MR Linac Research Articles

Inter-fraction Dynamics during Adaptive Hypofractionated Radiotherapy for Brain Metastases with a MR LINAC

This study examined the displacement and deformation in brain metastases (BMs) during adaptive hypofractionated radiotherapy (HFRT) on a magnetic resonance imaging linear accelerator (MR LINAC). In addition, the contouring variability between enhanced T1 (T1+c) and T2/FLAIR (T2f) sequence to define gross tumor volume (GTV) was compared. Patients with 1-3 BMs and treated with MR LINAC were enrolled. T1+c sequence was acquired at initial planning, while T2/T2f was acquired during each fraction. GTV at initial planning (GTVi) and fraction 1-n (GTV1-n) were contoured in all images. Dice similarity coefficient (DSC) was used to quantify the contouring variability between different sequences at initial planning. The three-dimensional coordinate values of geometric centers of GTVi and GTV1-n were recorded and the distance was calculated. Statistical analysis was performed using two-sided paired t-test. Between December 2019 and October 2022, 19 patients with 22 BMs were analyzed. The median age was 64 y (37-84 y) and the major primary tumor was lung cancer (89.5%). The median dose was 52 Gy in 13 fractions (30 Gy/5f- 60 Gy/20 f). The median GTVi on T1c, T2f and T2 sequences were 6.70cc (0.41-84.85 cc), 6.70 cc (0.35-84.14 cc, p = 0.924) and 6.16 cc (0.32-79.44 cc, p = 0.117), respectively. The mean DSC was 0.95 (0.76-1.00) and 0.86 (0.64-0.97) when comparing GTVi on T1c/T2f and T1c/T2, respectively. All of the lesions achieved volume reduction during HFRT and the mean reduction rate was 28.8% (4.8%-71.0%) at the end of HFRT. 54.5% of the BMs were reduced by more than 20%. The median treatment course and BED to get 20% reduction was 2/3 (40%-93%) and 40.8 Gy (24.5-67.5 Gy), respectively. The median shift of center of GTV1-n was 0.8 mm (0-2.5mm). The center of 7 lesions (31.8%) deviated more than 1mm from GTVi. GTV contouring variability was seen between T1c, T2f and T2 sequences. The coincidence of T1+c and T2f was better than T1+c and T2 in BMs. Since reductions in volume and changes of lesion center was observed during HFRT, the use of MR-guided radiation therapy (RT) and treatment adaptation is needed. The optimal timing for treatment plan modification might be when the course of treatment reaches 2/3 for most large BMs. Further research to find out patients who may benefit form MR-guided adaptive RT is ongoing.

A Multicenter Study of Clinical to Planning Target Volume Margins for Adjuvant Partial Breast Irradiation Delivered on the 1.5T MR-Linear Accelerator

Adjuvant partial breast irradiation (APBI) for early-stage breast cancer patients delivered on a conventional Linac commonly uses a clinical to planning target volume (CTV-PTV) margin of 10 mm. Published data suggest this margin could be reduced using an MR-guided workflow. This study quantifies the CTV to PTV margin for APBI delivered on the 1.5T MR-Linac (MRL) using an Adapt to Position (ATP) workflow. All target contouring was done as per the IMPORT LOW trial and MRL Consortium guidelines. The CTV is the tumor bed defined by surgical clips including postsurgical changes. A single center cohort of ten patients was used to assess delineation error on ProKnow DS v1.28.0 by measuring CTV contour displacements on the CT planning scans (pCT) delineated by five breast radiation oncologists. All other error components were measured on treatment planning software on another single center cohort of ten patients. Target deformation error was measured as surgical clip displacements between the pCT and daily pre-treatment (pre-Tx) MRI scans. Intrafraction motion was determined by the CTV displacement between pre- and post-treatment MRIs (post-Tx) in available paired images from five patients. Matching error was estimated as the interobserver variation of three MRL radiographers registering the pCT with daily pre-Tx MRI. Technical delivery accuracy was estimated using the results from routine quality assurance measurements. Beam penumbral width (p) was estimated from the clinical treatment plans. The systematic (Σ) and random errors (σ) for each component were calculated in the left/right (X), superior/inferior (Y) and anterior/posterior (Z) directions. The contribution of these errors to the PTV margin, M was calculated using van Herk's formula with α and β being 2.50 and 1.64 respectively. For APBI using an MRL ATP workflow, a CTV-PTV margin of 5.7 to 7.6 mm is required to achieve a 90% confidence of CTV coverage by the 95% isodose. Individual error components are in. Table 1 delineation error remains the largest component of error. A minimum CTV-PTV margin of 6-8 mm is required for APBI using an MRL ATP workflow. Although smaller than margins used in conventional Linacs, the clinical benefits (in terms of fibrosis risk) of treating APBI patients on an MRL are likely to be modest. Further margin reductions may be possible using an "Adapt to Shape" workflow with daily online recontouring.

