MR signature matching (MRSIGMA) implementation for true real-time free-breathing volumetric imaging with sub-200 ms latency on an MR-Linac.

PURPOSE: Develop a true real-time implementation of MR signature matching (MRSIGMA) for free-breathing 3D MRI with sub-200 ms latency on the Elekta Unity 1.5T MR-Linac. METHODS: MRSIGMA was implemented on an external computer with a network connection to the MR-Linac. Stack-of-stars with partial kz sampling was used to accelerate data acquisition and ReconSocket was employed for simultaneous data transmission. Movienet network computed the 4D MRI motion dictionary and correlation analysis was used for signature matching. A programmable 4D MRI phantom was utilized to evaluate MRSIGMA with respect to a ground-truth translational motion reference. In vivo validation was performed on patients with pancreatic cancer, where 15 patients were employed to train Movienet and 7 patients to test the real-time implementation of MRSIGMA. Dice coefficients between real-time MRSIGMA and a retrospectively computed 4D reference were used to evaluate motion tracking performance. RESULTS: Motion dictionary was computed in under 5 s. Signature acquisition and matching presented 173 ms latency on the phantom and 193 ms on patients. MRSIGMA presented a mean error of 1.3-1.6 mm for all phantom experiments, which was below the 2 mm acquisition resolution along the motion direction. The Dice coefficient over time between MRSIGMA and reference contours was 0.88 ± 0.02 (GTV), 0.87 ± 0.02(duodenum-stomach), and 0.78 ± 0.02(small bowel), demonstrating high motion tracking performance for both tumor and organs at risk. CONCLUSION: The real-time implementation of MRSIGMA enabled true real-time free-breathing 3D MRI with sub-200 ms imaging latency on a clinical MR-Linac system, which can be used for treatment monitoring, adaptive radiotherapy and dose accumulation mapping in tumors affected by respiratory motion.

Evaluating contouring accuracy and dosimetry impact of current MRI-guided adaptive radiation therapy for brain metastases: a retrospective study.

BACKGROUND: Magnetic resonance imaging (MRI) guided adaptive radiotherapy (MRgART) has gained increasing attention, showing clinical advantages over conventional radiotherapy. However, there are concerns regarding online target delineation and modification accuracy. In our study, we aimed to investigate the accuracy of brain metastases (BMs) contouring and its impact on dosimetry in 1.5 T MRI-guided online adaptive fractionated stereotactic radiotherapy (FSRT). METHODS: Eighteen patients with 64 BMs were retrospectively evaluated. Pre-treatment 3.0 T MRI scans (gadolinium contrast-enhanced T1w, T1c) and initial 1.5 T MR-Linac scans (non-enhanced online-T1, T2, and FLAIR) were used for gross target volume (GTV) contouring. Five radiation oncologists independently contoured GTVs on pre-treatment T1c and initial online-T1, T2, and FLAIR images. We assessed intra-observer and inter-observer variations and analysed the dosimetry impact through treatment planning based on GTVs generated by online MRI, simulating the current online adaptive radiotherapy practice. RESULTS: The average Dice Similarity Coefficient (DSC) for inter-observer comparison were 0.79, 0.54, 0.59, and 0.64 for pre-treatment T1c, online-T1, T2, and FLAIR, respectively. Inter-observer variations were significantly smaller for the 3.0 T pre-treatment T1c than for the contrast-free online 1.5 T MR scans (P < 0.001). Compared to the T1c contours, the average DSC index of intra-observer contouring was 0.52‒0.55 for online MRIs. For BMs larger than 3 cm3, visible on all image sets, the average DSC indices were 0.69, 0.71 and 0.64 for online-T1, T2, and FLAIR, respectively, compared to the pre-treatment T1c contour. For BMs < 3 cm3, the average visibility rates were 22.3%, 41.3%, and 51.8% for online-T1, T2, and FLAIR, respectively. Simulated adaptive planning showed an average prescription dose coverage of 63.4‒66.9% when evaluated by ground truth planning target volumes (PTVs) generated on pre-treatment T1c, reducing it from over 99% coverage by PTVs generated on online MRIs. CONCLUSIONS: The accuracy of online target contouring was unsatisfactory for the current MRI-guided online adaptive FSRT. Small lesions had poor visibility on 1.5 T non-contrast-enhanced MR-Linac images. Contour inaccuracies caused a one-third drop in prescription dose coverage for the target volume. Future studies should explore the feasibility of contrast agent administration during daily treatment in MRI-guided online adaptive FSRT procedures.

Is it necessary to perform measurement-based patient-specific quality assurance for online adaptive radiotherapy with Elekta Unity MR-Linac?

