BioProton: Biologically relevant dose for Proton Therapy Planning

Oxygen plays an important role in life on earth. The air that we breathe provides cells with the oxygen required for energy production. This need for oxygen increases for cells that rapidly multiply such as those associated with cancer; however, the supply is limited. As a tumour increases in size not all parts will be located near to vessels carrying oxygen rich blood. This results in a reduction in the oxygen levels in cells located furthest away from the blood vessel. It has been shown that these cells with low levels of oxygen (termed hypoxic) are more resistant to damage from radiation than those that are well oxygenated. This is also known to be the case for irradiation with protons. In proton therapy, a beam of protons is fired at the tumour in order to destroy the DNA in the cancerous cells, thus killing the tumour. The amount of energy and number of protons required to achieve this is determined by the tumour volume. Currently in proton therapy the tumour is irradiated such that the whole tumour volume receives the same dose (energy deposited per unit mass). If, however, parts of the irradiated tumour are more resistant to the radiation than others this technique of delivering a uniform dose across the tumour volume is not optimal.
The research planned in this project aims to address this through the use of computer modelling and imaging to produce a method of increasing the dose to those low-oxygen radiation-resistant parts of the tumour whilst delivering an appropriately lower dose to the well oxygenated regions. This advancement will improve proton beam therapy and benefit any patient undergoing this form of cancer treatment. The benefits will include increased chance of survival and fewer side effects associated with the treatment

Advances in imaging and computing technology mean that PBT is an area, which has been developing exponentially, and the global market is expected to exceed $3bn by 2030. Although the UK has adopted PBT rather later than some countries it is in a good position to exploit this technology due to the recent investment of >£250M by NHS-England. The new NHS PBT clinical facility due to open at the Christie in Manchester in 2018, offers access to "state of the art technology" through a dedicated research room, within the clinical facility, that will occupy the 4th gantry space. This will be used entirely for research (it will not treat patients) and has a beamline rather than a clinical gantry. PBT is still a new technology and while it already offers significant benefits, if it is to achieve its full potential and deliver maximum advantage to patients (in terms of survival and quality of life) a number of scientific and technological challenges need to be addressed. BioProton considers the most intractable and arguably the most important of these challenges: how to deliver protons effectively to the most radiation resistant parts of the tumour and how to biologically optimise the dose so that it sterilises the whole tumour and its margins while causing minimal damage to surrounding healthy tissue.
This also opens a wealth of opportunities both to improve outcomes and quality of life for patients and develop new products, devices, software and services to benefit the UK economy and society. Through developing mathematical models which determine unique nano-dosimetric damage and repair parameters in hypoxic environments and imaging the tumour environment; BioProton offers the opportunity of biologically optimising the proton therapy plan and then delivering this plan using state of the art pencil beam scanning so the dose can be tailored to the tumour and weighted so that hypoxic, radiation resistant regions are given more dose. In this way more dose will be delivered to the tumour and resistant areas within it, while sparing the healthy tissue which surrounds it and minimising the dose to nearby sensitive organs at risk (OAR). Damage to normal tissue is normally the factor that limits the dose of radiation that can be used in radiotherapy. So reducing damage to normal tissue reduces both progressive side effects and the chances of secondary malignancies later in life. This is particularly important in children whose organs are more sensitive to radiation and because they are growing can experience severe side effects, which stay with them for life, if normal tissue damage is not minimised.
We believe that BioProton has the potential to deliver a paradigm change in PBT delivery and has been developed through an academic/clinical/industrial partnership. Working with Varian Medical we have already shown that we can incorporate nano-dosimetric parameters into their PBT planning system Eclipse. Don Whitley Scientific will help us develop the hypoxia cabinets needed to validate the models. By embedding BioProton in the clinical environment it will be informed by clinical priorities and its findings can be rapidly translated to the clinic through the translational elements of NIHR MBRC, CRUK MCRC and CRUK ART-NET grants. Our close working partnership with industry and NHS-England through the mentorship of Dr Crellin the national Clinical Lead for NHS-E Proton Therapy will ensure that BioProton is clinically focussed and has a route to policy makers in government. The existing EPSRC Network+ (EP/N027167) also facilitates this translation and our EU H2020 integrating activity INSPIRE widens the reach of the research as does our collaboration with Massachusetts General Hospital/ Harvard Medical School in USA. Likewise the links to PPRIG and CTRad provide a route for dissemination to patients and consumers and the wider clinical community.