Towards Automated Dosimetric Analysis of the Bladder Trigone: Deep-Learning-Based Joint Segmentation and Landmark Localization

The bladder trigone dosimetry is hypothesized to have a stronger correlation with post-SBRT urinary toxicity than that of the entire bladder. However, the trigone tends to move significantly between simulation and daily treatment. Its small size, large daily motion, and proximity to the target lead to potentially consequential but unaccounted-for dosimetric uncertainties. Manual segmentation of the structure can be inconsistent and time-consuming, even with MR-guided RT. Here, we propose and demonstrate a deep-learning-based framework for joint segmentation and landmark localization to support deformable registration and comprehensive dosimetric analysis. A total of 30 patients were randomly selected for training, and 20 were held out for testing. Each patient had 1 simulation and 5 daily pre-treatment images obtained from a clinical 0.35T MR Linac. The trigone is defined as the triangular bladder section among three landmarks (2 ureteral orifices and the internal urethral orifice). In the manual contouring process, the 3 landmarks were identified first, followed by trigone segmentation. The proposed joint method uses a modified 3D nnU-Net with 2 decoders, one for segmentation and the other for landmark localization. The shared encoder is expected to extract features useful for both tasks. The joint framework was compared with a baseline method using two separate 3D nnU-Nets for landmark localization and trigone segmentation, respectively. Since the trigone is small (∼2% of the bladder volume), we further experimented with a second-stage prediction mimicking the human contouring process. The predicted landmarks from the first stage were used to crop the trigone region, and a second network was trained on cropped images. Evaluation metrics included the Dice score, 95% Hausdorff distance (HD95), and average surface distance (ASD) for segmentation, and Euclidean distance (ED) between the predicted and ground truth landmarks for localization. The quantification metrics are summarized in the table below. The joint approach shows similar Dice performance to the baseline method but markedly better HD95 by 13%. For landmark localization, the proposed method is similar to the baseline, but the integration of the segmentation task stabilizes the training process. The two-stage approach further improves HD95, ASD, and ED by 27%, 24%, and 19%. Combining segmentation and landmark localization exhibits a synergistic effect. The proposed two-stage approach provided additional improvement. Future studies will explore the deformable registration of the trigone based on the segmentation and landmark detection, as well as analyze cumulated dose distribution.

Validation of Hypoxia Detection Sequences on the MR Linac

Magnetic resonance linear accelerator (MRL) systems permit acquisition of novel imaging at the time of radiotherapy. A validated MR hypoxia imaging biomarker could select patients for adaptive radiotherapy with hypoxia modification or dose escalation. The aims of this study were (1) to develop a protocol for quantitative hypoxia sensitive MRI (2) to validate these in prostate cancer (PCa) against pimonidazole-stained prostatectomy sections. Blood oxygen level dependent (BOLD), intravoxel incoherent motion (IVIM), oxygen-enhanced (OE) and dynamic contrast enhanced (DCE) MRI were used. Sequences were developed on a diagnostic 1.5 T MR (MRD) and MRL with healthy volunteers and PCa patients. The Hyprogen trial includes men with localized PCa scheduled for prostatectomy. Imaging is acquired twice prior to surgery and oral pimonidazole is taken 8-16 hours before surgery. Whole prostate (WP) and dominant prostatic lesion (DIL) were outlined on T2-weighted (T2W) images and a 'normal prostate' (NP) volume created by subtracting DIL from WP. Contours were applied to parametric maps from the quantitative MRI, with median and IQR extracted. Patient-specific 3D-printed prostate molds were created from WP volumes and used to guide prostate whole organ dissection. Three of 20 patients recruited to date. MRI data were acquired successfully. A personalized prostate mold was produced for each patient and facilitated dissection of the prostatectomy specimen in a matching plane to MRI to validate hypoxia detection of the MR protocol. Correlation with pimonidazole staining is underway. Imaging parameter median values for NP and DIL acquired on MRD and MRL for the first patient are shown (Table 1). The expected differences between NP and DIL for T1 and D are seen and median values for T2* are consistent with reported values in the literature. The MR hypoxia protocol can be acquired safely and is well-tolerated on the MRL. Once validated against pimonidazole staining adaptive radiotherapy protocols will be developed to use this information.

Favorable Survival after Definitive Ablative RT in Surgically Resectable Pancreatic Cancer Patients

