BioProton: Biologically relevant dose for Proton Therapy Planning

Lead Research Organisation: University of Manchester
Department Name: School of Medical Sciences

Abstract

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

Planned Impact

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.
 
Description First results of mechanistic models incorporated in to Eclipse treatment plans
International inter-comparison of measurement of LET and how this can be incorporated in to treatment plans
Anonymised patient data available from PBT patients treated overseas and at the Christie being made available for BioProton
HiC data allows a new way of mapping DNA damage on to the genome, this is the first time that this has been done and is a new way of looking at chromosome aberations which is much more meaningful biologically.
Exploitation Route biologically optimised treatment plans
Sectors Healthcare

 
Description POST note working with Science museum on new exhibit on PBT patient fact sheets Meetings on development of UK PBT clinical trials framework agreement with varian looking at spinning out PBT research room end-stations and PBT research room Development of a hypoxia cabinet with integrated robotic arm with Don Whitley Scientific BBC interview on FLASH radiotherapy
First Year Of Impact 2019
Sector Healthcare
Impact Types Cultural,Societal,Economic

 
Description Manchester RADNET
Amount £16,500,000 (GBP)
Organisation Cancer Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2019 
End 09/2026
 
Description Proton FLASH
Amount £227,974 (GBP)
Organisation Varian Inc 
Sector Private
Country United States
Start 09/2019 
End 08/2021
 
Title Proton Therapy Research room in the clinical PBT centre at the Christie 
Description Research infrastructure to conduct research in proton therapy, funded by Christie Charity £5.6M 
Type Of Material Improvements to research infrastructure 
Year Produced 2019 
Provided To Others? Yes  
Impact The plan is to make this research infrastructure available via UKRI and CRUK grants. The facility has to pay its own costs so funding would need to be applied for via competitive grants 
 
Title Anonymisation of PBT overseas data and data from patients treated at The Christie with PBT 
Description Means to access anonymised patient data from PBT patients treated overseas and at the Christie. This allows real patient data to be used to validate models developed in BioProton and other UKRI grants 
Type Of Material Database/Collection of data 
Year Produced 2020 
Provided To Others? No  
Impact Means research outputs can be validated on real patient data 
 
Title RCT TORPEDO 
Description TORPEO RCT has been developed and is funded by CRUK, it started recruiting patients in Feb 2020 
Type Therapeutic Intervention - Radiotherapy
Current Stage Of Development Refinement. Clinical
Year Development Stage Completed 2018
Development Status Under active development/distribution
Impact First UK RCT in PBT 
URL https://www.ncri.org.uk/ncri-blog/the-journey-of-torpedo-the-uks-first-proton-beam-therapy-clinical-...
 
Description BBC interview of FLASH radiotherapy 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact media interview for BBC on Flash proton therapy as part of CRUK RADNET launch
https://www.bbc.co.uk/news/uk-england-manchester-50289393
Year(s) Of Engagement Activity 2019
URL https://www.manchesterbrc.nihr.ac.uk/news-and-events/manchester-scientists-lead-way-next-generation-...
 
Description Film on proton therapy for GM cancer conference 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Film "what we have achieved in the last 12 months" which was shown during GM cancer conference. I also spoke at this conference
Year(s) Of Engagement Activity 2019
URL https://gmcancer.org.uk/greater-manchester-cancer-conference-2019/
 
Description One day workshop on FLASH radiotherapy: Transforming Radiotherapy in a FLASH 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact One day workshop organised with NCRI CTRad to inform UK researchers about Flash radiotherapy
Year(s) Of Engagement Activity 2020
URL https://www.eventbrite.co.uk/e/transforming-radiotherapy-in-a-flash-tickets-84136780375#
 
Description POST Note 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact POST note for members of the House of commons and Lords
Advances in Cancer Treatment
Year(s) Of Engagement Activity 2019
URL https://researchbriefings.parliament.uk/ResearchBriefing/Summary/POST-PN-0598
 
Description PTCOG 58 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Largest conference ever held on particle therapy attracted over 1355 people to a 5.5 day event in Manchester and contributed over 2.5M to the local economy
Year(s) Of Engagement Activity 2019
URL https://ptcog58.org/
 
Description radiotherapy and me 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Patients, carers and/or patient groups
Results and Impact event to listen to patients experience of radiotherapy
Year(s) Of Engagement Activity 2019
URL https://publicprogrammes.co.uk/radiotherapy-and-me