MRI-guided Radiotherapy Research Articles

THeragnostic utilities for neoplastic DisEases of the rectum by MRI guided radiotherapy (THUNDER 2) phase II trial: interim safety analysis

BackgroundThe THUNDER-2 phase II single institutional trial investigates the benefits of MRI-guided radiotherapy (MRIgRT) in treating locally advanced rectal cancer (LARC). This study focuses on evaluating the impact of escalating radiation therapy dose in non-responder patients using the Early Tumour Regression Index (ERI) for predicting complete response (CR). The trial’s primary endpoint is to increase the CR rate in non-responders by 10% and assess the feasibility of the delta radiomics-based MRIgRT predictive model. This interim analysis assesses the feasibility and safety of the proposed MRIgRT dose escalation strategy in terms of acute toxicity (gastrointestinal, genitourinary and haematological) and treatment adherence.MethodsStage cT2-3, N0-2, or cT4 patients with anal sphincter involvement, N0-2a, M0, but without high-risk features were enrolled. MRIgRT treatment consisted of a standard dose of 55 Gy to the Gross Tumor Volume (GTV) and mesorectum, and 45 Gy to the mesorectum and drainage nodes in 25 fractions with concomitant chemotherapy. 0.35 T MRI was used for simulation imaging and daily alignment. ERI was calculated at the 10th fraction. Non-responders with an ERI above 13.1 received intensified dose escalation from the 11th fraction, resulting in a total dose of 60.1 Gy. Acute toxicity was assessed using the CTCAE v.5 scale.ResultsFrom March 2021 to November 2022, 33 out of the total number of 63 patients to be enrolled (52.4%) were included, with one withdrawal unrelated to treatment. Sixteen patients (50%) underwent dose escalation. Treatment was well tolerated, with only one patient (3.1%) in the standard treatment group experiencing acute Grade 3 diarrhea, proctitis, and cystitis. No significant differences in toxicity were observed between the two groups (p = 0.5463).ConclusionsMRIgRT treatment with dose escalation up to 60.1 Gy is well tolerated in LARC patients predicted as non-responders by ERI, confirming the feasibility and safety of this approach. The THUNDER-2 trial’s primary and secondary endpoints will be fully analyzed when all planned patients will be enrolled.

MRI-based inter- and intrafraction motion analysis of the pancreatic tail and spleen as preparation for adaptive MRI-guided radiotherapy in neuroblastoma

BackgroundIn pediatric radiotherapy treatment planning of abdominal tumors, dose constraints to the pancreatic tail/spleen are applied to reduce late toxicity. In this study, an analysis of inter- and intrafraction motion of the pancreatic tail/spleen is performed to estimate the potential benefits of online MRI-guided radiotherapy (MRgRT).Materials and methodsTen randomly selected neuroblastoma patients (median age: 3.4 years), irradiated with intensity-modulated arc therapy at our department (prescription dose: 21.6/1.8 Gy), were retrospectively evaluated for inter- and intrafraction motion of the pancreatic tail/spleen. Three follow-up MRIs (T2- and T1-weighted ± gadolinium) were rigidly registered to a planning CT (pCT), on the vertebrae around the target volume. The pancreatic tail/spleen were delineated on all MRIs and pCT. Interfraction motion was defined as a center of gravity change between pCT and T2-weighted images in left-right (LR), anterior-posterior (AP) and cranial-caudal (CC) direction. For intrafraction motion analysis, organ position on T1-weighted ± gadolinium was compared to T2-weighted. The clinical radiation plan was used to estimate the dose received by the pancreatic tail/spleen for each position.ResultsThe median (IQR) interfraction motion was minimal in LR/AP, and largest in CC direction; pancreatic tail 2.5 mm (8.9), and spleen 0.9 mm (3.9). Intrafraction motion was smaller, but showed a similar motion pattern (pancreatic tail, CC: 0.4 mm (1.6); spleen, CC: 0.9 mm (2.8)). The differences of Dmean associated with inter- and intrafraction motions ranged from − 3.5 to 5.8 Gy for the pancreatic tail and − 1.2 to 3.0 Gy for the spleen. In 6 out of 10 patients, movements of the pancreatic tail and spleen were highlighted as potentially clinically significant because of ≥ 1 Gy dose constraint violation.ConclusionInter- and intrafraction organ motion results into unexpected constrain violations in 60% of a randomly selected neuroblastoma cohort, supporting further prospective exploration of MRgRT.

Experimental comparison of linear regression and LSTM motion prediction models for MLC-tracking on an MRI-linac.