Surgical resection has been considered the only curative option for patients with pancreatic adenocarcinoma (PDAC). Ablative RT ≥100Gy BED10 (A-RT) is associated with favorable survival in patients with locally advanced unresectable disease. We sought to evaluate A-RT outcomes in patients with technically resectable disease who did not undergo surgery. Our prospectively maintained database of patients treated with A-RT was queried for consecutive patients with radiographic T1/T2 resectable PDAC. Patients were treated with a standardized technique within a large academic cancer center regional network. Ablative RT using several hypofractionated regimens was delivered on either standard Linacs with respiratory motion management, CBCT image guidance and selective adaptive replanning or MR-Linac with compression belt and daily on-line adaptive replanning. Freedom from local progression (FFLP), distant metastasis-free and overall survival (DMFS and OS, respectively) were analyzed using the Kaplan Meier estimates. Between 2016 and 2022, 28 patients (54% male) with radiographically resectable PDAC received definitive A-RT. Median age was 80 (interquartile range, 77-84) years and 23 (82.1%) had KPS of 80 or below. Eighteen patients (64.3%) had T2 cancer, 5 (17.9%) were node positive, and 23 (82.1%) had head location. Median size was 2.6 (range, 1.6-4.0) cm with a median carbohydrate antigen 19-9 (CA19-9) of 160.5 (0-1823) U/mL. Twenty patients (71.4%) received induction chemotherapy for a median of 2.4 (0-6.2) months. RT regimens delivered on conventional Linacs unless otherwise indicated included 75Gy in 25 fractions (n = 15), 67.5Gy in 15 fractions (n = 10), 50Gy in 5 (N = 2, MR Linac), 60Gy in 10 (n = 1). 24-month FFLP and DMFS were 78.8% (52.3-91.7%) and 17.7% (95% CI, 5.8%-34.8%), respectively. 24-month and 48-month rate of OS from A-RT were 49.1% (95% CI, 27.53-67.5%) and 36.3 (95%16.0-57.1%). Grade 3 acute and late GI toxicity was noted in 3 and 1 patients, respectively, including 2 bleeding events treated with transfusions. There were no ≥ grade 4 events. In patients with surgically resectable PDAC we found that definitive A-RT following multiagent induction therapy was associated with oncologic outcomes similar to resection with minimal toxicity.

Proton Based Stereotactic Radiotherapy for Skull Base Patients: Dosimetric Comparison to 4 Modern Radiation Treatment Modalities

Re-irradiation with ablative doses to a smaller target volume and strict critical structure constraint is a challenge for modern radiation planning and delivery systems. Several advanced radiation treatment techniques can be used for fractionated stereotactic ablative radiosurgery (FSRS) in select patients with unresectable recurrent head and neck tumors. In this study, in order to better understand the dosimetry advantage of each technique, we compare the stereotactic treatment plans of our new small spot size Hitachi proton treatment unit to those of CyberKnife stereotactic radiosurgery (CK), Gamma Knife radiosurgery (GK), volumetric modulated arc therapy (VMAT), and MR Linac radiotherapy (MRL). Ten FSRS skull base patients treated at our institution using VMAT (n = 5) or GK (n = 5) techniques. Intensity-modulated proton therapy (IMPT) plans were created in Raystation using Monte Carlo dose calculation algorithm. VMAT, CK, GK and MRL plans were generated in RayStation, Accuray Precision, Leksell Gamma Plan, and Monaco treatment planning systems, separately. Planning goals were to achieve the best target coverage of prescribed dose without compromising the critical organs at risk dose volume constraints of the clinical treatment plans. Plans were compared based on percent CTV coverage, Paddick conformity index (PCI), gradient index (GI, V50/V100), dose homogeneity index (HI, (D2-D98)/D50), low dose bath volume (LDBV, ratio of total volume irradiated between 20% and 50% prescription dose and the target volume), beam-on-time (BOT), and mean/maximum doses to brainstems. The median target volume was 15.5 cm3 (range 1.0 - 36.23 cm3). The prescription was 45 Gy in 5 fractions for VMAT patients, and 21 - 27 Gy in 3 fractions for GK patients. The comparison of the treatment plans of these 5 delivery modalities was shown in table. All techniques achieved comparable CTV coverage. GI was superior for GK plans and outstanding in CK and IMPT plans. IMPT plans were also outstanding in regard to BOT and PCI. Significantly improved HI, LDBV and brainstem mean doses were achieved in IMPT plans. For adjacent brainstem and other OARs, maximum doses were comparable among all techniques. In these five advanced radiation therapy modalities, proton therapy SBRT showed dosimetric advantage over other modalities to spare nearby OARs without sacrifice of target coverage. Further studies are needed to utilize this clinical benefit and investigate plan robustness.

Single Institution Preliminary Evaluation of a National Study for the Development of Daily Online Magnetic Resonance Image Guided Radiotherapy