This study aimed to investigate the necessity of measurement-based patient-specific quality assurance (PSQA) for online adaptive radiotherapy by analyzing measurement-based PSQA results and calculation-based 3D independent dose verification results with Elekta Unity MR-Linac. There are two workflows for Elekta Unity enabled in the treatment planning system: adapt to position (ATP) and adapt to shape (ATS). ATP plans are those which have relatively slighter shifts from reference plans by adjusting beam shapes or weights, whereas ATS plans are the new plans optimized from the beginning with probable re-contouring targets and organs-at-risk. PSQA gamma passing rates were measured using an MR-compatible ArcCHECK diode array for 78 reference plans and corresponding 208 adaptive plans (129 ATP plans and 79 ATS plans) of Elekta Unity. Subsequently, the relationships between ATP, or ATS plans and reference plans were evaluated separately. The Pearson's r correlation coefficients between ATP or ATS adaptive plans and corresponding reference plans were also characterized using regression analysis. Moreover, the Bland-Altman plot method was used to describe the agreement of PSQA results between ATP or ATS adaptive plans and reference plans. Additionally, Monte Carlo-based independent dose verification software ArcherQA was used to perform secondary dose check for adaptive plans. For ArcCHECK measurements, the average gamma passing rates (ArcCHECK vs. TPS) of PSQA (3%/2 mm criterion) were 99.51% ± 0.88% and 99.43% ± 0.54% for ATP and ATS plans, respectively, which were higher than the corresponding reference plans 99.34% ± 1.04% (p < 0.05) and 99.20% ± 0.71% (p < 0.05), respectively. The Pearson's r correlation coefficients were 0.720 between ATP and reference plans and 0.300 between ATS and reference plans with ArcCHECK, respectively. Furthermore, >95% of data points of differences between both ATP and ATS plans and reference plans were within ±2σ (standard deviation) of the mean difference between adaptive and reference plans with ArcCHECK measurements. With ArcherQA calculation, the average gamma passing rates (ArcherQA vs. TPS) were 98.23% ± 1.64% and 98.15% ± 1.07% for ATP and ATS adaptive plans, separately. It might be unnecessary to perform measurement-based PSQA for both ATP and ATS adaptive plans for Unity if the gamma passing rates of both measurements of corresponding reference plans and independent dose verification of adaptive plans have high gamma passing rates. Periodic machine QA and verification of adaptive plans were recommended to ensure treatment safety.

The impact of margin reduction on radiation dose distribution of ultra-hypofractionated prostate radiotherapy utilizing a 1.5-T MR-Linac.

BACKGROUND: We examined the effects of reducing the planning target volume (PTV) margin in MR-guided radiotherapy (MRgRT) on the distribution of radiation dose to target volumes and organs-at-risk (OARs). Thus, we compared MR-Linac (MRL) plans with and without reduced margin and intensity-modulated radiotherapy (IMRT) plan with conventional linac for low-risk prostate cancer patients receiving 36.25 Gy in five fractions of ultra-hypofractionated radiation therapy. MATERIALS AND METHODS: Twenty low-risk prostate cancer patients treated with 1.5 T MR-Linac were evaluated. The same planning CT images were used for four plans: the MRL-R plan with reduced margin planning target volume (PTV-R) and the MRL-N plan with normal margin PTV (PTV-N), which is also used for IMRT plan. In four plans, PTV doses, organs-at-risk (OARs) doses, the homogeneity index (HI), and monitor units were compared. RESULTS: All plans met the criteria for PTV coverage and OARs dose constraints. The maximum and mean PTV doses were significantly higher in the MRL-R and MRL-N plans compared to the IMRT plan. The HI was lowest in the IMRT plan (0.040 ± 0.013) and highest in the MRL-N plan (0.055 ± 0.012; p < 0.001). There was no significant difference in the PTV dosimetric parameters between the MRL-R and the MRL-N plans. The high doses in the rectum was significantly lower in the MRL-R compared to other plans. The bladder V36.25 Gy was significantly lower in the MRL-R plan (2.43 ± 1.87 Gy) compared to MRL-N (4.50 ± 2.42 Gy; p < 0.001), and IMRT plans (4.76 ± 2.77 Gy; p < 0.001). There was no significant difference in the low-dose volumes of the body, maximum femur doses, or monitor units across each plan. CONCLUSIONS: Ultra-hypofractionated MR-guided RT with 1.5 T MRL is dosimetrically feasible for patients with prostate cancer. The improved soft tissue contrast and the online adaptive plan for 1.5 T MR-Linac allows for PTV margin reduction resulted in a significant dose reduction in OARs.

Receive coil quality assurance procedure and automated analysis for ViewRay MRIdian MR-Linac.