Magnetic resonance imaging (MRI)-guided radiotherapy with multileaf collimator (MLC)-tracking is a promising technique for intra-fractional motion management, achieving high dose conformality without prolonging treatment times. To improve beam-target alignment, the geometric error due to system latency should be reduced by using temporal prediction. To experimentally compare linear regression (LR) and long-short-term memory (LSTM) motion prediction models for MLC-tracking on an MRI-linac using multiple patient-derived traces with different complexities. Experiments were performed on a prototype 1.0T MRI-linac capable of MLC-tracking. A motion phantom was programmed to move a target in superior-inferior (SI) direction according to eight lung cancer patient respiratory motion traces. Target centroid positions were localized from sagittal 2D cine MRIs acquired at 4Hz using a template matching algorithm. The centroid positions were input to one of four motion prediction models. We used (1) a LSTM network which had been optimized in a previous study on patient data from another cohort (offline LSTM). We also used (2) the same LSTM model as a starting point for continuous re-optimization of its weights during the experiment based on recent motion (offline+online LSTM). Furthermore, we implemented (3) a continuously updated LR model, which was solely based on recent motion (online LR). Finally, we used (4) the last available target centroid without any changes as a baseline (no-predictor). The predictions of the models were used to shift the MLC aperture in real-time. An electronic portal imaging device (EPID) was used to visualize the target and MLC aperture during the experiments. Based on the EPID frames, the root-mean-square error (RMSE) between the target and the MLC aperture positions was used to assess the performance of the different motion predictors. Each combination of motion trace and prediction model was repeated twice to test stability, for a total of 64 experiments. The end-to-end latency of the system was measured to be (389 ± 15)ms and was successfully mitigated by both LR and LSTM models. The offline+online LSTM was found to outperform the other models for all investigated motion traces. It obtained a median RMSE over all traces of (2.8 ± 1.3)mm, compared to the (3.2 ± 1.9)mm of the offline LSTM, the (3.3 ± 1.4)mm of the online LR and the (4.4 ± 2.4)mm when using the no-predictor. According to statistical tests, differences were significant (p-value <0.05) among all models in a pair-wise comparison, but for the offline LSTM and online LR pair. The offline+online LSTM was found to be more reproducible than the offline LSTM and the online LR with a maximum deviation in RMSE between two measurements of 10%. This study represents the first experimental comparison of different prediction models for MRI-guided MLC-tracking using several patient-derived respiratory motion traces. We have shown that among the investigated models, continuously re-optimized LSTM networks are the most promising to account for the end-to-end system latency in MRI-guided radiotherapy withMLC-tracking.

Prior knowledge based deep learning auto-segmentation in magnetic resonance imaging-guided radiotherapy of prostate cancer

Background and purposeAutomation is desirable for organ segmentation in radiotherapy. This study compared deep learning methods for auto-segmentation of organs-at-risk (OARs) and clinical target volume (CTV) in prostate cancer patients undergoing fractionated magnetic resonance (MR)-guided adaptive radiation therapy. Models predicting dense displacement fields (DDFMs) between planning and fraction images were compared to patient-specific (PSM) and baseline (BM) segmentation models. Materials and methodsA dataset of 92 patients with planning and fraction MR images (MRIs) from two institutions were used. DDFMs were trained to predict dense displacement fields (DDFs) between the planning and fraction images, which were subsequently used to propagate the planning contours of the bladder, rectum, and CTV to the daily MRI. The training was performed either with true planning-fraction image pairs or with planning images and their counterparts deformed by known DDFs. The BMs were trained on 53 planning images, while to generate PSMs, the BMs were fine-tuned using the planning image of a given single patient. The evaluation included Dice similarity coefficient (DSC), the average (HDavg) and the 95th percentile (HD95) Hausdorff distance (HD). ResultsThe DDFMs with DSCs for bladder/rectum of 0.76/0.76 performed worse than PSMs (0.91/0.90) and BMs (0.89/0.88). The same trend was observed for HDs. For CTV, DDFM and PSM performed similarly yielding DSCs of 0.87 and 0.84, respectively. ConclusionsDDFMs were found suitable for CTV delineation after rigid alignment. However, for OARs they were outperformed by PSMs, as they predicted only limited deformations even in the presence of substantial anatomical changes.

Treatment Delivery Gating of MRI-Guided Stereotactic Radiotherapy for Prostate Cancer: An Exploratory Analysis of a Phase III Randomized Trial of CT-Vs. MR-Guided Radiotherapy (MIRAGE)

Compared to CT-guided radiotherapy, MRI-guided radiotherapy (MRgRT) has been shown to reduce acute physician-scored and patient-reported gastrointestinal and genitourinary (GU) toxicities associated with prostate stereotactic body radiotherapy (SBRT) in the MIRAGE randomized trial (NCT04384770). We hypothesize that real-time intrafraction tracking/gating is important and is a critical enabler of aggressive margin reduction with MRgRT. 79 patients received MRgRT on the MIRAGE trial with a planning margin of 2mm around the prostate and proximal seminal vesicles, which were treated to 40 Gy in five fractions on an MR-Linac. Tracking was performed at 4 frames/second in the sagittal plane during treatment with a gating boundary of 3mm for automatic beam hold. An in-house tool was developed to extract treatment time and beam gating status based on treatment logs and real-time cine images. The ratio of the time that the target was within the gating window/total time of target inside or outside the gating boundary was defined as the duty cycle (DC). Target contours were extracted from each frame of tracking and overlaid to create a motion-convolved target occupancy map. Minimum isotropic expansions of the prostate to cover 85%, 90% and 95% of the intrafraction motion were calculated with and without gating. Median treatment time per fraction including image guidance procedure and beam delivery was 24.3 min (IQR: 22.2-27.7 min). The median time for image guidance 5.4 min (IQR: 4.2-6.7 min). A total of 391 treatment fractions were analyzed and the median DC per fraction was 0.974 (IQR: 0.926 -0.983). 89 (22.8%) and 35 (9.0%) of fractions had DC<90% and <80%, respectively, corresponding to 50/79 (62.3%) and 24/79 (30.4%) of patients having at least one fraction with a DC<90% and <80%, respectively. The minimum duty cycle of all fractions was lower among patients with grade ≥2 GU toxicity compared to those with grade 0-1 GU toxicity (mean 79.8% vs. 85.9%, p = 0.06). The proportion of patients with grade ≥2 GU toxicity was also greater in patients with a minimum gating cycle <80% (37.5% vs. 18.2%, p = 0.06). Gating significantly decreased the minimum isotropic expansion of the prostate to cover 85%, 90% and 95% of the intrafraction motion (p<0.0001 for all). Prostate intrafraction motion tended to be along the bladder-rectum axis secondary to bladder filling, rectal gas and bulk motion. Fractions with large prostate motion were mostly stochastic. A large fraction (30%) of patients had at least of one treatment fraction with DC<80%, which correlated with increased acute GU toxicity. Gating effectively reduces the expansion needed to cover prostate intrafraction motion, and is necessary for real-time motion management given the unpredictable nature of prostate motion.