A 4-stage non-comparative prospective feasibility study to assess and develop imaging protocols for MRIgRT was opened at the first two centers using MR Linac technology in the UK. The primary aims of this study were to determine a) the acceptability of MR images for target and organ at risk delineation and registration; b) inter/intra observer registration and delineation variation. This work reports on the initial results from a single center. In June 2019, following ethical and regulatory approvals the 2nd UK centre began study recruitment as follows: Stage A: non-patient volunteer imaging to determine sequence suitability for normal tissue in 6 anatomical sites (head & neck (H&N), chest wall/breast, lung/esophagus, abdomen, male and female pelvis). Volunteers were recruited in cohorts of 3 participants per region, and image quality was assessed by 3 independent observers using a visual guidance assessment tool (VGA). Stage B: the most suitable sequences defined in stage A used to assess the visibility of targets/normal tissues in patient volunteers using the same methods as in stage A. Stage C: patient volunteers were imaged using sequences selected from stage B to determine inter and intra observer segmentation and registration variation. Stage D recruitment of patient and non-patient volunteers for further image develop and refinement of MRIgRT workflows. All participants completed experience questionnaires to optimize workflows. Participants were asked to undergo 1-12 imaging sessions, lasting no more than 60. To date 151 participants (61 non-patients; 90 patients) have undergone 231 imaging sessions. From stage B, vendor provided, in-workflow sequences have been agreed from 47 completed VGAs by prioritizing high scores in either the tumor (e.g., lung) or organs at risk (e.g., cervix). T2w 3D sequences scored best in cervix, pancreas, prostate, bladder, liver, soft-tissue metastases and rectal cancers; T1w 3D sequences for H&N, and patient a specific approach for lung. No suitable sequences have been selected for partial breast. Research sequences (e.g., diffusion weighted or motion corrected imaging) have been agreed or are in development in stages C & D for H&N, cervix, bladder and prostate cancers. The mean interobserver (n = 8) vector variation in 5 H&N patients was largest (3.6mm) using T1-CT boney registrations and smallest (2.1mm) using T1-T1 soft-tissue registrations (mean observer match confidence 3.7/5). Analyses using MR to CT, MR to MR and CT to CT registrations in lung, pancreas, cervix, bladder, and prostate have also been completed. Interobserver delineation studies are on-going. Using a 4-stage non-comparative prospective feasibility study has facilitated clinical implementation MRIgRT of multiple treatment sites at our institution.

A comparison of measured and treatment planning system out-of-field dose for a 1.5 T MR linac.

Objective
Dose due to the electron streaming effect (ESE) is a significant contribution to out-of-field dose on the Elekta Unity MR-Linac. The aim of this work is to provide a systematic comparison of calculated and measured streaming dose for this system. 
Approach
Beams 1.0 × 1.0 cm2 to 5.0 × 5.0 cm2, gantry 90.0°, 1000 MU, were incident on an in-house phantom. At the beam entrance and exit surfaces of the phantom, ESE was generated in the Y-direction (IEC 61217). EBT3 film, orientated within the X-Z plane and at 14.0 mm depth in a solid water block, was used to determine ESE dose 5.0 cm beyond the phantom. The experimental arrangement was simulated in the Monaco v5.4 treatment planning system (TPS), utilising a CT phantom dataset with differing relative electron densities (RED) for the surrounding air. Horizontal (X direction) and vertical (Z direction) film dose profiles were compared to the corresponding TPS profiles. 
Main results
For each field, the maximum ESE dose was observed at the beam exit, the magnitude of which decreases with decreasing field size. For the 5.0 × 5.0 cm2 field, the exit and entry ESE doses were 19.6 % and 7.0 % of the Dmax dose to water, respectively. Across horizontal profiles, differences (simulated - measured) were reduced with smaller fields and lower RED. The maximum absolute profile difference was 1.7 % of the Dmax dose to water for optimal RED and isocentre location. In vertical profiles an offset consistent with the Lorentz force was observed relative to the X-Y isoplane.
Significance
For the fields investigated, maximum absolute differences (simulated - measured)  5.2 % occurred in peak regions of ESE, at the beam entrance and exit from the phantom. Generally, there is good agreement between Monaco simulated and measured ESE. Simulated out-of-field dose is sensitive to the RED assigned to air structures and unforced RED optimises OFD calculation accuracy.&#xD.

Evaluation of hypofractionated adaptive radiotherapy using the MR Linac in localised pancreatic cancer: protocol summary of the Emerald-Pancreas phase 1/expansion study located at Oxford University Hospital, UK

IntroductionOnline adaptive MR-guided radiotherapy allows for dose escalation to pancreatic cancer while sparing surrounding critical organs. We seek to evaluate the safety of delivering hypofractionated five-fraction, three-fraction and single-fraction MR-guided...

Characterization of mechanical and radiation isocenter on an MR-guided radiotherapy (MRgRT) Linac.