PURPOSE: Regular receiving coil quality assurance (QA) is required to ensure image quality of an MRIdian Linac system. The manufacturer provides a spherical phantom and positioning tube for single-slice signal-to-noise ratio (SNR) and uniformity assessments. We aimed to improve imaging setup and coverage and eliminate inter-scan variability by employing multi-slice imaging of a stable phantom. Additionally, we strived to expedite analysis by developing objective, automated analysis software. METHODS: A 5300 mL cylindrical plastic bottle placed in plastic bins was scanned at isocenter using a spin-echo sequence with NEMA-recommended parameters and 18 axial slices, avoiding phantom repositioning. Acquisition was repeated with and without prescan normalization filtering and by saving uncombined element images. Obtained data were analyzed using custom open-source MATLAB code. Signal and noise images were automatically assigned, and ROIs for SNR and uniformity calculations were defined using image thresholding. SNR and uniformity pass/fail decisions were made using baseline comparisons. RESULTS: The proposed method was successfully implemented as monthly coil QA for 3.5 years. Setup and scanning took 41 min on average for a coil set. Automated image analysis was completed in a few minutes. Signal intensity peaked around +90 or -90 mm for Torso or Head/Neck coil unfiltered images. Noise peaked and minimized SNR inside ±30 mm from isocenter, while maximizing it around ±130 mm. Prescan normalization smoothed signal response, reduced SNR and increased uniformity. Individual coil element image analysis identified their position, signal or noise response and SNR. SNR and uniformity pass/fail thresholds were set for already tested and new coils. Conspicuous and subtle Torso coil malfunctions were detected considering baseline deviations of combined and individual element results. CONCLUSIONS: Our QA method eliminated observer bias and provided insights into coil function, image filtering performance and coil element location. It provided SNR and uniformity thresholds and identified faulty coil elements.

Optimization of treatment workflow for 0.35T MR-Linac system.

PURPOSE: This study presents a novel and comprehensive framework for evaluating magnetic resonance guided radiotherapy (MRgRT) workflow by integrating the Failure Modes and Effects Analysis (FMEA) approach with Time-Driven Activity-Based Costing (TDABC). We assess the workflow for safety, quality, and economic implications, providing a holistic understanding of the MRgRT implementation. The aim is to offer valuable insights to healthcare practitioners and administrators, facilitating informed decision-making regarding the 0.35T MRIdian MR-Linac system's clinical workflow. METHODS: For FMEA, a multidisciplinary team followed the TG-100 methodology to assess the MRgRT workflow's potential failure modes. Following the mitigation of primary failure modes and workflow optimization, a treatment process was established for TDABC analysis. The TDABC was applied to both MRgRT and computed tomography guided RT (CTgRT) for typical five-fraction stereotactic body RT (SBRT) treatments, assessing total workflow and costs associated between the two treatment workflows. RESULTS: A total of 279 failure modes were identified, with 31 categorized as high-risk, 55 as medium-risk, and the rest as low-risk. The top 20% risk priority numbers (RPN) were determined for each radiation oncology care team member. Total MRgRT and CTgRT costs were assessed. Implementing technological advancements, such as real-time multi leaf collimator (MLC) tracking with volumetric modulated arc therapy (VMAT), auto-segmentation, and increasing the Linac dose rate, led to significant cost savings for MRgRT. CONCLUSION: In this study, we integrated FMEA with TDABC to comprehensively evaluate the workflow and the associated costs of MRgRT compared to conventional CTgRT for five-fraction SBRT treatments. FMEA analysis identified critical failure modes, offering insights to enhance patient safety. TDABC analysis revealed that while MRgRT provides unique advantages, it may involve higher costs. Our findings underscore the importance of exploring cost-effective strategies and key technological advancements to ensure the widespread adoption and financial sustainability of MRgRT in clinical practice.

MR-linac MLC positioning QA by digitally stitching dual double-exposed films.

PURPOSE: The picket fence (PF) test is highly recommended for multi-leaf collimator (MLC) quality assurance. However, since the electronic portal imaging device (EPID) on the Elekta Unity only covers a small area, it is not feasible to perform the PF test for the entire MLC. Here, we propose a technique for the PF test by stitching two double-exposed films. METHODS: Two EBT3 films were used to encompass the entire MLC, with each one covering one half of the area. Two fields were employed to apply double exposure: a PF pattern consisting of 11 2 mm wide pickets and a 2.84 cm x 22 cm open field. The edges of the open field defined by the diaphragms were used to correct film rotation as well as align them horizontally. The PF pattern was also measured with the EPID where the pickets were used to align the films vertically. Individual leaf positions were detected on the merged film for quantitative analysis. Various MLC positioning errors were introduced to evaluate the technique's sensitivity. RESULTS: The merged films covered 72 leaf pairs properly (four leaf pairs on both sides were outside the treatment couch). With the EPID, the leaf positioning accuracy was -0.02 ± 0.07 mm (maximum: 0.29 mm) and the picket width variation was 0.00 ± 0.03 mm (maximum: 0.11 mm); with the films, the position accuracy and width variation were -0.03 ± 0.13 mm (maximum: 0.80 mm) and 0.00 ± 0.13 mm (maximum: 0.74 mm), respectively. The EPID was able to detect errors of 0.5 mm or above with submillimeter accuracy; the films were only able to detect errors > 1.0 mm. CONCLUSION: We developed a quantitative technique for the PF test on the Elekta Unity. The merged films covered nearly the entire MLC leaf banks. The technique exhibited clinically acceptable accuracy and sensitivity to MLC positioning errors.

