Advanced Radiotherapy Network + (ARN+) extension

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

Abstract

In the UK, one in two people will be diagnosed with cancer during their lifetime and of those who survive, 41% can attribute their cure to a treatment including radiotherapy. Radiotherapy is very cost effective, accounting for only 6% of the total cost of cancer care in the UK.
In radiotherapy the way the radiation dose is delivered and conformed to the tumour uses a treatment plan, which is based around a CT scan of the patient and their tumour. The treatment plan uses beams of radiation at different angles, to maximise the dose (and damage) to the tumour and to minimise the damage to the surrounding healthy tissue. Constraints are also applied for "organs at risk" which are often more sensitive to radiation and so require the dose to be as low as possible. Radiotherapy is normally delivered in fractions, with a fraction being typically 1-2 Gy. A course of radiotherapy is typically 1 fraction every week-day over a period of 4-6 weeks.

Radiotherapy seeks to maximise the damage to the tumour (to sterilise it) while minimising the damage to the surrounding healthy tissue (to reduce side effects). In recent years radiotherapy has developed rapidly with the development of new machines and methodologies. These in turn, have resulted in better imaging, treatment planning and dosimetry, which enable the dose to be more accurately delivered and conformed to the tumour. This has resulted in better cancer survival and reduced side effects for patients. However, to maintain this rate of advancement and deliver even better treatments for patients we require innovation and solutions to the challenges, which still confront advanced RT.

This is exactly where the STFC community can make an enormous impact, working in partnership with the clinical community, as they together they have exactly the skill set which is needed to effectively tackle these new challenges as they arise. In addition, the latest developments in radiotherapy - such as MR-linacs and proton therapy - evidence the need for the STFC community to work in partnership with the clinical community and commercial partners. If the UK is to remain competitive and deliver even better treatments for patients, and produce income and impact for the UK economy, it can no longer rely on serendipitous partnerships. This is what this Advanced Radiotherapy Network + (ARN+) seeks to address. Working actively with the clinical community through the National Cancer Research Institute (NCRI) Clinical and Translational working group on Radiotherapy (CTRad) it has been able to establish a new community drawn from across STFC with clinicians and clinical scientists from the NHS.

This application is an extension of an existing successful ARN + and is aimed at both consolidating the success of the ARN+ and taking it one step further by developing a global dimension for its activities by working with the IAEA. It also seeks to showcase its activities to industry and develop a pipeline of innovation to the clinic. Finally it looks to work with STFC within the framework of UK Research and Innovation to build a national consensus, research roadmap and funding strategy in the field of Advanced Radiotherapy.

Planned Impact

The Advanced Radiotherapy Network (ARN+) was designed to bring the clinical radiotherapy and STFC communities together and to develop synergies and research collaboration between them. ARN+ has been successful and now seeks to build on this success and translate its research for patient benefit by actively working with industry and the NHS. In this extension to ARN+ it seeks to further engage with industry to take the research initiated in ARN+ up the technology readiness levels.
Global Impact In ARN+ extension, ARN+ also seeks to work with the IAEA to expand the international scope of its activities and to work together with the developing world to come up with solutions to some of the problems they currently face. Key to this approach is listening and testing understanding, so that the solutions proposed are fit for purpose. We will also work with industry to ensure that the work of ARN+ both complements what is already available and has a route for exploitation.
Academic impact arising from ARN+ activities and pump-priming projects will be realised through joint grant applications (across the Research Councils and Innovate UK) and will be fostered by the work, which will be done with STFC on providing a framework and roadmap for radiotherapy research. Research outputs will be another output as will the 3 PhD students, who are 50% funded through ARN+, and who will submit and graduate during ARN+ extension.
Economic Impact will arise from translating ARN+ activities up the technology readiness levels and engaging stakeholders from public and private sectors in ARN+ Showcase events. The Knowledge Hub on the new ARN+ web site will be designed so that it takes potential industrial partners quickly to the information they need and will also highlight where ARN+ has already been successful in industrial collaborations. Knowledge Exchange will be facilitated by a number of the ARN+ activities. ARN + will work closely with the Innovations Directorate, the Innovation Partnership Scheme (IPS) Fellows and STFC Innovations Ltd (based in Harwell). The Impact Sandpit (in Jan 2019) carried out through the existing ARN+ will also provide a forum for highlighting ARN+ research and the opportunities for its translation up the technology readiness levels.
Societal Impact will arise from continuing to have patient and carer representation on ARN+ through close collaboration with NCRI CTRad. From the outset ARN+ has tried to ensure that the patient voice and their views are central to ARN+ and this will continue in ARN+ extension. The ARN+ Knowledge Hub will also provide information for patents and carers, which has been generated by working closely with focus groups (of patients and carers) and Charities.
Policy Makers: The ARN+ extension will allow ARN+ in partnership with NCRI CTRad to work with STFC within the framework of UK Research and Innovation to build a national consensus, research roadmap and funding strategy in the field of Advanced Radiotherapy. This will involve working with key stakeholders including government, NHS, UK Research and Innovation, industry and Charities. In this way ARN+ can impact on national policy and use its Knowledge Hub to promote its activities and outcomes to the wider community.