In the emerging paradigm of stereotactic radiosurgery being proposed for MR-guided radiotherapy (MRgRT), assessment of mechanical geometric accuracy is critical for the implementation of stereotactic delivery. We benchmarked the mechanical accuracy of an MR Linac system that lacks an onboard detector/array. Our mechanical tests utilize a half beam block (HBB) geometry that takes advantage of the sensitivity of a partially occluded detector. Mechanical tests benchmarked the couch, MLC, and gantry geometric accuracy for an MR-Linac system. An HBB technique was used to irradiate an ionization chamber profiler (ICP) array with partial occlusion of individual detectors for characterization of MLC skew, beam divergence displacement, and RT isocenter localization. The sensitivity of the partially occluded detector's ICP-X (detector width) and ICP-Y (detector length) was characterized by displacing the detector relative to radiation isocenter by 0.2mm increments, introduced through couch motion. The accuracy of the HBB ICP technique was verified with a starshot using radiochromic film, and the reproducibility was verified on a conventional C-arm Linac and compared to Winston-Lutz. The sensitivity of the HBB technique as quantified through the dose difference normalized to open field as a function of displacement from RT isocenter was 6.4%/mm and 13.0%/mm for the ICP-X and ICP-Y orientation, respectively, due to the oblong detector orientation. Couch positional accuracy and sag was within ±0.1mm. Maximum MLC positional displacement was 0.7mm with mean MLC skew at 0.07°. The maximum beam divergence displacement was 0.03mm. The gantry angle was within 0.1°. Independent verification of the RT isocenter localization procedure produced repeatable results. This work serves for characterizing the mechanical and geometric radiation accuracy for the foundation of an MR-guided stereotactic radiosurgery program, as demonstrated with high sensitivity and independent validation.

Longitudinal monitoring of Apparent Diffusion Coefficient (ADC) in patients with prostate cancer undergoing MR-guided radiotherapy on an MR-Linac at 1.5 T: a prospective feasibility study.

Hybrid MRI linear accelerators (MR-Linac) might enable individualized online adaptation of radiotherapy using quantitative MRI sequences as diffusion-weighted imaging (DWI). The purpose of this study was to investigate the dynamics of lesion apparent diffusion coefficient (ADC) in patients with prostate cancer undergoing MR-guided radiation therapy (MRgRT) on a 1.5T MR-Linac. The ADC values at a diagnostic 3T MRI scanner were used as the reference standard. In this prospective single-center study, patients with biopsy-confirmed prostate cancer who underwent both an MRI exam at a 3T scanner (MRI3T) and an exam at a 1.5T MR-Linac (MRL) at baseline and during radiotherapy were included. Lesion ADC values were measured by a radiologist and a radiation oncologist on the slice with the largest lesion. ADC values were compared before vs. during radiotherapy (during the second week) on both systems via paired t-tests. Furthermore, Pearson correlation coefficient and inter-reader agreement were computed. A total of nine male patients aged 67 ± 6 years [range 60 - 67 years] were included. In seven patients, the cancerous lesion was in the peripheral zone, and in two patients the lesion was in the transition zone. Inter-reader reliability regarding lesion ADC measurement was excellent with an intraclass correlation coefficient of (ICC) > 0.90 both at baseline and during radiotherapy. Thus, the results of the first reader will be reported. In both systems, there was a statistically significant elevation of lesion ADC during radiotherapy (mean MRL-ADC at baseline was 0.97 ± 0.18 × 10-3 mm2/s vs. mean MRL-ADC during radiotherapy 1.38 ± 0.3 × 10-3 mm2/s, yielding a mean lesion ADC elevation of 0.41 ± 0.20 × 10-3 mm2/s, p < 0.001). Mean MRI3T-ADC at baseline was 0.78 ± 0.165 × 10-3 mm2/s vs. mean MRI3T-ADC during radiotherapy 0.99 ± 0.175 × 10-3 mm2/s, yielding a mean lesion ADC elevation of 0.21 ± 0.96 × 10-3 mm2/s p < 0.001). The absolute ADC values from MRL were consistently significantly higher than those from MRI3T at baseline and during radiotherapy (p < = 0.001). However, there was a strong positive correlation between MRL-ADC and MRI3T-ADC at baseline (r = 0.798, p = 0.01) and during radiotherapy (r = 0.863, p = 0.003). Lesion ADC as measured on MRL increased significantly during radiotherapy and ADC measurements of lesions on both systems showed similar dynamics. This indicates that lesion ADC as measured on the MRL may be used as a biomarker for evaluation of treatment response. In contrast, absolute ADC values as calculated by the algorithm of the manufacturer of the MRL showed systematic deviations from values obtained on a diagnostic 3T MRI system. These preliminary findings are promising but need large-scale validation. Once validated, lesion ADC on MRL might be used for real-time assessment of tumor response in patients with prostate cancer undergoing MR-guided radiation therapy.

PO-1370 Real-World Data of Pancreatic Cancer Treated with Ablative Radiation on a 1.5 tesla MR Linac

PO-1370 Real-World Data of Pancreatic Cancer Treated with Ablative Radiation on a 1.5 tesla MR Linac

Evaluation of an MRI linac magnetic isocenter walkout with gantry rotation in the presence of angle-specific corrections