A virtual phantom for patient-specific QA On A 1.5T MR-linac.

Create a virtual ArcCHECK-MR phantom, customized for a 1.5T MR-linac, with consideration of the different density regions within the quality assurance (QA) phantom, aiming to streamline the utilization of this specialized QA device. A virtual phantom was constructed in the treatment planning system (TPS) to replicate the ArcCHECK-MR's composition, consisting of five distinct layers: "Outer" (representing the outer PMMA ring), "Complex" (simulating the printed circuit boards), "Detectors" (encompassing the detector area), "Inner" (signifying the inner PMMA ring) and "Insert" (representing the PMMA insert). These layers were defined based on geometric data and represented as contour points on a set of dummy CT images. Additionally, a setup platform was integrated as contoured structures. To determine the relative electron density (RED) values of the external and internal PMMA components, measurements were taken at 25 points in the insert using an ion chamber. A novel method for establishing the exit/entrance dose ratio (EEDR) for ArcCHECK-MR was introduced. The RED of higher density region was derived by evaluating the local gamma index passing rate results with criteria of 2% dose difference and 2 mm distance-to-agreement. The performance of the virtual phantom was assessed for Unity 7 FFF beams with a 1.5T magnetic field. The radii of the five ring structures within the virtual phantom measured 133.0 mm, 110.0 mm, 103.4 mm, 100.0 mm, and 75.0 mm for the "Outer," "Complex," "Detectors," "Inner" and "Insert" regions, respectively. The RED values were as follows: ArcCHECK-MR PMMA had a RED of 1.130, "Detectors" were assumed to have a RED of 1.000, "Complex" had a RED of 1.200, and the setup QA phantom justified a RED of 1.350. Early validation results demonstrate that the 5-layer virtual phantom, when compared to the commonly used bulk overridden phantom, offers improved capability in MR-linac environments. This enhancement led to an increase in passing rates for the local gamma index by approximately 5 ∼ 6%, when applying the criteria of 2%, 2 mm. We have successfully generated a virtual representation of the distinct regions within the ArcCHECK-MR using a TPS, addressing the challenges associated with its use in conjunction with a 1.5T MR-linac. We consistently observed favorable local gamma index passing rates across two 1.5T MR-linac and ArcCHECK-MR unit combinations. This approach has the potential to minimize uncertainties in the creation of the QA phantom for ArcCHECK-MR across various institutions.

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

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

Electron streaming dose measurements and calculations on a 1.5 T MR-Linac.

PURPOSE: To evaluate the accuracy of different dosimeters and the treatment planning system (TPS) for assessing the skin dose due to the electron streaming effect (ESE) on a 1.5 T magnetic resonance (MR)-linac. METHOD: Skin dose due to the ESE on an MR-linac (Unity, Elekta) was investigated using a solid water phantom rotated 45° in the x-y plane (IEC61217) and centered at the isocenter. The phantom was irradiated with 1 × 1, 3 × 3, 5 × 5, 10 × 10, and 22 × 22 cm2 fields, gantry at 90°. Out-of-field doses (OFDs) deposited by electron streams generated at the entry and exit surface of the angled phantom were measured on the surface of solid water slabs placed ±20.0 cm from the isocenter along the x-direction. A high-resolution MOSkin™ detector served as a benchmark due to its shallower depth of measurement that matches the International Commission on Radiological Protection (ICRP) recommended depth for skin dose assessment (0.07 mm). MOSkin™ doses were compared to EBT3 film, OSLDs, a diamond detector, and the TPS where the experimental setup was modeled using two separate calculation parameters settings: a 0.1 cm dose grid with 0.2% statistical uncertainty (0.1 cm, 0.2%) and a 0.2 cm dose grid with 3.0% statistical uncertainty (0.2 cm, 3.0%). RESULTS: OSLD, film, the 0.1 cm, 0.2%, and 0.2 cm, 3.0% TPS ESE doses, underestimated skin doses measured by the MOSkin™ by as much as -75.3%, -7.0%, -24.7%, and -41.9%, respectively. Film results were most similar to MOSkin™ skin dose measurements. CONCLUSIONS: These results show that electron streams can deposit significant doses outside the primary field and that dosimeter choice and TPS calculation settings greatly influence the reported readings. Due to the steep dose gradient of the ESE, EBT3 film remains the choice for accurate skin dose assessment in this challenging environment.

Technical note: A simple method for patient-specific quality assurance for lateral targets on a 1.5 T MR-Linac.