Randomized Trial of Five or Two MRI-guided Adaptive Radiotherapy Treatments for Prostate Cancer (FORT)

The objective of this randomized clinical trial is to demonstrate that 2 treatments of real-time MRI-guided radiotherapy (RT) does not significantly increase patient-reported GI and GU symptoms compared to 5 treatments of RT 2 years after treatment completion (24 months). Key Eligibility Criteria: Inclusion Criteria 1. Men aged > 18 with histologically confirmed low or intermediate risk prostate cancer per NCCN guidelines. 2. ECOG 0 - 1 3. IPSS < 18 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. Hip replacements. 4. History of bladder neck or urethral stricture. 5. TURP < 8 weeks prior to RT 6. Metastatic (pelvic nodal or distant) disease on CT, Bone, and/or PSMA PET scan. Study Design/Endpoints: This is a randomized phase II non-inferiority trial comparing 2 fractions of ultrahypofractionated RT (25 Gy total with optional PSMA/MRI boost to 28 Gy) versus 5 fractions of ultra-hypofractionated RT (37.5 Gy total with optional PSMA/MRI boost to 45 Gy) in the definitive setting for prostate cancer. Subjects will be stratified based on pre-specified stratification factors and randomized 1:1 to receive 2 or 5 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. 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 country of treatment. Enrollment: Twenty patients. To be determined. To be determined.

Comprehensive Beam Modeling, Secondary Dose Computations and Treatment Planning for a 1.5 T MRgRT System

Magnetic resonance imaging guided radiotherapy (MRgRT) combines soft tissue visualization with online adaptive radiotherapy. The MRgRT workflow is characterized by many steps which needs to be performed swiftly and therefore greatly benefits from automation. The purpose of this study was to model a MRgRT system for dose computation and intensity modulated radiotherapy (IMRT) planning within a 1.5 T magnetic field in an independent treatment planning system (iTPS) with automation functionalities. A beam model for a 1.5 T MRgRT system was commissioned in an iTPS using beam profiles and output factor measurements. The cryostat of the MRgRT system was modeled using a cylindrical multi-layer combination of epoxy and aluminum and matched to source-to-surface dependent cryostat scatter measurement in air, and corrected for angular dependent cryostat transmission readings. The beam model was used with a fast Monte Carlo dose engine to account for the electron return and electron streaming effects within an external magnetic field. The multi-leaf collimator (MLC) was characterized with a novel synchronous and asynchronous sweeping gap (aSG) test. The aSGs have a shift (between 0 - 40 mm) between adjacent leaves which remains constant over the sweep. Measured doses map the shadowing due to the tongue-and-groove (TG) exposure and TG and leaf tip (LT) parameters are derived to match this within the iTPS. Clinical IMRT plans of 10 prostate, 5 lymph node and 5 rectal plans created in the default clinical TPS were recomputed in the iTPS and evaluated with the corresponding plan-specific quality assurance measurements. In addition, three IMRT plans were optimized within the iTPS, delivered with the MRgRT system and evaluated using PSQA using a 3%/3mm gamma criterium with a 10% threshold. Monte Carlo dose computation in the iTPS closely resembled the measured profiles in the presence of the 1.5 T magnetic field. The cryostat scatter simulations were <0.7% compared to the measurements and literature. The aSG/SGs test demonstrated that the TG width gradually increased up to 1 mm for a distance of 15 mm away from the leaf tip end. These effects were closely replicated in the iTPS with a difference of <1.5% for 95% of the aSGs. The difference between the clinical dose and the dose calculation in the iTPS was, on average, <0.5% within the volume receiving 50% of the maximum dose. The gamma pass rate was 100% for 98% of the PSQA results. The plans optimized within the iTPS were successfully delivered at the MRgRT system. We successfully modeled and commissioned a 1.5 T MRgRT system in an independent TPS. The beam model can be used for a second opinion dose computation in a magnetic field and for direct treatment planning. Next, the beam model will be incorporated in a semi-automated and adaptive workflow using the iTPS.

Early Outcomes of MR-Guided SBRT for Patients with Recurrent Pancreatic Adenocarcinoma