Objective. To reduce the magnetic isocenter position variation with gantry rotation on an 0.35 T MRI-guided linac to a practically negligible level. Approach. Central fRequency (CF) offset, eddy current calibration, cross-term calibration, gradient delay, and gradient offsets are tuned for each MR linac installation at every 30° of gantry rotation and stored in a look-up table (LUT). During treatment, the CF is tuned only once in the beginning at an arbitrary gantry angle. After that, imaging paramters are offset based on the stored LUT values for any given gantry angle. Main results. For the same hardware configuration, the implementation of the gantry-angle-specific parameter corrections reduced the total isocenters range of travel in the transverse plane from 1.1 to 0.3 mm and from 0.8 to 0.2 mm in horizontal and vertical directions, respectively. With the longitudinal shift always being negligible (≤0.2 mm), the radius of the sphere encompassing the isocenter locations was reduced from 0.6 to 0.2 mm. Geometric distortion improved as well; in particular, the gantry-angle-averaged maximum longitudinal distortion within a 35 cm diameter sphere was reduced from 1.4 to 0.8 mm. Since the CF is tuned only once during treatment, imaging may resume promptly after the gantry reaches the next target position. Significance. The MRI-guided linear accelerator was conceived primarily as an instrument for precision image-guided therapy. Thus, it is important to keep the treatment and imaging isocentres as close as possible while minimizing the geometric distortion. The described solution reduces the walkout of the imaging isocenter to a fraction of 1 mm, while keeping geometric distortion in a substantial volume below 1 mm. The approach is robust and does not increase the overall procedure time.

First-in-human technique translation of oxygen-enhanced MRI to an MR Linac system in patients with head and neck cancer

Background and purposeTumour hypoxia is prognostic in head and neck cancer (HNC), associated with poor loco-regional control, poor survival and treatment resistance. The advent of hybrid MRI – radiotherapy linear accelerator or ‘MR Linac’ systems – could permit imaging for treatment adaptation based on hypoxic status. We sought to develop oxygen-enhanced MRI (OE-MRI) in HNC and translate the technique onto an MR Linac system. Materials and methodsMRI sequences were developed in phantoms and 15 healthy participants. Next, 14 HNC patients (with 21 primary or local nodal tumours) were evaluated. Baseline tissue longitudinal relaxation time (T1) was measured alongside the change in 1/T1 (termed ΔR1) between air and oxygen gas breathing phases. We compared results from 1.5 T diagnostic MR and MR Linac systems. ResultsBaseline T1 had excellent repeatability in phantoms, healthy participants and patients on both systems. Cohort nasal concha oxygen-induced ΔR1 significantly increased (p < 0.0001) in healthy participants demonstrating OE-MRI feasibility. ΔR1 repeatability coefficients (RC) were 0.023–0.040 s−1 across both MR systems. The tumour ΔR1 RC was 0.013 s−1 and the within-subject coefficient of variation (wCV) was 25% on the diagnostic MR. Tumour ΔR1 RC was 0.020 s−1 and wCV was 33% on the MR Linac. ΔR1 magnitude and time-course trends were similar on both systems. ConclusionWe demonstrate first-in-human translation of volumetric, dynamic OE-MRI onto an MR Linac system, yielding repeatable hypoxia biomarkers. Data were equivalent on the diagnostic MR and MR Linac systems. OE-MRI has potential to guide future clinical trials of biology guided adaptive radiotherapy.

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

TPS400 Background: The objective of this randomized clinical trial is to demonstrate that 2 weeks (5 fractions) of real-time MRI-guided radiotherapy (RT) with an MR Linac does not significantly increase patient-reported GI and GU symptoms compared to 4 weeks (20 fractions) of RT 2 years after treatment completion. Methods: Key Eligibility Criteria: Inclusion Criteria 1. Men aged &gt; 18 with histologically confirmed prostate cancer after prostatectomy with detectable PSA. 2. KPS &gt; 70. 3. Patients with no evidence of distant metastatic disease on PET/CT/MRI/bone scan&lt; 180 days prior to enrollment. 4. Ability to receive MRI-guided radiotherapy. 5. Ability to complete the Expanded Prostate Cancer Index Composite (EPIC) questionnaire. Exclusion Criteria 1. Prior history of receiving pelvic RT. 2. Patient with history of IBD. 3. History of bladder neck or urethral stricture. Study Design/Endpoints: This is a randomized phase II non-inferiority trial comparing 5 fractions of ultrahypofractionated RT (32.5 Gy total with optional PSMA/MRI boost to 40 Gy) versus 20 fractions of hypofractionated RT (55 Gy total with optional PSMA/MRI boost to 60 Gy) in the post-operative setting for prostate cancer. Subjects will be stratified based on pre-specified stratification factors and randomized 1:1 to receive 5 or 20 fractions using permuted block randomization. The primary endpoint is the change in patient-reported GI and GU symptoms as measured by EPIC at 2 years from end of treatment. Secondary endpoints will include both the safety endpoints including change in GI and GU symptoms at 3, 6, 12 and 60 months from end of treatment, and multiple efficacy endpoints including time to progression, prostate cancer specific survival and overall survival. Sample Size: The sample size is calculated based on a non-inferiority design. The non-inferiority margins are set to be a change score of 6 points for the GI symptoms and 5 points for the GU symptoms. The standard deviations of the change scores are assumed to be 13.2 for the GI symptoms and 10.5 for the GU symptoms based on estimates generated in RTOG 0415 trial. This level of change in scores are deemed as clinically meaningful. For example, 6 points of change score for GI symptoms corresponds to two symptoms worsening by 1 level (i.e., loose stools and frequency of bowel movements change from “no problem” to “very small problem”) or one of the symptoms worsening by 2 levels (i.e., loose stool change from “no problem” to “small problem”). A sample size of 122 with 61 in each arm will ensure 80% power for GI endpoint and 83% power for GU endpoint to detect non-inferiority using a one-sided two-sample t-test at the significance level of 0.05. Adjusting for a projected 10% EPIC/non-compliance rate, 136 patients (68 per arm) will be randomized. Stratification Factors: Patients will be stratified according to baseline EPIC bowel and urinary domain scores and use of nodal treatment and ADT. Enrollment: 91 patients. Clinical trial information: NCT04422132 .

