Title: Four-dimensional Magnetic Resonance Imaging (4D-MRI) to guide radiotherapy for stage II-III non-small cell lung cancer: an assessment of its precision and accuracy.
Funder: Department of Health and Social Care

Abstract: BackgroundThe standard-of-care for inoperable stage II-III non-small cell lung cancer is radiotherapy (RT) given in daily sessions ('fractions') over 4-6 weeks, although targeting lung tumours with radiation is challenging because they move as patients breathe.4D-computed tomography (4D-CT) is used to image lung tumours for RT planning, but the images provide poor soft-tissue contrast and may not capture the entire range of tumour motion. Immediately before fractions, tumour positions are verified using images from cone-beam CT scanners integrated with treatment machines. However, the tumours are seen less clearly on the cone-beam images than on standard 4D-CT imaging, and tumour movement during irradiation cannot be monitored via CT. Resulting tumour localisation uncertainties necessitate broad planning margins, meaning critical healthy tissues surrounding tumours receive radiation doses which may cause severe toxicity.4D magnetic resonance imaging (4D-MRI) provides superior soft-tissue contrast to 4D-CT and gives zero radiation dose, enabling tumour position and motion changes to be monitored more frequently and for longer, potentially describing respiratory motion more accurately.Furthermore, RT machines with integrated MRI scanners can image tumours in real-time during RT delivery. Real-time imaging provides a moving picture limited to a few slices, allowing radiation delivery to be paused when a tumour lies outside its expected positional range.Such benefits suggest MRI may improve tumour localization during RT. We will determine any associated safe reductions in planning margins and resulting dose reductions to healthy tissues.Research questions Can tumour location and the extent of tumour respiratory motion be determined more accurately and precisely using 4D-MRI than 4D-CT? How much do tumour position and tumour respiratory motion change between planning, pre-fraction verification and RT delivery? By how much can planning margins be narrowed and doses to critical healthy tissues be reduced using 4D-MRI scans for planning and targeting each day's treatment? What residual uncertainty remains in the real-time localization of whole tumour volumes when just two orthogonal tumour slices are repeatedly imaged, and what margin size is required to account for this uncertainty?Methods 4D-MR and 4D-CT images of a phantom that simulates breathing motion will be checked against direct measurements of the phantom geometry, and the spatial accuracy, contrast and resolution of these images will be compared.4D-MR and 4D-CT images will also be collected for 20 RT lung cancer patients, comparing tumour contours and respiratory motion amplitudes defined on the images. For each patient, repeat 4D-MRI scans will be collected ten minutes and one week after a first set, and used to measure changes in tumour motion over seconds, minutes and days. The accuracy with which whole tumour volumes can be localised using just two real-time slices will be determined.Finally, from standard margin recipes we will calculate potential safe reductions in planning margins achievable using MRI rather than CT, and determine resulting reductions in normal tissue doses and estimated toxicity.Patient InvolvementThe research steering group includes patient representatives from the Roy Castle Lung Foundation, who have improved study participants' comfort during imaging, and continue to inform research plans.

Lay abstract: BackgroundRadiotherapy given in daily doses over 4-6 weeks is used to treat lung cancer, although precise targeting of lung tumours with radiation is difficult because the tumours move as patients breathe. The best information about tumour position is presently provided by four-dimensional computed tomography (4D-CT), a type of X-ray image. 4D-CT images are used to plan radiotherapy one week before treatment starts, but do not show the full extent of tumour motion during breathing, nor provide good contrast between tumours and healthy tissues. Immediately before daily radiation treatments, we adjust the targeting of tumours using images collected by CT scanners built into the machines that deliver radiotherapy. But these images are poor quality, and while some tissues like bone are seen clearly, centrally-located tumours and their motion are not.To avoid missing tumours, planning margins which include non-cancerous tissues are added to the regions targeted with high radiation doses. For larger lung tumours lying close to critical organs, persistent side-effects of radiotherapy such as severe pain during swallowing and breathing difficulties are more likely.A new treatment machine called an MRI-linac can take four-dimensional magnetic resonance images (4D-MRI). These images provide sharper contrast than 4D-CT, and can be taken more often and over longer periods. This may allow us to see better where tumours are, and to take steps immediately before treatment to avoid delivering radiation to healthy tissues. Unlike 4D-CT, 4D-MRI can also provide partial pictures of tumour motion in real-time during radiation delivery, allowing a radiation treatment to be stopped if a tumour moves outside its expected range of positions.In this project we will test how accurately and precisely 4D-MRI can describe tumour position and motion. We will also determine whether planning margins can be narrowed as a result of any improvements in tumour localization from 4D-MRI, and calculate resulting reductions in radiation doses to critical organs. The findings will guide the design of more accurate radiotherapy treatments, aiming to reduce side-effects and potentially to improve cure rates.MethodsThe project will address four questions - Is the tumour location and motion captured better on 4D-MRI than on 4D-CT? How much do tumour location and motion change between planning and treatment? Can planning margins be narrowed and doses to critical healthy tissues reduced by using 4D-MRI scans for planning and for targeting of each day's treatment, and by how much? Can partial pictures from 4D-MRI be used to track tumour motion accurately in real-time?We will collect 4D-MR and 4D-CT images of a 'phantom', a realistic physical model of a patient which can simulate a breathing-type motion. The 4D-CT and 4D-MR phantom images will be compared with direct physical measurements of the phantom geometry, allowing us to gauge which type of image is more accurate.4D-MR and 4D-CT images will also be collected for 20 lung cancer patients treated using radiotherapy, their tumours still being targeted using standard CT methods. The shapes and movement of tumours in 4D-MR and 4D-CT images will be compared. Using repeat sets of 4D-MR images collected ten minutes and 1 week after the first set acquired for each patient, we will also measure changes in tumour motion over seconds, minutes and days.From these results we will determine by how much it would be safe to shrink planning margins. Then using a computerised treatment planning system, we will calculate reductions in healthy tissue doses that result from the narrowed margin.Patient Involvement Patient representatives have helped prepare this application and have improved parts of the proposed project. They are represented on the project steering group.

Research activity codes: 6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CANCER AND NEOPLASMS