The integration of magnetic resonance imaging (MRI) for guidance in external beam radiotherapy has faced significant research and development efforts in recent years. The current availability of linear accelerators with an embedded MRI unit, providing volumetric imaging at excellent soft tissue contrast, is expected to provide novel possibilities in the implementation of image-guided adaptive radiotherapy (IGART) protocols. This study reviews open medical physics issues in MR-guided radiotherapy (MRgRT) implementation, with a focus on current approaches and on the potential for innovation in IGART. Daily imaging in MRgRT provides the ability to visualize the static anatomy, to capture internal tumor motion and to extract quantitative image features for treatment verification and monitoring. Those capabilities enable the use of treatment adaptation, with potential benefits in terms of personalized medicine. The use of online MRI requires dedicated efforts to perform accurate dose measurements and calculations, due to the presence of magnetic fields. Likewise, MRgRT requires dedicated quality assurance (QA) protocols for safe clinical implementation. Reaction to anatomical changes in MRgRT, as visualized on daily images, demands for treatment adaptation concepts, with stringent requirements in terms of fast and accurate validation before the treatment fraction can be delivered. This entails specific challenges in terms of treatment workflow optimization, QA, and verification of the expected delivered dose while the patient is in treatment position. Those challenges require specialized medical physics developments towards the aim of fully exploiting MRI capabilities. Conversely, the use of MRgRT allows for higher confidence in tumor targeting and organs-at-risk (OAR) sparing. The systematic use of MRgRT brings the possibility of leveraging IGART methods for the optimization of tumor targeting and quantitative treatment verification. Although several challenges exist, the intrinsic benefits of MRgRT will provide a deeper understanding of dose delivery effects on an individual basis, with the potential for further treatment personalization.

MRI-treatment units enable 2D cine-MRI centred in the tumour for motion detection in radiotherapy, but they lack 3D information due to spatio-temporal limits. To derive time-resolved 3D information, different approaches have been proposed in the literature, but a rigorous comparison among these strategies has not yet been performed. The goal of this study is to quantitatively investigate five published strategies that derive timeresolved volumetric MRI in MRI-guided radiotherapy: Propagation, out-of-plane motion compensation, Fayad model, ROI-based model and Stemkens model. Comparisons were performed using an MRI digital phantom generated with six different patient-derived motion signals and tumour-shapes. An average 4D cycle was generated as well as 2D cine-MRI data with corresponding 3D in-room ground truth. Quantitative analysis was performed by comparing the estimated 3D volume to the ground truth available for each 2D cine-MRI sample. A grouped patient statistical analysis was performed to evaluate the performance of the selected methods, in case of tumour tracking or motion estimation of the whole anatomy. Analyses were also performed based on patient characteristics. Quantitative ranking of the investigated methods highlighted that Propagation and ROIbased model strategies achieved an overall median tumour centre of mass 3D distance from the ground truth of 1.1mm and 1.3mm respectively, and a diaphragm distance below 1.6mm. Higher errors and variabilities were instead obtained for other methods, which lack the ability to compensate for in-room variations and to account for regional changes. These results were especially evident when further analysing patient characteristics, where errors above 2mm/5mm in tumour/diaphragm were found for more irregular breathing patterns in case of out-of-plane motion compensation, Fayad and Stemkens models. These findings suggest the potential of the proposed in-silico framework to develop and compare strategies to estimate time-resolved 3DMRI in MRI-guided radiotherapy.

Skull-base chordoma (SBC) can be treated with carbon ion radiotherapy (CIRT) to improve local control (LC). The study aimed to explore the role of multi-parametric radiomic, dosiomic and clinical features as prognostic factors for LC in SBC patients undergoing CIRT. Before CIRT, 57 patients underwent MR and CT imaging, from which tumour contours and dose maps were obtained. MRI and CT-based radiomic, and dosiomic features were selected and fed to two survival models, singularly or by combining them with clinical factors. Adverse LC was given by in-field recurrence or tumour progression. The dataset was split in development and test sets and the models’ performance evaluated using the concordance index (C-index). Patients were then assigned a low- or high-risk score. Survival curves were estimated, and risk groups compared through log-rank tests (after Bonferroni correction α = 0.0083). The best performing models were built on features describing tumour shape and dosiomic heterogeneity (median/interquartile range validation C-index: 0.80/024 and 0.79/0.26), followed by combined (0.73/0.30 and 0.75/0.27) and CT-based models (0.77/0.24 and 0.64/0.28). Dosiomic and combined models could consistently stratify patients in two significantly different groups. Dosiomic and multi-parametric radiomic features showed to be promising prognostic factors for LC in SBC treated with CIRT.

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Purpose Proton therapy could benefit from noninvasively gaining tumor microstructure information, at both planning and monitoring stages. The anatomical location of brain tumors, such as meningiomas, often hinders the recovery of such information from histopathology, and conventional noninvasive imaging biomarkers, like the apparent diffusion coefficient (ADC) from diffusion‐weighted MRI (DW‐MRI), are nonspecific. The aim of this study was to retrieve discriminative microstructural markers from conventional ADC for meningiomas treated with proton therapy. These markers were employed for tumor grading and tumor response assessment. Methods DW‐MRIs from patients affected by meningioma and enrolled in proton therapy were collected before (n = 35) and 3 months after (n = 25) treatment. For the latter group, the risk of an adverse outcome was inferred by their clinical history. Using Monte Carlo methods, DW‐MRI signals were simulated from packings of synthetic cells built with well‐defined geometrical and diffusion properties. Patients’ ADC was modeled as a weighted sum of selected simulated signals. The weights that best described a patient’s ADC were determined through an optimization procedure and used to estimate a set of markers of tumor microstructure: diffusion coefficient (D), volume fraction (vf), and radius (R). Apparent cellularity (ρapp) was estimated from vf and R for an easier clinical interpretability. Differences between meningothelial and atypical subtypes, and low‐ and high‐grade meningiomas were assessed with nonparametric statistical tests, whereas sensitivity and specificity with ROC analyses. Similar analyses were performed for patients showing low or high risk of an adverse outcome to preliminary evaluate response to treatment. Results Significant (P < 0.05) differences in median ADC, D, vf, R, and ρapp values were found when comparing meningiomas’ subtypes and grades. ROC analyses showed that estimated microstructural parameters reached higher specificity than ADC for subtyping (0.93 for D and vf vs 0.80 for ADC) and grading (0.75 for R vs 0.67 for ADC). High‐ and low‐risk patients showed significant differences in ADC and microstructural parameters. The skewness of ρapp was the parameter with highest AUC (0.90) and sensitivity (0.75). Conclusions Matching measured with simulated ADC yielded a set of potential imaging markers for meningiomas grading and response monitoring in proton therapy, showing higher specificity than conventional ADC. These markers can provide discriminative information about spatial patterns of tumor microstructure implying important advantages for patient‐specific proton therapy workflows.

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