Clinical implementation and feasibility of long-course fractionated MR-guided chemoradiotherapy for patients with esophageal cancer: An R-IDEAL stage 1b/2a evaluation of technical innovation

Purpose: This R-Ideal stage 1b/2a study describes the workflow and feasibility of long-course fractionated online adaptive MR-guided chemoradiotherapy with reduced CTV-to-PTV margins on the 1.5T MR-Linac for patients with esophageal cancer. Methods: Patients with esophageal cancer scheduled to undergo chemoradiation were treated on a 1.5T MR-Linac. Daily MR-images were acquired for online contour adaptation and replanning. Contours were manually adapted to match the daily anatomy and an isotropic CTV-to-PTV margin of 6 mm was applied. Time was recorded for all individual steps in the workflow. Feasibility and patient tolerability were defined as on-table time of ≤60 min and completion of >95% of the fractions on the MR-Linac, respectively. Positioning verification and post-treatment MRIs were retrospectively analyzed and dosimetric parameters were compared to standard non-adaptive conventional treatment plans. Results: Nine patients with esophageal cancer were treated with chemoradiation; eight patients received 41.4 Gy in 23 fractions and one received 50.4 Gy in 28 fractions. Four patients received all planned fractions on the MR-Linac, whereas for two patients >5% of fractions were rescheduled to a conventional linac for reasons of discomfort. A total of 183 (86%) of 212 scheduled fractions were successfully delivered on the MR-Linac. Three fractions ended prematurely due to technical issues and 26 fractions were rescheduled on a conventional linac due to MR-Linac downtime (n = 10), logistical reasons (n = 3) or discomfort (n = 13). The median time per fraction was 53 min (IQR = 3 min). Daily adapted MR-Linac plans had similar target coverage, whereas dose to the organs-at-risk was significantly reduced compared to conventional treatment (26% and 12% reduction in mean lung and heart dose, respectively). Conclusion: Daily online adaptive fractionated chemoradiotherapy with reduced PTV margins is moderately feasible for esophageal cancer and results in better sparing of heart and lungs. Future studies should focus on further optimization and acceleration of the current workflow

Prostate intrafraction motion during the preparation and delivery of MR-guided radiotherapy sessions on a 1.5T MR-Linac

Purpose: To evaluate prostate intrafraction motion using MRI during the full course of online adaptive MR-Linac radiotherapy (RT) fractions, in preparation of MR-guided extremely hypofractionated RT. Material and methods: Five low and intermediate risk prostate cancer patients were treated with 20 × 3.1 Gy fractions on a 1.5T MR-Linac. Each fraction, initial MRI (Pre) scans were obtained at the start of every treatment session. Pre-treatment planning MRI contours were propagated and adapted to this Pre scan after which plan re-optimization was started in the treatment planning system followed by dose delivery. 3D Cine-MR imaging was started simultaneously with beam-on and acquired over the full beam-on period. Prostate intrafraction motion in this cine-MR was determined with a previously validated soft-tissue contrast based tracking algorithm. In addition, absolute accuracy of the method was determined using a 4D phantom. Results: Prostate motion was completely automatically determined over the full on-couch period (approx. 45 min) with no identified mis-registrations. The translation 95% confidence intervals are within clinically applied margins of 5 mm, and plan adaption for intrafraction motion was required in only 4 out of 100 fractions. Conclusion: This is the first study to investigate prostate intrafraction motions during entire MR-guided RT sessions on an MR-Linac. We have shown that high quality 3D cine-MR imaging and prostate tracking during RT is feasible with beam-on. The clinically applied margins of 5 mm have proven to be sufficient for these treatments and may potentially be further reduced using intrafraction plan adaptation guided by cine-MR imaging

3-Dimensional target coverage assessment for MRI guided esophageal cancer radiotherapy

Purpose: This study aimed to quantify the coverage probability for esophageal cancer radiotherapy as a function of a preset margin for online MR-guided and (CB)CT-guided radiotherapy. Methods: Thirty esophageal cancer patients underwent six T2-weighted MRI scans, 1 prior to treatment and 5 during neoadjuvant chemoradiotherapy at weekly intervals. Gross tumor volume (GTV) and clinical target volume (CTV) were delineated on each individual scan. Follow-up scans were rigidly aligned to the bony anatomy and to the clinical target volume itself, mimicking two online set-up correction strategies: a conventional CBCT-guided set-up and a MR-guided set-up, respectively. Geometric coverage probability of the propagated CTVs was assessed for both set-up strategies by expanding the reference CTV with an isotropic margin varying from 0 mm to 15 mm with an increment of 1 mm. Results: A margin of 10 mm could resolve the interfractional changes for 118 out of the 132 (89%) analyzed fractions when applying a bone-match registration, whereas the CTV was adequately covered in 123 (93%) fractions when the registration was directly performed at the CTV itself (soft-tissue registration). Closer analyses revealed that target coverage violation predominantly occurred for distal tumors near the junction and into the cardia. Conclusion: Online MR-guided soft-tissue registration protocols exhibited modest improvements of the geometric target coverage probability as compared to online CBCT-guided bone match protocols. Therefore, highly conformal target irradiation using online MR-guidance can only be achieved by implementing on-table adaptive workflows where new treatment plans are daily generated based on the anatomy of the day