The Elekta Unity magnetic resonance (MR) linac is limited to longitudinal couch motion and a sagittal-only laser, which restricts the ability to perform patient-specific quality assurance (PSQA) intensity-modulated radiotherapy (IMRT) measurements for very lateral targets. This work introduces a simple method to perform PSQA using the Sun Nuclear ArcCheck-MR phantom at left and right lateral positions without additional equipment or in-house construction. The proposed setup places the center of the phantom 1.3 cm vertical and 12.9 cm lateral to isocenter in either the left or right direction. Computed tomography (CT) scans are used to simulate the setup and create a QA plan template in the Monaco treatment planning system (TPS). The workflow is demonstrated for four patients, with an average axial distance from the center of the bore to the planning target volume (PTV) of 12.4 cm. Gamma pass rates were above 94% for all plans using global 3%/2 mm gamma criterion with a 10% threshold. Setup uncertainties are slightly larger for the proposed lateral setup compared to the centered setup on the Elekta platform (∼1 mm compared to ∼0.5 mm), but acceptable pass rates are achievable without optimizing shifts in the gamma analysis software. In general, adding the left and right lateral positions increases the axial area in the bore encompassed by the cylindrical measurement array by 147%, substantially increasing the flexibility of measurements for offset targets. Based on this work, we propose using the lateral QA setup if the closest distance to the PTV edge from isocenter is larger than the array radius (10.5 cm) or the percent of the PTV encompassed by the diode array would be increased with the lateral setup compared to the centered setup.

Assessment of intrafractional prostate motion and its dosimetric impact in MRI-guided online adaptive radiotherapy with gating.

PURPOSE: This study aimed to evaluate the intrafractional prostate motion captured during gated magnetic resonance imaging (MRI)-guided online adaptive radiotherapy for prostate cancer and analyze its impact on the delivered dose as well as the effect of gating. METHODS: Sagittal 2D cine-MRI scans were acquired at 4 Hz during treatment at a ViewRay MRIdian (ViewRay Inc., Oakwood Village, OH, USA) MR linac. Prostate shifts in anterior-posterior (AP) and superior-inferior (SI) directions were extracted separately. Using the static dose cloud approximation, the planned fractional dose was shifted according to the 2D gated motion (residual motion in gating window) to estimate the delivered dose by superimposing and averaging the shifted dose volumes. The dose of a hypothetical non-gated delivery was reconstructed similarly using the non-gated motion. For the clinical target volume (CTV), rectum, and bladder, dose-volume histogram parameters of the planned and reconstructed doses were compared. RESULTS: In total, 174 fractions (15.7 h of cine-MRI) from 10 patients were evaluated. The average (±1 σ) non-gated prostate motion was 0.6 ± 1.0 mm in the AP and 0.0 ± 0.6 mm in the SI direction with respect to the centroid position of the gating boundary. 95% of the shifts were within [-3.5, 2.7] mm in the AP and [-2.9, 3.2] mm in the SI direction. For the gated treatment and averaged over all fractions, CTV D98% decreased by less than 2% for all patients. The rectum and the bladder D2% increased by less than 3% and 0.5%, respectively. Doses reconstructed for gated and non-gated delivery were similar for most fractions. CONCLUSION: A pipeline for extraction of prostate motion during gated MRI-guided radiotherapy based on 2D cine-MRI was implemented. The 2D motion data enabled an approximate estimation of the delivered dose. For the majority of fractions, the benefit of gating was negligible, and clinical dosimetric constraints were met, indicating safety of the currently adopted gated MRI-guided treatment workflow.

Randomized phase II trial of MRI-guided salvage radiotherapy for prostate cancer in 4 weeks versus 2 weeks (SHORTER).

BACKGROUND: Ultra-hypofractionated image-guided stereotactic body radiotherapy (SBRT) is increasingly used for definitive treatment of localized prostate cancer. Magnetic resonance imaging-guided radiotherapy (MRgRT) facilitates improved visualization, real-time tracking of targets and/or organs-at-risk (OAR), and capacity for adaptive planning which may translate to improved targeting and reduced toxicity to surrounding tissues. Given promising results from NRG-GU003 comparing conventional and moderate hypofractionation in the post-operative setting, there is growing interest in exploring ultra-hypofractionated post-operative regimens. It remains unclear whether this can be done safely and whether MRgRT may help mitigate potential toxicity. SHORTER (NCT04422132) is a phase II randomized trial prospectively evaluating whether salvage MRgRT delivered in 5 fractions versus 20 fractions is non-inferior with respect to gastrointestinal (GI) and genitourinary (GU) toxicities at 2-years post-treatment. METHODS: A total of 136 patients will be randomized in a 1:1 ratio to salvage MRgRT in 5 fractions or 20 fractions using permuted block randomization. Patients will be stratified according to baseline Expanded Prostate Cancer Index Composite (EPIC) bowel and urinary domain scores as well as nodal treatment and androgen deprivation therapy (ADT). Patients undergoing 5 fractions will receive a total of 32.5 Gy over 2 weeks and patients undergoing 20 fractions will receive a total of 55 Gy over 4 weeks, with or without nodal coverage (25.5 Gy over 2 weeks and 42 Gy over 4 weeks) and ADT as per the investigator's discretion. The co-primary endpoints are change scores in the bowel and the urinary domains of the EPIC. The change scores will reflect the 2-year score minus the pre-treatment (baseline) score. The secondary endpoints include safety endpoints, including change in GI and GU symptoms at 3, 6, 12 and 60 months from completion of treatment, and efficacy endpoints, including time to progression, prostate cancer specific survival and overall survival. DISCUSSION: The SHORTER trial is the first randomized phase II trial comparing toxicity of ultra-hypofractionated and hypofractionated MRgRT in the salvage setting. The primary hypothesis is that salvage MRgRT delivered in 5 fractions will not significantly increase GI and GU toxicities when compared to salvage MRgRT delivered in 20 fractions. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04422132. Date of registration: June 9, 2020.