Publications

10 25 50

 
Title Bragg peak glass 
Description working with a glassblower on a glass sculpture to represent the Bragg peak 
Type Of Art Artwork 
Year Produced 2020 
Impact this will form a piece of artwork 
 
Description Heavy Charged Particle Beam Therapy and related new Radiotherapy technologies: The Clinical Potential, Physics and Technical Developments Required to Deliver Benefit for Patients with Cancer
Geographic Reach National 
Policy Influence Type Participation in a national consultation
Impact 2 day meeting to look at clinical implications of heavy ion charged particle therapy and develop a road map. This is now published and formed the basis for the UK ITRF
URL https://www.research.manchester.ac.uk/portal/en/publications/heavy-charged-particle-beam-therapy-and...
 
Description Work with IAEA on developing a resource and training in partocle therapy
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in a national consultation
Impact Working with IAEA to provide an international guidance document on proton therapy which looks at staffing and skillset involved. This will be used by countries looking to set up new PBT facilities. Web page will follow shortly once document released
 
Description Workstream 4 CoChair NCRI CTRad
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
Impact National body pioneering new developments in radiotherapy
URL https://www.ncri.org.uk/how-we-work/ctrad/
 
Description Cockcroft Phase 4 Award
Amount £7,772,375 (GBP)
Funding ID Cockcroft phase 4 
Organisation Science and Technologies Facilities Council (STFC) 
Sector Public
Country United Kingdom
Start 03/2021 
End 03/2025
 
Description Infrastructure in FLASH Radiotherapy
Amount £199,904 (GBP)
Funding ID RRNIA-Feb22\100002 
Organisation Cancer Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 05/2022 
End 05/2024
 
Description Manchester RADNET
Amount £16,500,000 (GBP)
Organisation Cancer Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2019 
End 09/2026
 
Description Modelling anomalous transport of nanoparticles and DNA repair to improve radiotherapy
Amount £702,576 (GBP)
Funding ID EP/V008641 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 03/2021 
End 03/2024
 
Description Proton FLASH
Amount £227,974 (GBP)
Organisation Varian Inc 
Sector Private
Country United States
Start 08/2019 
End 08/2021
 
Description Topol Digital Fellowship
Amount £20,000 (GBP)
Organisation Health Education England 
Sector Public
Country United Kingdom
Start 04/2022 
End 04/2023
 
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. Over the past year we have been comissioning the research room and bioprep room. This has been slowed down due to Covid. first experiments March 2021 Experiments are now ongoing in the research room and the hypoxia cabinet with integrated robotic arm (designed with don Whitley Scientific) is now fully operational and performing high throughput experiments. Accurate QA and dosimetry < 3% comparable with clinical system achieved for protons. FLASH capability delivered, dosimetry <5% one of the best in the world. 
Type Of Material Improvements to research infrastructure 
Year Produced 2020 
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. CRUK now funding research room through RadNet as a national proton hub and have just funded a national FLASH infrastructure. 
URL https://protonsinspire.eu/facilities/the-christie-nhs-foundation-trust
 
Title zoomorphic phantoms produced using tissue equivalent material and 3D printing 
Description 3D printed mouse phantom for in vivo dosimetry measurements 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2019 
Provided To Others? Yes  
Impact We plan to make this phantom available for photon dosimetry measurements and later proton dosimetry measurements. Audit using phatom recently completed with photon measurements 
 
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 
 
Description IAEA PBT 
Organisation International Atomic Energy Agency
Country Austria 
Sector Charity/Non Profit 
PI Contribution international guidance on developing a PBT centre
Collaborator Contribution developing international guidance on training and workforce for governments or institutions wishing to develop a new PBT centre
Impact international guidance document being developed
Start Year 2019
 
Description Modelling national demand for radiotherapy internationally 
Organisation International Atomic Energy Agency
Country Austria 
Sector Charity/Non Profit 
PI Contribution This work also involves ESTRO HERO project the project combines radiotherapy demand with health economic costing models to understand the real cost of RT, PBT and in the future new modalities such as FLASH therapy
Collaborator Contribution access to IAEA costing methodology; access to ESTRO HERO costing methodology. Will feed in to ESTRO EPTN WP7. Also allows impact of Covid to be assessed.
Impact publications being written ESTRO presentations
Start Year 2020
 
Description Topas nBio 
Organisation University of Oxford
Country United Kingdom 
Sector Academic/University 
PI Contribution Open access Topas-nBio software includes our research in the radiobiological gold standard
Collaborator Contribution Working together on joint projects and sharing research to incorporate in to Topas n-Bio
Impact Joint publications Joint abstract submission PTCOG, AAPM, FRPT New software release in Topas n-Bio
Start Year 2020
 