Local treatment options for patients with locally recurrent pancreatic adenocarcinoma (L-PAC) are limited, with expected median survival time (MST) of 8-11 months (mo) following recurrence. MRI-guided radiation therapy (MRgRT) provides the ability to dose escalate while sparing normal tissue. The literature for MR-guided Stereotactic Body Radiotherapy (MRgSBRT) for L-PAC is sparse. Here we report on the early outcomes of MRgSBRT in patients with L-PAC. Patients with prior resection of pancreatic adenocarcinoma with post-operative chemotherapy as indicated followed by local recurrence of disease at prior surgical site and treated with MRgSBRT at a single tertiary referral center from 5-2021 to 8-2022 for L-PAC were identified from our prospective database. MRgSBRT was delivered to 40-50 Gy in 4-5 fractions with target and OAR delineation per institutional standards. Descriptive analysis of the patient, disease, and treatment characteristics were performed. Endpoints included local control, defined as absence of tumor progression per RECIST criteria, distant failure, overall survival (OS), and acute and chronic toxicities per Common Terminology Criteria for Adverse Events (CTCAE), version 5. Eleven patients with L-PAC were identified with median follow-up of 10.7 mo (3.2 - 22.3). Ten of those underwent surgical resection at the treating radiation facility and one patient underwent preoperative radiation for 50.4 Gy in 28 fractions followed by surgical resection at an outside hospital. MRgRT was delivered a median of 18.8 mo (3.5 - 48.0) following resection. There were 5 females and 6 males, with a median age of 72 years (52-83) and median KPS of 80 (60-100). OS rates following initial diagnosis at 12, 18 and 24 mo were 100%, 82%, and 61%, respectively, with an MST of 25.3 mo (12.4-53.1). OS rates following recurrence at 6 and 12 mo were 82% and 52%, respectively, with an MST of 10.7 mo (3.2 - 21.9). One patient experienced local failure at 7.8 mo, and 9 patients experienced distant failure at a median of 3.4 mo (0.3 - 21.9) following MRgSBRT. Five patients experienced distant failure less than 3 mo following radiation. Grade 1 or 2 acute GI toxicity was noted in 45% of patients and chronic GI toxicity, in 18% of patients. No Grade≥3 AEs were noted. MRgSBRT for recurrent pancreatic adenocarcinoma demonstrates good local control with acceptable acute and chronic toxicity as well as reasonable overall survival. Distant failure remains a substantial problem with a significant number of patients demonstrating metastases immediately following radiation, suggesting the presence of micro-metastatic disease prior to local therapy. Adequate patient selection for MRgSBRT, and proper integration of systemic therapy in this patient population remains a topic of discussion that requires further exploration.

Dynamic Changes of Molecular Subtype Classification and Genomic Classifier Scores in High-Risk Prostate Cancer Patients Undergoing Pre-Operative Stereotactic Body Radiation Therapy

The radiobiology of irradiated human prostate cancer (PCa) remains poorly understood as irradiated tissues often remain in situ. PREPARE-SBRT (NCT03663218) is a clinical trial testing the safety of neoadjuvant MRI-guided stereotactic body radiation therapy (SBRT) for men with high-risk PCa. We leveraged paired samples from pre-treatment biopsy and irradiated prostatectomy (RP) specimens to evaluate transcriptomic changes in irradiated tumors at acute timepoints following SBRT. Tumor RNA expression profiles were generated using Decipher GRID by Veracyte on 12 subjects enrolled on NCT03663218 with paired pre/post-SBRT tissues (n = 24). Descriptive statistics using Decipher Genomic Classifier (GC) Score [0-1] and GC risk group (low/int/high) were generated from a validated 22-gene GC. Tumor biology signatures reported as dichotomous variables evaluated changes in androgen receptor (AR) activity [higher v lower] and cell cycle progression (CCP) [lower v higher]. Decipher prostate subtype classifier [PSC, luminal differentiated (LD), luminal proliferating (LP), basal immune (BI), basal neuroendocrine like (BN)] classification and PAM50 molecular subtype [luminal A (lumA), luminal B (lumB), basal] at pre/post-SBRT timepoints were reported. A control cohort of transcriptomic profiles of 803 matched untreated biopsy and RP samples from the same patients were used to control for signature differences attributable to sample type. The median pre- and post-SBRT GC scores were 0.55 and 0.72 (Δ+0.17), respectively. By comparison, median GC scores in a control cohort (n = 803) of biopsy and RP specimens were 0.50 and 0.56 (Δ+0.06), respectively. SBRT increased GC score in 9/12 subjects (75%) with a median increase of 0.3. Changes in GC score resulted in reclassification of baseline GC risk in 7 of 12 subjects with 71% of reclassified subjects (5/7) transitioning to a higher genomic risk. 92% of subjects (11/12) had higher AR activity scores at baseline. Of this subgroup, 5/11 (45%) converted to lower AR activity score after SBRT. CCP signatures remained stable in 9 of 12 subjects (75%) with 7/12 subjects exhibiting lower CCP score at baseline and only 1 subject transitioning from lower to higher CCP score. Distribution of PAM50 molecular subtype at baseline and after SBRT was lumA (33>53%), lumB (25>17%), basal (42>25%) resulting in 83% of subjects (10/12) annotated to a different PAM50 molecular subtype at pre/post-SBRT assessment. PSC subtype distribution at baseline was LD (33%), LP (25%), BI (33%) and BN (8%). Strikingly, after SBRT, 92% (11/12) of subjects were classified as BI molecular subtype with several immune activation signatures also increased after SBRT. A majority of subjects demonstrate a post-SBRT increase in GC score with reclassification of genomic-prognostic risk group in 58%. An enrichment of the basal-immune molecular subtype was observed following SBRT suggesting a convergence towards this biology in irradiated tumors.