Development of MRI Prostate Cancer Hypoxia Detection Sequences on the MR Linac

Purpose: Sub-regions of hypoxia within the tumour microenvironment are associated with genetic instability and adverse prognosis after surgery or radiotherapy [1]. Identification of hypoxic tumours in patients prior to and during radiotherapy (RT) would facilitate stratification to hypoxia-modifying treatments, such as hypoxic cell radiosensitisers [2], hypoxic region RT dose escalation and avoidance of ultra-fractionated RT regimens. As validated hypoxia detection sequences on the MR Linac would allow the targeting and tracking of hypoxia during RT, we undertook sequence development for three candidate MR hypoxia detection biomarkers for use on the MR Linac.

Feasibility of using a dual isocentre technique for treating cervical cancer on the 1.5 T MR-Linac

Objective. Patients treated for cervical cancer exhibit large inter and intra-fraction anatomical changes. The Unity MR-Linac (MRL) can image these patients with MR prior to and during treatment which enables daily plan adaptation. However, the MRL has a limited treatment field in the sup/inf direction of 22 cm which can restrict the treatment of patients who require longer treatment fields. Here we explore potential adaptive workflows in combination with a dual isocentre approach, to widen the range of cervix patients that can benefit from this treatment. Approach. Ten cervical cancer patients were retrospectively planned with a dual isocentre technique to deliver 45 Gy in 25 fractions. 5 node-negative and 5 node-positive patients were planned using the EMBRACE II protocol. A 2 cm overlap region between the two isocentres was positioned entirely in the nodal region. A treatment workflow was simulated to account for inter-fraction anatomical change. Isocentre shifts of 3 and 6 mm were applied to investigate the effect of intra-fraction motion. Main results. Dual isocentre adapted plans ensured significantly better coverage than non-adapted (recalculated) plans with a larger benefit seen for the node-negative cases. The difference to the reference plan for the V4275 cGy to the ITV was −0.8 cGy and −8.2 cGy for the adapted and recalculated plans respectively. Movements superiorly did not affect the coverage of the ITV by more than 1%, but shifting it inferiorly caused the ITV coverage on the plan to reduce by ∼2.4% per mm. Significance. A dual isocentre technique for cervical cancer treatments and adaptive workflows have been demonstrated to recover the required plan quality for inter-fraction changes. This illustrates the feasibility of a dual isocentre technique for the MRL.

Initial clinical experience with magnetic resonance-guided radiotherapy in pediatric patients: Lessons learned from a single institution with proton therapy.

Magnetic resonance-guided radiotherapy (MRgRT) is increasingly used in a variety of adult cancers. To date, published experience regarding the use of MRgRT in pediatric patients is limited to two case reports. We report on the use of MRgRT for pediatric patients at our institution during a four-year period and describe important considerations in the selection and application of this technology in children. All patients treated with MRgRT since inception at our institution between 4/2018 and 4/2022 were retrospectively reviewed. We also evaluated all pediatric patients treated at our institution during the same period who received either imaging or treatment using our magnetic resonance-guided linear accelerator (MR Linac). We summarize four clinical cases where MRgRT was selected for treatment in our clinic, including disease outcomes and toxicities and describe our experience using the MR Linac for imaging before and during treatment for image fusion and tumor assessments. Between 4/2018 and 4/2022, 535 patients received MRgRT at our center, including 405 (75.7%) with stereotactic ablative radiotherapy (SABR). During this period, 347 distinct radiotherapy courses were delivered to pediatric patients, including 217 (62.5%) with proton therapy. Four pediatric patients received MRgRT. One received SABR for lung metastasis with daily adaptive replanning and a second was treated for liver metastasis using a non-adaptive workflow. Two patients received fractionated MRgRT for an ALK-rearranged non-small cell lung cancer and neuroblastoma. No Grade 2 or higher toxicities were observed or reported during MRgRT or subsequent follow-up. Twelve patients underwent MR imaging without contrast during treatment for brain tumors to assess for tumor/cystic changes. Two patients treated with other modalities underwent MR simulation for target volume delineation and organ at risk sparing due to anatomic changes during treatment or unexpected delays in obtaining diagnostic MR appointments. In four pediatric patients treated with MRgRT, treatment was well tolerated with no severe acute effects. At our center, most pediatric patients are treated with proton therapy, but the cases selected for MRgRT demonstrated significant organ at risk sparing compared to alternative modalities. In particular, MRgRT may provide advantages for thoracic/abdominal/pelvic targets using gated delivery and adaptive replanning, but selected patients treated with fractionated radiotherapy may also benefit MRgRT through superior organ at risk sparing.

