patients with hepatocellular carcinoma (HCC) or metastases treated on trials of liver SBRT (30-57 Gy, 6 fractions) and concurrent sorafenib were analyzed. SBRT doses were accumulated using biomechanical deformable registration of daily cone-beam CT. Dose deviations (accumulated-planned) for normal tissues were compared for patients with liver volume reductions > 100 cc versus stable volumes, and accumulated doses were reported for three patients with grade 3-5 luminal gastrointestinal toxicities. RESULTS: Patients with reduced (N = 12) liver volumes had larger mean deviations of 0.4-1.3 Gy in normal tissues, versus -0.2-0.4 Gy for stable cases (N = 20), P > 0.05. Deviations > 5% of the prescribed dose occurred in both groups. Two HCC patients with toxicities to small and large bowel had liver volume reductions and deviations to the maximum dose of 4% (accumulated 36.9 Gy) and 3% (accumulated 33.4 Gy) to these organs respectively. Another HCC patient with a toxicity of unknown location plus tumor rupture, had stable liver volumes and deviations to luminal organs of -6% to 4.5% (accumulated < 30.5 Gy). CONCLUSION: Liver volume reductions during SBRT and concurrent sorafenib were associated with larger increases in accumulated dose to normal tissues versus stable liver volumes. These dosimetric changes may have further contributed to toxicities in HCC patients who have higher baseline risks.

Development of an abdominal dose accumulation tool and assessments of accumulated dose in gastrointestinal organs.

Objective.Online adaptive radiotherapy has demonstrated improved dose conformality in response to inter-fraction geometric variations in the abdomen. The dosimetric impact of intra-fractional variations in anatomic configuration resulting from breathing, gastric contraction and slow configuration motion, however, have been largely ignored, leading to differences between delivered and planned. To investigate the impact of intra-fractional abdominal motions on delivered dose, anatomical deformations due to these three motion modes were extracted from dynamic MRI data using a previously developed hierarchical motion modeling methodology.Approach. Motion magnitudes were extracted from deformation fields between a reference state and all other motion states of the patient. Delivered dose estimates to various gastrointestinal organs (stomach, duodenum, small bowel and colon) were calculated on each motion state of the patient and accumulated to estimate the delivered dose to each organ for the entire treatment fraction.Main results. Across a sample of 10 patients, maximal motions of 33.6, 33.4, 47.6 and 49.2 mm were observed over 20 min for the stomach, duodenum, small bowel and colon respectively. Dose accumulation results showed that motions could lead to average increases of 2.0, 2.1, 1.1, 0.7 Gy to the maximum dose to 0.5cc (D0.5cc) and 3.0, 2.5, 1.3, 0.9 Gy to the maximum dose to 0.1cc (D0.1cc) for these organs at risk. From the 40 dose accumulations performed (10 for each organ at risk), 27 showed increases of modeled delivered dose compared to planned doses, 4 of which exceeded planned dose constraints.Significance. The use of intra-fraction motion measurements to accumulate delivered doses is feasible, and supports retrospective estimation of dose delivery to improve estimates of delivered doses, and further guide strategies for both plan adaptation as well as advances in intra-fraction motion management.