MRinRT: Swansea University and SWWCC Collaboration Study.

Background Advances in radiotherapy technology have allowed treatments to become more conformal with steeper dose gradients, meaning target volumes are smaller and dose to surrounding normal tissues reduced. This is possible, in part, due to improvements in imaging used in radiotherapy planning and in the development of Intensity Modulated Radiotherapy. The current standard of care for most tumour sites is for target volumes to be delineated on a planning CT scan, with additional information from diagnostic imaging such as MRI or PET which can be fused with the planning CT scan. MRI is known to give clearer images of soft tissues and tissue planes allowing for more accurate target volume delivery. The fusion of MRI to the planning CT scan to aid target volume delineation is a standard of care for certain tumour sites, e.g. brain, but not in others such as oesophagogastric cancers.

Optimisation of MRI protocols for Novel Tumour sites Our group undertook a scoping review into the use of MRI for radiotherapy target volume delineation for gastric cancers and has found that although there is evidence of improved contrast resolution with MRI in comparison to CT, clinical utility for radiotherapy planning is yet to be demonstrated. The research group has also performed a pilot study assessing the addition MRI to CT planning scans for radiotherapy planning for gastric cancers which demonstrated potential for clinical benefit. The limitations of this study were small patient numbers and that MRIs used were diagnostic scans optimised for liver imaging rather than gastric cancers. An issue identified was poor anatomical correlation of the MRI to CT planning scan due to differences in stomach filling. Our study will build on this work to optimise the MRI sequences for improved clarity of imaging and to identify and standardise optimal pre-examination preparation.

It is possible to acquire a range of MRI sequences with each giving different information. Furthermore, contrast agents may be used during image acquisition to improve visualisation of the target of interest. The choice of contrast agent and sequences depends on whether the aim is to assess the size/location of the tumour or to assess a functional aspect of the tumour allowing the potential to act as a predictive or prognostic imaging biomarker. This study aims to optimise the choice of MRI sequences for target volume delineation in various anatomical regions and to assess the potential impact of MR imaging on radiotherapy planning in anatomical regions where it is not currently routine practice. In the UK there is an ongoing similar study that aims to optimise the MRI sequences for use on MRI-Linear Accelerator (MR-Linac) machines. Our study will follow similar principles in order to optimise MRI sequences for radiotherapy planning from stand-alone MRI scanners. The investigators postulate that our findings will be more generalisable compared to the recruiting MR-Linac study, as the vast majority of UK Oncology Centres do not have access to MR-Linac machines.

The potential for an MRI-Adaptive workflow Radical (curative-intent) or neoadjuvant radiotherapy treatment is often delivered as multiple treatment fractions given over several weeks. The current standard of care is to generate a radiotherapy plan based on a pre-treatment CT planning scan with guidance from additional diagnostic investigations depending on tumour site. Unless an issue is detected during treatment, e.g. detected by the on-treatment cone-beam CT(CBCT) set-up verification process, the patient would complete their whole course of treatment as per the radiotherapy plan based on the pre-treatment CT planning scan. This does not account for changes in the position, size or shape of the tumour that occur over the whole radiotherapy treatment course. Clinicians therefore add margins around the target volume to account for these potential uncertainties, leading to a larger target volumes and increased dose to surrounding normal structures, which can lead to increased toxicity. A potential solution to this issue could be to re-image and re-plan during the treatment course, termed 'adaptive radiotherapy'. MRI is already utilised for adapted radiotherapy workflow, particularly when an MR-Linac is available. This study will explore whether a diagnostic MRI may be used for RT plan adaptation. Of note, similar strategies have been assessed using CBCT with a 'plan of the day' approach in bladder cancer and there is also ongoing work assessing the benefit of adapting RT based on a mid-treatment PET scan in the PEARL study for oropharyngeal cancers.

Exploring Imaging Biomarkers MRI can also be used to determine quantitative information about functional biological processes, via the use of quantitative imaging biomarkers. These are defined as 'an objective characteristic derived from an in vivo image measured on a ratio or interval scale as an indicator of normal biological processes, pathogenic processes, or a response to a therapeutic intervention'. Current protocols include sequences which can be used to estimate functional characteristics of a tumour and surrounding tissues which could act as a biomarker to predict response to treatment or likelihood of a patient developing toxicity from treatment. However, there is limited validation of these biomarkers in clinical settings, in particular there is a lack of data assessing the repeatability and reproducibility.

Rationale and Risks/Benefits MRI is a non-invasive imaging technique which does not rely on ionising radiation exposure. It gives clearer images of soft tissues and tissue planes allowing for more accurate target volume delineation. More accurate delineation may allow clinicians to use smaller margins and therefore to spare surrounding normal tissues from radiotherapy induced damage thereby reducing toxicity.