A randomized phase II trial of MR-guided prostate stereotactic body radiotherapy administered in 5 or 2 fractions for localized prostate cancer (FORT).

BACKGROUND: Ultra-hypofractionated regimens for definitive prostate cancer (PCa) radiotherapy are increasingly utilized due in part to promising safety and efficacy data complemented by greater patient convenience from a treatment course requiring fewer sessions. As such, stereotactic body radiation therapy (SBRT) is rapidly emerging as a standard definitive treatment option for patients with localized PCa. The commercially available magnetic resonance linear accelerator (MR-LINAC) integrates MR imaging with radiation delivery, providing several theoretical advantages compared to computed tomography (CT)-guided radiotherapy. MR-LINAC technology facilitates improved visualization of the prostate, real-time intrafraction tracking of prostate and organs-at-risk (OAR), and online adaptive planning to account for target movement and anatomical changes. These features enable reduced treatment volume margins and improved sparing of surrounding OAR. The theoretical advantages of MR-guided radiotherapy (MRgRT) have recently been shown to significantly reduce rates of acute grade ≥ 2 GU toxicities as reported in the prospective randomized phase III MIRAGE trial, which compared MR-LINAC vs CT-based 5 fraction SBRT in patients with localized PCa (Kishan et al. JAMA Oncol 9:365-373, 2023). Thus, MR-LINAC SBRT-utilizing potentially fewer treatments-is warranted and clinically relevant for men with low or intermediate risk PCa electing for radiotherapy as definitive treatment. METHODS/DESIGN: A total of 136 men with treatment naïve low or intermediate risk PCa will be randomized in a 1:1 ratio to 5 or 2 fractions of MR-guided SBRT using permuted block randomization. Randomization is stratified by baseline Expanded PCa Index Composite (EPIC) bowel and urinary domain scores. Patients undergoing 5 fractions will receive 37.5 Gy to the prostate over 10-14 days and patients undergoing 2 fractions will receive 25 Gy to the prostate over 7-10 days. The co-primary endpoints are GI and GU toxicities as measured by change scores in the bowel and urinary EPIC domains, respectively. The change scores will be calculated as pre-treatment (baseline) score subtracted from the 2-year score. DISCUSSION: FORT is an international, multi-institutional prospective randomized phase II trial evaluating whether MR-guided SBRT delivered in 2 fractions versus 5 fractions is non-inferior from a gastrointestinal (GI) and genitourinary (GU) toxicity standpoint at 2 years post-treatment in men with low or intermediate risk PCa. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT04984343 . Date of registration: July 30, 2021. PROTOCOL VERSION: 4.0, Nov 8, 2022.

MR-guided prostate SBRT in prostate cancer patients with low-volume metastatic disease.

BACKGROUND: Recent data have found an overall survival benefit from prostate-directed radiotherapy in patients with low-volume metastatic prostate cancer. Prostate SBRT is an attractive treatment in this setting and may be optimised with MR-guided adaptive treatment. Here, we share our institutional experience delivering stereotactic MR-guided adaptive prostate SBRT (SMART) for patients with low-volume metastatic disease. METHODS: We reviewed patients with low-volume metastatic disease who received prostate SMART from October 2019 to December 2021 on a 0.35T MR-Linac. The cohort included 14 patients. Genitourinary (GU) and gastrointestinal (GI) toxicities were assessed using CTCAE v 5.0. Progression was defined as a change in systemic or hormonal therapy regimen as a result of PSA rise or disease progression. RESULTS: The median follow-up time was 29 months. Seven patients had hormone sensitive prostate cancer and 7 had castrate resistant prostate cancer (CRPC). 13 patients received 36.25 Gy in 5 fractions and one patient received 33 Gy in 5 fractions. At the time of last follow-up, 11 patients had not experienced progression and three patients, all with CRPC, had experienced progression. No patients developed local progression in the prostate after SMART. One patient experienced acute grade 2 urinary toxicity (7%) and no patients experienced acute grade 2 GI toxicity (0%). No grade 3 + acute toxicities were observed. CONCLUSIONS: Prostate SMART was found to be well tolerated and all patients had local control of disease within the prostate at the time of last follow-up. Prostate SMART may represent a low-risk and well-tolerated approach for delivering prostate-directed radiotherapy for patients with limited metastatic disease.

Evaluation of Unity 1.5 T MR-linac plan quality in patients with prostate cancer.