Radiation Therapy and Irreversible Electroporation for Intermediate Risk Prostate Cancer (RTIRE)

The objective of the RTIRE clinical trial (NCT05345444) is to demonstrate the feasibility, safety, and early oncologic efficacy of combining MRI-guided stereotactic body radiation therapy (MRgSBRT) with irreversible electroporation (IRE) for men with intermediate-risk localized prostate cancer. Inclusion criteria: 1) Men aged ≥18, 2) ECOG 0 -1, 3) Histologically confirmed intermediate risk prostate cancer per NCCN guidelines, 4) Focal grade group 2 (GG2) or 3 (GG3) cancer in multi-parametric magnetic resonance imaging (mpMRI) target, 5) Gland size < 80cc, 6) Ability to undergo IRE, 7) Ability to receive MRI-guided SBRT, 8) Ability to complete the HRQOL assessment surveys, 9) Willingness to undergo 12 month follow up biopsy. 1) Prior TURP, 2) Prior history of focal therapy, 3) Prior history of receiving pelvic radiotherapy, 4) Patient with history of inflammatory bowel disease, 5) History of bladder neck or urethral stricture. Study Design/Endpoints: This is a feasibility and safety study assessing the ability to perform IRE followed by real-time MRgSBRT. Subjects will undergo focal IRE followed by MRgSBRT (≥6 weeks after IRE) to the prostate +/- seminal vesicles prescribed to 32.5 Gy in 5 fractions. The primary endpoint of the first portion of the trial is feasibility, defined as at least 80% of subjects (8 of 10 subjects) undergoing assessment at 12-weeks post-IRE and at 6-weeks post-MRgSBRT within 1 year from enrollment of the first subject. The expansion phase will include an additional 40 subjects to assess side effect profile and early oncologic efficacy (n = 50) at 12 months post RTIRE. RTIRE has enrolled 8 subjects in 3 months and will proceed to the expansion phase. Secondary endpoints include: 1) short-term safety as measured by treatment-related adverse events, 2) oncologic efficacy as measured by number of subjects with presence of ≥GG2 cancer at 12 months post-RTIRE therapy, 3) health-related quality of life (HRQOL) as measured by Expanded Prostate Cancer Index Composite for Clinical Practice (EPIC-CP), International Prostate Symptom Score (IPSS), International Index of Erectile Function (IIEF-5) 4) post-RTIRE prostate-specific antigen (PSA) kinetics including time to PSA nadir and post-nadir PSA stability, 5) assessment of pre and post-RTIRE mpMRI changes to evaluate the area of necrosis and presence of residual tissue, 6) rates of biochemical and clinical progression and the need for secondary or adjuvant treatment following RTIRE. Enrollment: 11 Subjects RESULTS: To be determined. To be determined.

Patient Selection is Critical When Evaluating Candidates for 5-Fraction Stereotactic MRI-Guided Adaptive Radiotherapy (SMART) for Locally Advanced Pancreatic Cancer

Stereotactic magnetic resonance image-guided adaptive radiotherapy (SMART) allows for the safe delivery of biologically effective doses (BED10 ∼ 100 Gy) to patients with pancreatic cancer who otherwise have limited therapeutic avenues. In this study, we analyze long-term outcomes in the largest cohort of patients with borderline-resectable (BR), locally advanced (LA), or medically inoperable (MI) pancreatic cancer treated with a 5-fraction SMART technique. A single institution analysis of patients with BR, LA, or MI pancreatic cancer treated with SMART between 2015 and 2021 was performed. Patients with locally recurrent disease, non-adenocarcinoma histology, de-novo metastatic disease, or who did not receive induction chemotherapy were excluded. Baseline and treatment characteristics were collected. Local control (LC), progression free survival (PFS), and overall survival (OS) were calculated using the Kaplan-Meier method, and factors associated with outcomes were evaluated using Cox regression analyses. Oncologic outcomes measured from time of initial diagnosis; local control defined as freedom from local progression. A total of 129 patients were reviewed. Median age at diagnosis was 67 years. The majority were male (60%) and White (84%). 23% of patients had an ECOG 2. Most patients had LA disease (66%), followed by BR (20%) and MI (14%). Median follow up was 17.0 months (6-61 months). Median LC was not reached, and LC was 81%, 54%, and 48% at 1, 2, and 3-years, respectively. Median PFS was 12.9 months [95% confidence interval 11.8-14.71] with 1, 2, and 3-year PFS of 60%, 20%, and 7%, respectively. Median OS was 17.7 months [15.7-19.7] with 1, 2, and 3-year OS of 78%, 28%, 11%, respectively. On univariate analysis, increased duration of induction chemotherapy had a statistically significant impact on PFS and OS. Those receiving equal to or greater than 4 months of induction chemotherapy had a median OS of 19.2 months [17.2-21.2] as compared to 13.6 [11.9-15.3] for those with less than 4 months. In this patient population which included a large portion of patients with ECOG of 2 or greater and those deemed MI, a 5-fraction SMART regimen yielded durable long-term LC. The impact of increasing duration of induction chemotherapy underlies the importance of patient selection and improved understanding of tumor-specific biology when selecting patient's with locally advanced pancreatic cancer for aggressive local therapy.

Adaptive Auto-Segmentation for MRI-Guided Online Adaptive Radiotherapy of Cervical Carcinoma

Accurate and efficient delineation of organs and targets on session images is critical in MRI-guided online adaptive radiotherapy (MRgOART). This study proposes a registration-guided deep learning image segmentation framework to assist online delineation of cervical carcinoma. A total of 300 T2-weighted MR images were acquired for patients with cervical carcinoma treated by a 1.5T Unity MR-Linac. The CTV, bladder, rectum, pelvic bone and femoral joints were delineated on each MRI by the same radiation oncologist. To overcome these obstacles to online MRI segmentation, we propose a registration-guided DL (RgDL) segmentation framework that integrates image registration algorithms and DL segmentation models. Firstly, the DL segmentation model was trained using nnU-net. Then, for each treatment fraction, the deformable image registration (DIR) algorithm generates initial contours from previous treatment fraction, which were used as guidance by DL model to obtain the accurate current segmentation. The segmentation accuracy of alone DIR, DL and RgDL were evaluated by dice similarity coefficients (DSC) and other distance-based metrics. Compared to the baseline approaches using the DIR and the DL alone, RgDL achieved a DSC of 91.12% on CTV, higher than DIR and DL alone by 15.54% and 10.13%. The DSC of RgDL were improved to 95.58%, 93.65%, 87.8% and 94.84% for bladder, pelvic bone, rectum and femoral joints, higher than DIR and DL alone by 9.61% on average. The proposed adaptive auto-segmentation method can achieve accurate and efficient segmentation and potentially overcome these obstacles to MRgOART.