This is a non-interventional, prospective study and therefore the investigators do not anticipate any serious adverse events directly relating to the scanning protocols. Standard MRI safety screening will be conducted to minimise the risk of serious adverse events such as those caused by permitting non-MR Safe individuals (as outlined in the exclusion criteria) to approach the magnetic field (e.g., malfunction of cardiac pacemaker). This study will investigate contrast enhanced sequences using licensed IV gadolinium-based contrast agents. These are widely used in clinical practice and are generally well tolerated but can present a risk of severe allergic reaction in 0.004%-0.7% patients and if given to patients with impaired renal function there is a risk of nephrogenic systemic fibrosis. Such contrast agents will be given to patients in line with the university's contrast agent policy and always under the supervision of a clinician.

Pre-examination participant preparation may be achieved through administration of oral contrast/filling agents. These can be used to improve visibility of the stomach lining and provide organ distention where appropriate. Most commonly, water has been administered but other food grade, non-medicinal contrast agents have been explored, most notably fruit juices e.g., pineapple and blueberry, or milk based drinks. Prior to administration, all participants will undergo an allergy check. Selecting the optimal oral contrast agent for MRI to aid radiotherapy planning will depend on factors such as disease location, purpose for which MRI sequences are to be obtained and importantly patient preference. There is currently limited published data regarding which is the optimal choice of oral contrast agent with respect to the imaging quality and also the patient experience of taking oral contrast agents for MRI scans.

For patients participating in this study, their radiotherapy planning will be as standard of care and their inclusion in the study not have any effect on their radiotherapy pathway.

Hypotheses

1. Optimisation of MRI protocols MRI protocols, including pre-examination participant preparation, may be optimised to support radiotherapy planning and applied to novel tumour sites and to tumour sites where MRI planning is already a standard of care. 2. Assess the effect of MRI-CT Integration in the radiotherapy pathway The integration of MRI with CT planning scans will enhance visualisation and accuracy of delineation of target volumes and organs at risk (OARs) and subsequent radiotherapy treatment planning, thereby enabling more precise treatment delivery and reducing radiotherapy-induced toxicity. 3. MRI-Adapted Radiotherapy MRI-adapted radiotherapy is feasible across multiple target sites and will improve clinical outcomes by enabling more accurate dose delivery, reducing radiation exposure to normal tissues, and consequently lowering treatment-related toxicity. 4. Imaging Biomarkers The investigators hypothesise current and novel MRI sequences are feasible, predictive and prognostic imaging biomarkers that can be developed and tested in the clinical setting. Quantitative MRI has the potential to assess of treatment response, inform clinical decision-making, and support patients in making more informed choices about their care.

Study Aims:

1. Optimisation of MRI protocols To have clinically-ready MRI protocols for use in clinical practice. This will entail optimising MRI sequences for radiotherapy planning, including optimising the pre-examination preparation and patient experience. Initial work will focus on 3 tumour sites

1. Oesophago-gastric 2. Pancreas 3. Brain

On completion of these subsites, proposed further anatomical sites include: * Head and Neck * Thorax - chest wall and breast * Thorax - lung * Abdomen * Pelvis - male * Pelvis - female 2. Assess the effect of MRI-CT Integration on quality of radiotherapy To determine if the addition of the information acquired from MRI, in addition to the current CT, will provide superior visualisation of the anatomy and extent of tumour, improving the accuracy of radiotherapy. The feasibility and clinical benefit of the addition of MRI will be determined by comparing the resulting delineation and subsequent dose distribution with that using CT alone.

Secondary Aims:

1. MRI-Adapted Radiotherapy To determine if repeat MRI scans undertaken during a course of radiotherapy can give additional information over CT alone, that will inform changes in the radiotherapy plan which lead to better outcomes for the patient. Radiotherapy plans at start and during treatment, using CT alone versus CT plus MRI scanning will be compared. The effect on dose distribution and the impact of this on tumour control and toxicity will be assessed. 2. Imaging Biomarkers Identify and develop structural and functional MRI sequences for use as imaging biomarkers in selected tumour sites. These biomarkers could be used to predict which patients may benefit from radiotherapy and/or assess the response to RT during and after treatment.

Study Design The study will consist of three parallel strands. These strands form the underpinning methodology for individual sub-studies which will investigate different tumour sites.

Strand 1 - Optimising MRI protocols and assessing the effect of MRI-CT integration in the radiotherapy pathway

This strand will progress over 4 stages:

1. Optimisation of MRI protocols: Healthy Volunteer Initial Imaging Studies of Normal Tissue Up to 15 healthy volunteers will be scanned to ascertain the best MRI sequences and parameters to obtain optimal images of the organ of interest. Pre-examination tissue preparation (e.g. stomach filling volumes and material) for abdominal MRI will also examined and optimised. Images will be assessed qualitatively for improvements in image quality, such as SNR and contrast. Trade-offs, such as increased examination time will also be considered to evaluate feasibility in a clinical setting. This stage will be considered complete once the success criteria below is ac

• MRI-Adapted Radiotherapy 1 [Срок оценки: From enrolment to analysis, on average 4-6 weeks]
• MRI-Adapted Radiotherapy 2 [Срок оценки: From enrolment to analysis, on average 4-6 weeks]
• MRI-Adapted Radiotherapy 3 [Срок оценки: From enrolment to analysis, on average 4-6 weeks]