The Unity magnetic resonance (MR) linear accelerator (MRL) with MR-guided adaptive radiotherapy (MRgART) is capable of online MRgART where images are acquired on the treatment day and the radiation treatment plan is immediately replanned and performed. We evaluated the MRgART plan quality and plan reproducibility of the Unity MRL in patients with prostate cancer. There were five low- or moderate-risk and five high-risk patients who received 36.25 Gy or 40 Gy, respectively in five fractions. All patients underwent simulation magnetic resonance imaging (MRI) and five online adaptive MRI. We created plans for 5, 7, 9, 16, and 20 beams and for 60, 100, and 150 segments. We evaluated the target and organ doses for different number of beams and segments, respectively. Variation in dose constraint between the simulation plan and online adaptive plan was measured for each patient to assess plan reproducibility. The plan quality improved with the increasing number of beams. However, the proportion of significantly improved dose constraints decreased as the number of beams increased. For some dose parameters, there were statistically significant differences between 60 and 100 segments, and 100 and 150 segments. The plan of five beams exhibited limited reproducibility. The number of segments had minimal impact on plan reproducibility, but 60 segments sometimes failed to meet dose constraints for online adaptive plan. The optimization and delivery time increased with the number of beams and segments. We do not recommend using five or fewer beams for a reproducible and high-quality plan in the Unity MRL. In addition, many number of segments and beams may help meet dose constraints during online adaptive plan. Treatment with the Unity MRL should be performed with the appropriate number of beams and segments to achieve a good balance among plan quality, delivery time, and optimization time.

Online adaptive radiotherapy and dose delivery accuracy: A retrospective analysis.

PURPOSE: With online adaptive radiotherapy (ART), patient-specific quality assurance (PSQA) testing cannot be performed prior to delivery of the adapted treatment plan. Consequently, the dose delivery accuracy of adapted plans (i.e., the ability of the system to interpret and deliver the treatment as planned) are not initially verified. We investigated the variation in dose delivery accuracy of ART on the MRIdian 0.35 T MR-linac (Viewray Inc., Oakwood, USA) between initial plans and their respective adapted plans, by analyzing PSQA results. METHODS: We considered the two main digestive localizations treated with ART (liver and pancreas). A total of 124 PSQA results acquired with the ArcCHECK (Sun Nuclear Corporation, Melbourne, USA) multidetector system were analyzed. PSQA result variations between the initial plans and their respective adapted plans were statistically investigated and compared with the variation in MU number. RESULTS: For the liver, limited deterioration in PSQA results was observed, and was within the limits of clinical tolerance (Initial = 98.2%, Adapted = 98.2%, p = 0.4503). For pancreas plans, only a few significant deteriorations extending beyond the limits of clinical tolerance were observed and were due to specific, complex anatomical configurations (Initial = 97.3%, Adapted = 96.5%, p = 0.0721). In parallel, we observed an influence of the increase in MU number on the PSQA results. CONCLUSION: We show that the dose delivery accuracy of adapted plans, in terms of PSQA results, is preserved in ART processes on the 0.35 T MR-linac. Respecting good practices, and minimizing the increase in MU number can help to preserve the accuracy of delivery of adapted plans as compared to their respective initial plans.

Evaluation of MRI-only based online adaptive radiotherapy of abdominal region on MR-linac.

PURPOSE: A hybrid magnetic resonance linear accelerator (MRL) can perform magnetic resonance imaging (MRI) with high soft-tissue contrast to be used for online adaptive radiotherapy (oART). To obtain electron densities needed for the oART dose calculation, a computed tomography (CT) is often deformably registered to MRI. Our aim was to evaluate an MRI-only based synthetic CT (sCT) generation as an alternative to the deformed CT (dCT)-based oART in the abdominal region. METHODS: The study data consisted of 57 patients who were treated on a 0.35 T MRL system mainly for abdominal tumors. Simulation MRI-CT pairs of 43 patients were used for training and validation of a prototype convolutional neural network sCT-generation algorithm, based on HighRes3DNet, for the abdominal region. For remaining test patients, sCT images were produced from simulation MRIs and daily MRIs. The dCT-based plans were re-calculated on sCT with identical calculation parameters. The sCT and dCT were compared in terms of geometric agreement and calculated dose. RESULTS: The mean and one standard deviation of the geometric agreement metrics over dCT-sCT-pairs were: mean error of 8 ± 10 HU, mean absolute error of 49 ± 10 HU, and Dice similarity coefficient of 55 ± 12%, 60 ± 5%, and 82 ± 15% for bone, fat, and lung tissues, respectively. The dose differences between the sCT and dCT-based dose for planning target volumes were 0.5 ± 0.9%, 0.6 ± 0.8%, and 0.5 ± 0.8% at D2% , D50% , and D98% in physical dose and 0.8 ± 1.4%, 0.8 ± 1.2%, and 0.6 ± 1.1% in biologically effective dose (BED). For organs-at-risk, the dose differences of all evaluated dose-volume histogram points were within [-4.5%, 7.8%] and [-1.1 Gy, 3.5 Gy] in both physical dose and BED. CONCLUSIONS: The geometric agreement metrics were within typically reported values and most average relative dose differences were within 1%. Thus, an MRI-only sCT-based approach is a promising alternative to the current clinical practice of the abdominal oART on MRL.