Treatment Outcomes and Toxicity Profile of MRI-Guided Gated-Real Time Online Adaptive Stereotactic Body Radiotherapy to Patients with Pancreatic Tumors

Stereotactic body radiation therapy (SBRT) to patients with inoperable pancreas cancer has shown promising outcomes. Dose escalation is challenging given the associated risks to nearby organs at risk and requires treatment plan adaptation and motion management. This study reports the treatment related adverse events and treatment outcomes of MRI-guided SBRT utilizing gated-real time online adaptive radiotherapy to patients with pancreatic tumors. This is a single institution retrospective IRB approved study and included patients with pancreatic tumors who were treated with MRI-guided SBRT utilizing gated-real time online adaptive radiotherapy, consecutively between 2019 and 2022. All patients were treated with 0.35T MRI linear accelerator. All patients' charts and radiation plans were reviewed for this study. The study included 25 patients treated consecutively to 125 radiation fractions with MRI-guided SBRT. The study included 15 females and 10 males, 19 white, 2 Asians, 1 Latin American and 2 African Americans. The median age was 74, and all patients had pancreatic adenocarcinoma (92%) except two patients who had biopsy proven renal cell carcinoma metastatic to the pancreas without evidence of disease elsewhere. Most patients (68%) received chemotherapy (FOLFIRINOX or Gemcitabine / Protein-bound paclitaxel) prior to SBRT. The median dose to gross target volume (GTV) was 50 Gy, and to planning target volume (PTV) was 35 Gy. All patients were treated in 5 radiation fractions. Thirteen patients (52%) received elective nodal irradiation (ENI). All patients had at least a single real-time online adaptive replanning (median 3 fractions, range 1-5 fractions). All treatment fractions were gated (100%) with MRI guidance. The 1-, 2-, & 3- year local-regional control (LRC) were 81%, 57%, & 57% respectively (Median 16 months). The 1-, 2-, & 3- year Distant Control (DC) were 81%, 74%, & 56% respectively (Median 14 months). The 1-, 2-, 3-year overall survival (OS) were 77%, 35%, & 24% (Median 21 months). Planning Target Volume (PTV) dose ≥40Gy was significantly associated with improved local-regional control (p = 0.02). Gross Target Volume (GTV) dose <50Gy was significantly associated with lower DC (p = 0.03). ENI showed a trend towards improved local-regional control but was not statistically significant (p = 0.1). None of the patients experienced ≥ grade 3 toxicities. Most common adverse event were grades 1 or 2 fatigue (24%), nausea (16%), and abdominal discomfort (12%). In this cohort, MRI-guided SBRT utilizing gated-real time online adaptive radiotherapy was a safe and effective approach for patients with pancreatic tumors who are not surgical candidates. In this study, dose escalation was significantly associated with improved local-regional (PTV ≥40 Gy) and distant control (GTV ≥50Gy). None of the patients experienced grade ≥3 radiation induced adverse events.

MRI-Guided Radiation Therapy for Prostate Cancer: The Next Frontier in Ultrahypofractionation.

Technological advances in MRI-guided radiation therapy (MRIgRT) have improved real-time visualization of the prostate and its surrounding structures over CT-guided radiation therapy. Seminal studies have demonstrated safe dose escalation achieved through ultrahypofractionation with MRIgRT due to planning target volume (PTV) margin reduction and treatment gating. On-table adaptation with MRI-based technologies can also incorporate real-time changes in target shape and volume and can reduce high doses of radiation to sensitive surrounding structures that may move into the treatment field. Ongoing clinical trials seek to refine ultrahypofractionated radiotherapy treatments for prostate cancer using MRIgRT. Though these studies have the potential to demonstrate improved biochemical control and reduced side effects, limitations concerning patient treatment times and operational workflows may preclude wide adoption of this technology outside of centers of excellence. In this review, we discuss the advantages and limitations of MRIgRT for prostate cancer, as well as clinical trials testing the efficacy and toxicity of ultrafractionation in patients with localized or post-prostatectomy recurrent prostate cancer.

Human factors in the clinical implementation of deep learning-based automated contouring of pelvic organs at risk for MRI-guided radiotherapy.