Integration of quantitative imaging biomarkers in clinical trials for MR-guided radiotherapy: Conceptual guidance for multicentre studies from the MR-Linac Consortium Imaging Biomarker Working Group

Quantitative imaging biomarkers (QIBs) derived from MRI techniques have the potential to be used for the personalised treatment of cancer patients. However, large-scale data are missing to validate their added value in clinical practice. Integrated MRI-guided radiotherapy (MRIgRT) systems, such as hybrid MRI-linear accelerators, have the unique advantage that MR images can be acquired during every treatment session. This means that high-frequency imaging of QIBs becomes feasible with reduced patient burden, logistical challenges, and costs compared to extra scan sessions. A wealth of valuable data will be collected before and during treatment, creating new opportunities to advance QIB research at large. The aim of this paper is to present a roadmap towards the clinical use of QIBs on MRIgRT systems. The most important need is to gather and understand how the QIBs collected during MRIgRT correlate with clinical outcomes. As the integrated MRI scanner differs from traditional MRI scanners, technical validation is an important aspect of this roadmap. We propose to integrate technical validation with clinical trials by the addition of a quality assurance procedure at the start of a trial, the acquisition of in vivo test-retest data to assess the repeatability, as well as a comparison between QIBs from MRIgRT systems and diagnostic MRI systems to assess the reproducibility. These data can be collected with limited extra time for the patient. With integration of technical validation in clinical trials, the results of these trials derived on MRIgRT systems will also be applicable for measurements on other MRI systems

Preoperative image-guided identification of response to neoadjuvant chemoradiotherapy in esophageal cancer (PRIDE) : A multicenter observational study

Background: Nearly one third of patients undergoing neoadjuvant chemoradiotherapy (nCRT) for locally advanced esophageal cancer have a pathologic complete response (pCR) of the primary tumor upon histopathological evaluation of the resection specimen. The primary aim of this study is to develop a model that predicts the probability of pCR to nCRT in esophageal cancer, based on diffusion-weighted magnetic resonance imaging (DW-MRI), dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and 18F-fluorodeoxyglucose positron emission tomography with computed tomography (18F-FDG PET-CT). Accurate response prediction could lead to a patient-tailored approach with omission of surgery in the future in case of predicted pCR or additional neoadjuvant treatment in case of non-pCR. Methods: The PRIDE study is a prospective, single arm, observational multicenter study designed to develop a multimodal prediction model for histopathological response to nCRT for esophageal cancer. A total of 200 patients with locally advanced esophageal cancer - of which at least 130 patients with adenocarcinoma and at least 61 patients with squamous cell carcinoma - scheduled to receive nCRT followed by esophagectomy will be included. The primary modalities to be incorporated in the prediction model are quantitative parameters derived from MRI and 18F-FDG PET-CT scans, which will be acquired at fixed intervals before, during and after nCRT. Secondary modalities include blood samples for analysis of the presence of circulating tumor DNA (ctDNA) at 3 time-points (before, during and after nCRT), and an endoscopy with (random) bite-on-bite biopsies of the primary tumor site and other suspected lesions in the esophagus as well as an endoscopic ultrasonography (EUS) with fine needle aspiration of suspected lymph nodes after finishing nCRT. The main study endpoint is the performance of the model for pCR prediction. Secondary endpoints include progression-free and overall survival. Discussion: If the multimodal PRIDE concept provides high predictive performance for pCR, the results of this study will play an important role in accurate identification of esophageal cancer patients with a pCR to nCRT. These patients might benefit from a patient-tailored approach with omission of surgery in the future. Vice versa, patients with non-pCR might benefit from additional neoadjuvant treatment, or ineffective therapy could be stopped. Trial registration: The article reports on a health care intervention on human participants and was prospectively registered on March 22, 2018 under ClinicalTrials.gov Identifier: NCT03474341