Quantifying uncertainties associated with reference dosimetry in an MR-Linac.

BACKGROUND: Magnetic resonance (MR)-guided radiation therapy provides capabilities to utilize high-resolution and real-time MR imaging before and during treatment, which is critical for adaptive radiotherapy. This emerging modality has been promptly adopted in the clinic settings in advance of adaptations to reference dosimetry formalism that are needed to account for the presence of strong magnetic fields. In particular, the influence of magnetic field on the uncertainty of parameters in the reference dosimetry equation needs to be determined in order to fully characterize the uncertainty budget for reference dosimetry in MR-guided radiation therapy systems. PURPOSE: To identify and quantify key sources of uncertainty in the reference dosimetry of external high energy radiotherapy beams in the presence of a strong magnetic field. METHODS: In the absence of a formalized Task Group report for reference dosimetry in MR-integrated linacs, the currently suggested formalism follows the TG-51 protocol with the addition of a quality conversion factor kBQ accounting for the effects of the magnetic field on ionization chamber response. In this work, we quantify various sources of uncertainty that impact each of the parameters in the formalism, and evaluate their overall contribution to the final dose. Measurements are done in a 1.5 T MR-Linac (Unity, Elekta AB, Stockholm, Sweden) which integrates a 1.5 T Philips MR scanner and a 7 MVFFF linac. The responses of several reference-class small volume ionization chambers (Exradin:A1SL, IBA:CC13, PTW:Semiflex-3D) and Farmer type ionization chambers (Exradin:A19, IBA:FC65-G) were evaluated throughout this process. Long-term reproducibility and stability of beam quality, TPR 10 20 ${\mathrm{TPR}}_{10}^{20}$ , was also measured with an in-house built phantom. RESULTS: Relative to the conventional external high energy linacs, the uncertainty on overall reference dose in MR-linac is more significantly affected by the chamber setup: A translational displacement along y-axis of ± 3 mm results in dose variation of < |0.20| ± 0.02% (k = 1), while rotation of ± 5° in horizontal and vertical parallel planes relative to relative to the direction of magnetic field, did not exceed variation of < |0.44| ± 0.02% for all 5 ionization chambers. We measured a larger dose variation for xy-plane (horizontal) rotations (< |0.44| ± 0.02% (k = 1)) than for yz-plane (vertical) rotations (< ||0.28| ± 0.02% (k = 1)), which we associate with the gradient of kB,Q as a function of chamber orientation with respect to direction of the B0 -field. Uncertainty in Pion (for two depths), Ppol (with various sub-studies including effects of cable length, cable looping in the MRgRT bore, connector type in magnetic environment), and Prp were determined. Combined conversion factor kQ × kB,Q was provided for two reference depths at four cardinal angle orientations. Over a two-year period, beam quality was quite stable with TPR 10 20 ${\mathrm{TPR}}_{10}^{20}$ being 0.669 ± 0.01%. The actual magnitude of TPR 10 20 ${\mathrm{TPR}}_{10}^{20}$ was measured using identical equipment and compared between two different Elekta Unity MR-Linacs with results agreeing to within 0.21%. CONCLUSION: In this work, the uncertainty of a number of parameters influencing reference dosimetry was quantified. The results of this work can be used to identify best practice guidelines for reference dosimetry in the presence of magnetic fields, and to evaluate an uncertainty budget for future reference dosimetry protocols for MR-linac.

Risk analysis of the Unity 1.5 T MR-Linac adapt-to-position workflow.

BACKGROUND AND PURPOSE: Newer technologies allow for daily treatment adaptation, providing the ability to account for setup variations and organ motion but comes at the cost of increasing the treatment workflow complexity. One such technology is the adapt-to-position (ATP) workflow on the Unity MR-Linac. Prospective risk assessment of a new workflow allows clinics to catch errors before they occur, especially for processes that include novel and unfamiliar steps. METHODS: As part of a quality management program, failure modes and effects analysis was performed on the ATP treatment workflow following the recommendations of AAPM's Task Group 100. A multidisciplinary team was formed to identify and evaluate failure modes for all the steps taken during a daily treatment workflow. Failure modes of high severity and overall score were isolated and addressed. RESULTS: Mitigations were determined for high-ranking failure modes and implemented into the clinic. High-ranking failure modes existed in all steps of the workflow. Failure modes were then rescored to evaluate the effectiveness of the mitigations. CONCLUSION: Failure modes and effects analysis on the Unity MR-Linac highlighted areas in the ATP workflow that could be prone to failures and allowed our clinic to change the process to be more robust.