Deep neural nets have revolutionized the science of auto-segmentation and present great promise for treatment planning automation. However, little data exists regarding clinical implementation and human factors. We evaluated the performance and clinical implementation of a novel deep learning-based auto-contouring workflow for 0.35T magnetic resonance imaging (MRI)-guided pelvic radiotherapy, focusing on automation bias and objective measures of workflow savings. An auto-contouring model was developed using a UNet-derived architecture for the femoral heads, bladder, and rectum in 0.35T MR images. Training data was taken from 75 patients treated with MRI-guided radiotherapy at our institution. The model was tested against 20 retrospective cases outside the training set, and subsequently was clinically implemented. Usability was evaluated on the first 30 clinical cases by computing Dice coefficient (DSC), Hausdorff distance (HD), and the fraction of slices that were used un-modified by planners. Final contours were retrospectively reviewed by an experienced planner and clinical significance of deviations was graded as negligible, low, moderate, and high probability of leading to actionable dosimetric variations. In order to assess whether the use of auto-contouring led to final contours more or less in agreement with an objective standard, 10 pre-treatment and 10 post-treatment blinded cases were re-contoured from scratch by three expert planners to get expert consensus contours (EC). EC was compared to clinically used (CU) contours using DSC. Student's t-test and Levene's statistic were used to test statistical significance of differences in mean and standard deviation, respectively. Finally, the dosimetric significance of the contour differences were assessed by comparing the difference in bladder and rectum maximum point doses between EC and CU before and after the introduction of automation. Median (interquartile range) DSC for the retrospective test data were 0.92(0.02), 0.92(0.06), 0.93(0.06), 0.87(0.04) for the post-processed contours for the right and left femoral heads, bladder, and rectum, respectively. Post-implementation median DSC were 1.0(0.0), 1.0(0.0), 0.98(0.04), and 0.98(0.06), respectively. For each organ, 96.2, 95.4, 59.5, and 68.21 percent of slices were used unmodified by the planner. DSC between EC and pre-implementation CU contours were 0.91(0.05*), 0.91*(0.05*), 0.95(0.04), and 0.88(0.04) for right and left femoral heads, bladder, and rectum, respectively. The corresponding DSC for post-implementation CU contours were 0.93(0.02*), 0.93*(0.01*), 0.96(0.01), and 0.85(0.02) (asterisks indicate statistically significant difference). In a retrospective review of contours used for planning, a total of four deviating slices in two patients were graded as low potential clinical significance. No deviations were graded as moderate or high. Mean differences between EC and CU rectum max-doses were 0.1±2.6Gy and -0.9±2.5Gy for pre- and post-implementation, respectively. Mean differences between EC and CU bladder/bladder wall max-doses were -0.9±4.1Gy and 0.0±0.6Gy for pre- and post-implementation, respectively. These differences were not statistically significant according to Student's t-test. We have presented an analysis of the clinical implementation of a novel auto-contouring workflow. Substantial workflow savings were obtained. The introduction of auto-contouring into the clinical workflow changed the contouring behavior of planners. Automation bias was observed, but it had little deleterious effect on treatment planning.

Hypothyroidism following Radiotherapy for Head and Neck Cancer: A Systematic Review of the Literature and Opportunities to Improve the Therapeutic Ratio.

(1) Background: Radiotherapy (RT) is a central component for the treatment of many head and neck cancers. In this systematic review of the literature, we aimed to characterize and quantify the published evidence on RT-related hypothyroidism, including estimated incidence, clinical risk factors, and dosimetric parameters that may be used to guide clinical decision making. Furthermore, we aimed to identify potential areas of improvement in the prevention and clinical management of RT-induced hypothyroidism, including the role of modern advanced therapeutic techniques. (2) Methods: We conducted a systemic review of the literature in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. PubMed and Google Scholar were searched to identify original research articles describing the incidence, mechanism, dosimetry, treatment, or prevention of radiation-related hypothyroidism for adults receiving RT for the treatment of head and neck cancers. The snowball method was used to identify additional articles. For identified articles, we tabulated several datapoints, including publication date, patient sample size, estimated hypothyroidism incidence, cancer site/type, follow-up period, radiation modality and technique, use of multimodality therapy, method of thyroid function evaluation, and proposed dosimetric predictors of hypothyroidism. (3) Results: One hundred and eleven articles met inclusion criteria, reflecting a range of head and neck cancer subtypes. There was a large variation in the estimated incidence of RT-related hypothyroidism, with a median estimate of 36% (range 3% to 79%). Reported incidence increased in later publication dates, which was likely related to improved screening and longer follow up. There were a wide variety of predictive metrics used to identify patients at high risk of hypothyroidism, the most common of which were volumetric and mean dosimetrics related to the thyroid gland (Vxx%, Dmean). More recently, there has been increasing evidence to suggest that the thyroid gland volume itself and the volume of the thyroid gland spared from high-dose radiation (VSxx) may better predict thyroid function after RT. There were no identified studies investigating the role of advanced radiotherapeutic techniques such as MRI-guided RT or particle therapy to decrease RT-related hypothyroidism. Conclusions: Hypothyroidism is a common toxicity resulting from therapeutic radiation for head and neck cancer with recent estimates suggesting 40-50% of patients may experience hypothyroidism after treatment. Dosimetric predictive models are increasingly able to accurately identify patients at risk of hypothyroidism, especially those utilizing thyroid VS metrics. Further investigation regarding the potential for advanced radiotherapeutic therapies to decrease RT-induced thyroid dysfunction is needed.

Development of Prostate Bed Delineation Consensus Guidelines for Magnetic Resonance Image-Guided Radiotherapy and Assessment of Its Effect on Interobserver Variability

