Development of MRI-guided radiation therapy

Radiation therapy involves delivering high-energy X-ray beams to tumours in order to kill cancer cells. For many people with cancer, radiation therapy is very effective and frequently cures their disease. Unfortunately, when treating tumours, nearby normal tissues will inevitably receive some of the radiation and this is associated with side effects. These side effects can vary from mild, temporary changes that disappear completely to severe, life-threatening, permanent effects that chronically affect a patient's quality of life. Therefore, when treating patients with radiotherapy, there is a clear need to ensure that the treatment is delivered as accurately as possible in order to avoid unnecessary treatment of normal tissues. In most cases, radiotherapy is planned using a CT scan to show the position of the tumour, but this is usually only done once before the treatment starts.
One of the major problems with accurate delivery of radiation lies in the fact that it can be very difficult to determine precisely where the tumour is, because it can be difficult to see on standard CT scans. The problem is compounded by the fact that radiation therapy is usually given as a series of doses (called fractions) divided over a period of weeks and the tumour may be in a slightly different position each day or may shrink during the course of treatment. To make matters even more difficult, tumours often occur in tissues that move. For example, lung tumours can move quite significantly as a patient breathes in and out. Therefore, when planning a course of radiation therapy, it is necessary to include a large margin around the tumour to make sure that the radiation beams do not miss their target. As a result, large volumes of normal tissues may receive unnecessarily high radiation doses.
In this research project, we aim to revolutionise the technique for delivering radiation therapy by developing a new type of machine called an MR Linac (or magnetic resonance imaging-guided linear accelerator). This machine combines a state-of-the-art radiation machine (called a linear accelerator) with a magnetic resonance imaging (MRI) scanner. MRI scanning is better than CT scanning at being able to tell the difference between tumour and normal tissues and does not expose patients to additional radiation doses. Therefore, such a machine will allow us to see very accurately where the tumour is at the time of each fraction of radiation therapy and it will also be able to track the movements of a tumour as they occur in real-time within a patient during a dose of radiation. With these improvements, we aim to be able to reduce the margins we place around tumours before we start a course of radiation therapy and yet still be confident that we are hitting the tumour target all of the time. For patients, this will have a number of benefits including greater confidence that the treatment will be effective against their disease with fewer side effects. The greater level of accuracy and the avoidance of normal tissues also means that we may be able to prescribe higher radiation doses to the tumour. For clinicians and scientists, the diagnostic power of MRI scanning will allow them to use the MR Linac to develop new approaches to modify the pattern of radiation delivery such that extra dose can be deposited in tumour areas that pose the greatest threat to the patient. Such areas can be identified using so-called functional imaging techniques on an MRI scanner.
Before MR-guided radiation therapy can become a reality, there are a number of challenges that need to be met to ensure that treatment can be delivered accurately and safely. The programme of research described in this proposal will enable us to use the MRI scanner to acquire accurate images of tumour and normal tissues while delivering precise radiation doses, even to moving tumour targets.

Effective conformal radiotherapy requires identification of the tumour's extent and dose delivery that is precise in space and time throughout the treatment course. Current state-of-the-art technology used to achieve this goal comprises treatment-integrated X-ray imaging (eg cone-beam CT, X-ray fluoroscopy) allowing 3D-imaging immediately before treatment, or acquisition of 2D-X-ray projections of moving targets during treatment. The treatment-integrated X-ray imaging strategy suffers from disadvantages of relatively low contrast between different soft tissues, and the delivery of additional radiation dose to the patient. At ICR/RM we aim to develop the next generation of image-guided radiotherapy by replacing conventional X-ray-guidance with treatment-integrated magnetic resonance image (MRI)-guided therapy (MRIgRT). The ability to use the superior soft-tissue contrast of MRI in real-time during treatment will revolutionize current clinical radiotherapy practice.
This research proposal focuses on developing MRIgRT using an MR Linac. This will permit clinical exploitation of the three major physical advantages of MRIgRT: excellent soft tissue contrast; avoidance of any additional imaging-dose; real-time/on-line MR guidance of the radiation beam. In order to do this, the physics-related research will optimise geometrical accuracy and imaging sequences for the MR component of the technology, establish dosimetry and treatment verification methodologies, develop MRI-based treatment planning for a range of different tumour sites and solve the problem of real-time MRI guidance of radiotherapy. Thereafter, we will conduct early-phase clinical studies to include safety and efficacy endpoints in different tumour sites. Specifically, we will study the benefits of enhanced soft tissue contrast in pelvic tumours, organ motion and tissue function management in lung tumours and motion management and avoidance of imaging dose in paediatric tumours.

Impact Summary

The ICR's aim is to ensure appropriate and effective exploitation and dissemination of research findings to maximise speed to patient benefit.

The ICR and RM were awarded NIHR-BRC status in 2007 as the only specialist BRC dedicated to cancer, and this was successfully renewed in 2012. This funding, together with that derived from being a Cancer Research UK (CRUK) Centre and an Experimental Cancer Medicine Centre, enables us to support an infrastructure in which we systematically take the findings of basic scientific research, including that in radiotherapy and physics, through to phase I proof of concept studies and tumour specific phase II clinical trials. Transition into large-scale network-adopted clinical trials is facilitated by the CRUK-funded, NCRI accredited, ICR Clinical Trials & Statistics Unit which has particular expertise in Radiotherapy, Breast, and Urology trials.

Where necessary, we work in collaboration with commercial organisations to facilitate the development of the product or service, and we monitor progress even after the formal collaboration period has ended to ensure that the impact is being realised. If partner organisations discontinue development, we have mechanisms in place to ensure that the results are returned to us so that we can seek other opportunities to exploit them. Where possible, ICR sets up commercial agreements that leave scientists freedom to operate and therefore able to help multiple companies in the same field. The consequence of the non-exclusive arrangements is less income but a greater likelihood of patient benefit.

Track-record - IMRT Case Study
The development by ICR researchers of conformal radiotherapy and then the refinement of that technique to create effective and deliverable IMRT has revolutionised radiation therapy. The impact has been seen both in terms of more effective disease control and improvements in patient wellbeing by decreasing the side-effects of healthy tissue irradiation. Tumours can be precisely targeted within a high intensity radiation volume, while adjacent normal structures can be spared, leading to reduced side effects. Because of reduced irradiation of adjacent tissues, higher doses can be delivered to the tumour - resulting in improved cure rates. In addition, cost-effective hypofractionation can be employed, providing economic benefit to the NHS.

As a result of the outcome of the ICR/RM clinical research trials programme, IMRT is now the approved treatment technique for many cancers in the UK and elsewhere, with changes made in clinical guidelines to implement this. This treatment modality is now recommended in guideline publications from the European Association of Urology (EAU), the European Society for Medical Oncology (ESMO) [2] and from the US [3]. The dose and fractions that are recommended in these guidelines are based on the ICR/RM trials, which are referenced as evidence in the guidelines.

Using test cases, ICR/RM medical physicists train staff in other UK hospitals to use this technique, thus driving the modernisation of radiotherapy throughout the NHS. The ICR runs a national IMRT course each year involving around 70 trainee radiography practitioners. All new radiotherapy equipment can deliver IMRT but without the training provided by the ICR/RM not all the hospitals would have the capability to use it. The governments Radiotherapy Innovation Fund funded a nationwide IMRT fundamentals course under the leadership of Professor Nutting, in collaboration with the Royal College of Radiologists, to increase clinician involvement in and awareness of IMRT.