Evaluation of therapeutic radiographer contouring for magnetic resonance image guided online adaptive prostate radiotherapy

Background and PurposeThe implementation of MRI-guided online adaptive radiotherapy has facilitated the extension of therapeutic radiographers’ roles to include contouring, thus releasing the clinician from attending daily treatment. Following undergoing a specifically designed training programme, an online interobserver variability study was performed. Materials and Methods117 images from six patients treated on a MR Linac were contoured online by either radiographer or clinician and the same images contoured offline by the alternate profession. Dice similarity coefficient (DSC), mean distance to agreement (MDA), Hausdorff distance (HD) and volume metrics were used to analyse contours. Additionally, the online radiographer contours and optimised plans (n = 59) were analysed using the offline clinician defined contours. After clinical implementation of radiographer contouring, target volume comparison and dose analysis was performed on 20 contours from five patients. ResultsComparison of the radiographers’ and clinicians’ contours resulted in a median (range) DSC of 0.92 (0.86 – 0.99), median (range) MDA of 0.98 mm (0.2–1.7) and median (range) HD of 6.3 mm (2.5–11.5) for all 117 fractions. There was no significant difference in volume size between the two groups. Of the 59 plans created with radiographer online contours and overlaid with clinicians’ offline contours, 39 met mandatory dose constraints and 12 were acceptable because 95 % of the high dose PTV was covered by 95 % dose, or the high dose PTV was within 3 % of online plan. A clinician blindly reviewed the eight remaining fractions and, using trial quality assurance metrics, deemed all to be acceptable.Following clinical implementation of radiographer contouring, the median (range) DSC of CTV was 0.93 (0.88–1.0), median (range) MDA was 0.8 mm (0.04–1.18) and HD was 5.15 mm (2.09–8.54) respectively. Of the 20 plans created using radiographer online contours overlaid with clinicians’ offline contours, 18 met the dosimetric success criteria, the remaining 2 were deemed acceptable by a clinician. ConclusionRadiographer and clinician prostate and seminal vesicle contours on MRI for an online adaptive workflow are comparable and produce clinically acceptable plans. Radiographer contouring for prostate treatment on a MR-linac can be effectively introduced with appropriate training and evaluation. A DSC threshold for target structures could be implemented to streamline future training.

High grade glioma radiation therapy on a high field 1.5 Tesla MR-Linac - workflow and initial experience with daily adapt-to-position (ATP) MR guidance: Afirst report.

This study reports the workflow and initial clinical experience of high grade glioma (HGG) radiotherapy on the 1.5 T MR-Linac (MRL), with a focus on the temporal variations of the tumor and feasibility of multi-parametric image (mpMRI) acquisition during routine treatment workflow. Ten HGG patients treated with radiation within the first year of the MRL's clinical operation, between October 2019 and August 2020, were identified from a prospective database. Workflow timings were recorded and online adaptive plans were generated using the Adapt-To-Position (ATP) workflow. Temporal variation within the FLAIR hyperintense region (FHR) was assessed by the relative FHR volumes (n = 281 contours) and migration distances (maximum linear displacement of the volume). Research mpMRIs were acquired on the MRL during radiation and changes in selected functional parameters were investigated within the FHR. All patients completed radiotherapy to a median dose of 60 Gy (range, 54-60 Gy) in 30 fractions (range, 30-33), receiving a total of 287 fractions on the MRL. The mean in-room time per fraction with or without post-beam research imaging was 42.9 minutes (range, 25.0-69.0 minutes) and 37.3 minutes (range, 24.0-51.0 minutes), respectively. Three patients (30%) required re-planning between fractions 9 to 12 due to progression of tumor and/or edema identified on daily MRL imaging. At the 10, 20, and 30-day post-first fraction time points 3, 3, and 4 patients, respectively, had a FHR volume that changed by at least 20% relative to the first fraction. Research mpMRIs were successfully acquired on the MRL. The median apparent diffusion coefficient (ADC) within the FHR and the volumes of FLAIR were significantly correlated when data from all patients and time points were pooled (R=0.68, p<.001). We report the first clinical series of HGG patients treated with radiotherapy on the MRL. The ATP workflow and treatment times were clinically acceptable, and daily online MRL imaging triggered adaptive re-planning for selected patients. Acquisition of mpMRIs was feasible on the MRL during routine treatment workflow. Prospective clinical outcomes data is anticipated from the ongoing UNITED phase 2 trial to further refine the role of MR-guided adaptive radiotherapy.