Background and purposeThe use of MRI in radiotherapy planning is becoming more widespread, particularly with the emergence of MRI-guided radiotherapy (MRIgRT) systems. Existing guidelines for defining the prostate bed clinical target volume (CTV) show considerable heterogeneity. This study aims to establish baseline interobserver variability (IOV) for prostate bed CTV contouring on MRI, develop international consensus guidelines and evaluate its effect on IOV. Methods and MaterialsParticipants delineated the CTV on three MRI scans, obtained from the xxx xxx MR-Linac, as per their normal practice. Radiation oncologist contours were visually examined for discrepancies and interobserver comparisons were evaluated against Simultaneous Truth and Performance Level Estimate (STAPLE) contours using overlap metrics (Dice similarity coefficient and Cohen's Kappa), distance metrics (mean distance to agreement and Hausdorff distance) and volume measurements.. A literature review of post-radical prostatectomy local recurrence patterns was performed and presented alongside IOV results to the participants. Consensus guidelines were collectively constructed and IOV assessment was repeated using these guidelines. ResultsSixteen radiation oncologists’ contours were included in the final analysis. Visual evaluation demonstrated significant differences in the superior, inferior and anterior borders. Baseline IOV assessment indicated moderate agreement for the overlap metrics whilst volume and distance metrics demonstrated greater variability. Consensus for optimal prostate bed CTV boundaries was established during a virtual meeting. Post-guideline development, a decrease in IOV was observed. The maximum volume ratio decreased from 4.7 to 3.1 and volume coefficient of variation reduced from 40% to 34%. The mean Dice similarity coefficient rose from 0.72 to 0.75 and the mean distance to agreement decreased from 3.63mm to 2.95mm. ConclusionsInterobserver variability in prostate bed contouring exists amongst international genitourinary experts, although this is lower than previously reported. Consensus guidelines for MRI-based prostate bed contouring have been developed and this has resulted in an improvement in contouring concordance. However, IOV persists and strategies such as an education program, development of a contouring atlas and further refinement of the guidelines may lead to additional improvements.

Efficient segmentation using domain adaptation for MRI-guided and CBCT-guided online adaptive radiotherapy

BackgroundDelineation of regions of interest (ROIs) is important for adaptive radiotherapy (ART) but it is also time consuming and labor intensive. AimThis study aims to develop efficient segmentation methods for magnetic resonance imaging-guided ART (MRIgART) and cone-beam computed tomography-guided ART (CBCTgART). Materials and methodsMRIgART and CBCTgART studies enrolled 242 prostate cancer patients and 530 nasopharyngeal carcinoma patients, respectively. A public dataset of CBCT from 35 pancreatic cancer patients was adopted to test the framework. We designed two domain adaption methods to learn and adapt the features from planning computed tomography (pCT) to MRI or CBCT modalities. The pCT was transformed to synthetic MRI (sMRI) for MRIgART, while CBCT was transformed to synthetic CT (sCT) for CBCTgART. Generalized segmentation models were trained with large popular data in which the inputs were sMRI for MRIgART and pCT for CBCTgART. Finally, the personalized models for each patient were established by fine-tuning the generalized model with the contours on pCT of that patient. The proposed method was compared with deformable image registration (DIR), a regular deep learning (DL) model trained on the same modality (DL-regular), and a generalized model in our framework (DL-generalized). ResultsThe proposed method achieved better or comparable performance. For MRIgART of the prostate cancer patients, the mean dice similarity coefficient (DSC) of four ROIs was 87.2%, 83.75%, 85.36%, and 92.20% for the DIR, DL-regular, DL-generalized, and proposed method, respectively. For CBCTgART of the nasopharyngeal carcinoma patients, the mean DSC of two target volumes were 90.81% and 91.18%, 75.17% and 58.30%, for the DIR, DL-regular, DL-generalized, and the proposed method, respectively. For CBCTgART of the pancreatic cancer patients, the mean DSC of two ROIs were 61.94% and 61.44%, 63.94% and 81.56%, for the DIR, DL-regular, DL-generalized, and the proposed method, respectively. ConclusionThe proposed method utilizing personalized modeling improved the segmentation accuracy of ART.

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

BackgroundUltra-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.MethodsA 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.DiscussionThe 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 registrationClinicalTrials.gov Identifier: NCT04422132. Date of registration: June 9, 2020.

Feasibility of quantitative diffusion-weighted imaging during intra-procedural MRI-guided brachytherapy of locally advanced cervical and vaginal cancers

PurposeTo determine the feasibility of quantitative apparent diffusion coefficient (ADC) acquisition during magnetic resonance imaging-guided brachytherapy (MRgBT) using reduced field-of-view (rFOV) diffusion-weighted imaging (DWI). Methods and MaterialsT2-weighted (T2w) MR and full-FOV single-shot echo planar (ssEPI) DWI were acquired in 7 patients with cervical or vaginal malignancy at baseline and prior to brachytherapy, while rFOV-DWI was acquired during MRgBT following brachytherapy applicator placement. The gross target volume (GTV) was contoured on the T2w images and registered to the ADC map. Voxels at the GTV's maximum Maurer distance comprised a central sub-volume (GTVcenter). Contour ADC mean and standard deviation were compared between timepoints using repeated measures ANOVA. ResultsssEPI-DWI mean ADC increased between baseline and prebrachytherapy from 1.03 ± 0.18 10−3 mm2/s to 1.34 ± 0.28 10−3 mm2/s for the GTV (p = 0.06) and from 0.84 ± 0.13 10−3 mm2/s to 1.26 ± 0.25 10−3 mm2/s at the level of the GTVcenter (p = 0.03), consistent with early treatment response. rFOV-DWI during MRgBT demonstrated mean ADC values of 1.28 ± 0.14 10−3 mm2/s and 1.28 ± 0.19 10−3 mm2/s for the GTV and GTVcenter, respectively (p = 0.02 and p = 0.03 relative to baseline). No significant differences were observed between ssEPI-DWI and rFOV-DWI ADC measurements. ConclusionsQuantitative ADC measurement in the setting of MRI guided brachytherapy implant placement for cervical and vaginal cancers is feasible using rFOV-DWI, with comparable mean ADC comparable to prebrachytherapy ssEPI-DWI, and may enable MRI-guided radiotherapy targeting of low ADC, radiation resistant sub-volumes of tumor.