Advanced concepts and novel technologies for the study of the impact of ionising radiation on tissue

Cancer is the second most common cause of death globally, accounting for 8.8 million deaths in 2015. It is estimated that radiotherapy is used in the treatment of approximately half of all cancer patients. In the UK, one new NHS proton-beam therapy facility has recently come online in Manchester and a second will soon be brought into operation in London. In addition, several new private proton-beam therapy facilities are being developed. The use of these new centres, and the research that will be carried out to enhance the efficacy of the treatments they deliver, will substantially increase demand. Worldwide interest in particle-beam therapy (PBT) is growing and a significant growth in demand in this technology is anticipated. By 2035, 26.9 million life-years in low- and middle-income countries could be saved if radiotherapy capacity could be scaled up. The investment required for this expansion will generate substantial economic gains.

Radiotherapy delivered using X-ray beams or radioactive sources is an established form of treatment widely exploited to treat cancer. Modern X-ray therapy machines allow the dose to be concentrated over the tumour volume. X-ray dose falls exponentially with depth so that the location of primary tumours in relation to heart, lungs, oesophagus and spine limits dose intensity in a significant proportion of cases. The proximity of healthy organs to important primary cancer sites implies a fundamental limit on the photon-dose intensities that may be delivered.

Proton and ion beams lose the bulk of their energy as they come to rest. The energy-loss distribution therefore has a pronounced 'Bragg peak' at the maximum range. Proton and ion beams overcome the fundamental limitation of X-ray therapy because, in comparison to photons, there is little (ions) or no (protons) dose deposited beyond the distal tumour edge. This saves a factor of 2-3 in integrated patient dose. In addition, as the Bragg peak occurs at the maximum range of the beam, treatment can be conformed to the tumour volume.

Protons with energies between 10MeV and 250MeV can be delivered using cyclotrons which can be obtained `off the shelf' from a number of suppliers. Today, cyclotrons are most commonly used for proton-beam therapy. Such machines are not able to deliver multiple ion species over the range of energies required for treatment. Synchrotrons are the second most common type of accelerator used for proton- and ion-beam therapy and are more flexible than cyclotrons in the range of beam energy that can be delivered. However, the footprint, complexity and maintenance requirements are all larger for synchrotrons than for cyclotrons, which increases the necessary investment and the running costs.

We propose to lay the technological foundations for the development of an automated, adaptive system required to deliver personalised proton- and ion-beam therapy by implementing a novel laser-driven hybrid accelerator system dedicated to the study of radiobiology. Over the two years of this programme we will:
* Deliver an outline CDR for the 'Laser-hybrid Accelerator for Radiobiological Applications', LhARA;
* Establish a test-bed for advanced technologies for radiobiology and clinical radiotherapy at the Clatterbridge Cancer Centre; and
* Create a broad, multi-disciplinary UK coalition, working within the international Biophysics Collaboration to place the UK in pole position to contribute to, and to benefit from, this exciting new biomedical science-and-innovation initiative.

The long-term objective of the research programme is to transform the delivery of proton- and ion-beam therapy using a system that is:
* Automated and is capable of adjusting the dose delivered in real time based on measurements of the position of the patient, tumour, organs at risk, and the dose-deposition profile;
* Capable of delivering a range of ion species from protons to carbon ions over a wide variety of dose rates, up to and including those required for FLASH radiotherapy, in the same treatment session; and
* Has a footprint small enough that provision of the therapy can be distributed across the country.
The societal benefits of the substantial increase in access to advanced proton- and ion-beam therapy for effective cancer treatment that would result from the successful execution of this programme is clear.

To lay the foundations of the technological programme required to deliver the outcomes outlined above we have formed an multidisciplinary collaboration composed of clinical oncologists, medical and academic physicists, biologists, engineers, and industrialists. We propose to take a holisitic `system' approach to the delivery of the programme. This requires that various technological developments required to implement a full system are brought forward in parallel. The creation of a project team that has the diverse skill set and motivation to take the project forward to deliver the long-term goal is a clear priority. Further, the sustainable development of the programme from proof of concept to spin out will require staff with a breadth of experience across the disciplines. The series of meetings and networking events that will be scheduled as part of our programme will be used to further enhance the collaborative network which will deliver our overall aims and goals.

We will prove the principle of the laser-hybrid accelerator system within a facility dedicated to radiobiology research. This facility will enable further characterisation of the radiobiological effects of proton and ion beams, particularly at the molecular and cellular level, leading to a significant scientific impact. Specifically the collaborative team has expertise in examining the impact of ionising radiation on cell survival in different tumour models linked with effects on DNA damage and repair, which will be used to deliver the current proposal for increased scientific knowledge and gain. Overall, our proof-of-principle system has the potential to deliver a step up in clinical capability by improving the delivery and efficacy of particle-beam therapy for the benefit of cancer patients. As well as the societal impact that this will achieve, we will engage with industrial partners to place the UK in a unique position to generate substantial economic gains through the industrialisation of the novel techniques that this proposal will develop.