Description Varian Framework agreement 
Organisation Varian Inc
Country United States 
Sector Private 
PI Contribution All IP through the Framework agreement belong to UoM / Christie but Varian have first refusal to exploit. Strong collaboration working on LET and RBE.
Collaborator Contribution Varian have provided access to latest versions of Eclipse software through T boxes (fair market value $75k). We can bid to Varian through Framework agreement for funding for projects. Amount shown is $1USD as actual amount is commercial in confidence.
Impact Publications Abstracts to international conferences Talks at Varian events
Start Year 2019
 
Title EMBRACE wearables clinical trial 
Description wearables for real time monitoring of cancer patients. A new trial opens in Greater Manchester today which is to test cutting-edge wearable technologies involving patients who have received cancer treatment. The commercially-available health sensors and devices produce a digital fingerprint of vital signs that could allow doctors to assess the progress of their patients. Called, EMBRaCE, (Enhanced Monitoring for Better Recovery and Cancer Experience), the trial is a collaboration between Manchester University NHS Foundation Trust, The Christie NHS Foundation Trust and The University of Manchester. The trial opens initially for blood cancer, lung, and colorectal cancer patients and will run across Greater Manchester. The technologies under investigation include: a smart ring, worn on any finger made by the company Oura the Withings ScanWatch, a hybrid smartwatch the Isansys system, which is worn on the chest. The technologies can assess a range of vital signs, including electrocardiogram (ECG), heart rate, temperature, physical activity levels and sleep. 
Type Diagnostic Tool - Non-Imaging
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2022
Development Status Under active development/distribution
Clinical Trial? Yes
UKCRN/ISCTN Identifier N/A
Impact Real time monitoring of patients. Has the potential of producing digital fingerprints to allow personalisation of treatment Cancer places a huge burden on the lives of people everywhere. This study uses cutting-edge technology that can monitor people during their treatment, with devices that they can wear all the time. We hope that it will provide new insights into how people cope with cancer treatment and what we can do to improve their recovery." This trial will assess if the latest wearable technology has a role in cancer care. "It will help us to identify ways that clinical staff can individualise treatment before, during, and after therapy. "We will find out if 24/7 data from these wearable sensors can be used to support patient recovery and provide accurate measurement outside clinic. "It could even support the development of new cancer treatments by developing a digital platform for clinical trials in cancer involving wearable devices or fitness trackers." 
URL https://www.manchester.ac.uk/discover/news/trial-of-wearable-health-technology-for-cancer-patients-o...
 
Title PARABLE Clinical Trial 
Description randomised Proton therapy clinical trial for breast cancer patients 
Type Therapeutic Intervention - Radiotherapy
Current Stage Of Development Late clinical evaluation
Year Development Stage Completed 2022
Development Status Under active development/distribution
Clinical Trial? Yes
Impact Bioproton is being used for the biologically augmented treatment planning in this trial 
 
Title RCT TORPEDO 
Description TORPEO RCT has been developed and is funded by CRUK, it started recruiting patients in Feb 2020 then paused due to Covid-19 and resumed again in late 2020 
Type Therapeutic Intervention - Radiotherapy
Current Stage Of Development Refinement. Clinical
Year Development Stage Completed 2022
Development Status Under active development/distribution
Clinical Trial? Yes
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-...
 
Title Topas nBio 
Description Since the open-source beta-release of TOPAS-nBio in 2019, the framework offers to connect energy deposition within irradiated cells (physics) via molecular reactions (chemistry) to cell kill/repair (biology) at the level of sub-cellular targets such as DNA. To facilitate the setup of simulations we further developed a Graphical User (GUI) Interface. TOPAS-nBio is an extension to TOPAS and layered on top of the Geant4/Geant4-DNA MC toolkit. The new release was built for TOPAS release 3.6 (based on Geant4.10.6.p3) and will be compatible with all future releases of TOPAS. First release in 2019 but our models incorporated 2020 onwards 
Type Of Technology Software 
Year Produced 2021 
Open Source License? Yes  
Impact The new features of TOPAS-nBio v1.0, offers improved modeling from initial DNA damage to cell outcome, Gold standard for radiobiology research 
URL https://topas-nbio.readthedocs.io/en/latest/getting-started/Members.html
 
Description Article in the Guardian newspaper Dec 2021 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact How radiotherapy became a lifesaver, advances in radiotherapy
https://www.theguardian.com/cancer-revolutionaries/2021/dec/21/how-radiotherapy-became-a-lifesaver-from-x-rays-to-the-proton-beam
Year(s) Of Engagement Activity 2021
URL https://www.theguardian.com/cancer-revolutionaries/2021/dec/21/how-radiotherapy-became-a-lifesaver-f...
 
Description Flash radiotherapy and Particle Therapy 
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 Development of a new international conference on FLASH in Dec 2021 with PCO Kenes and leading international reserchers. This conference was very successful and attracted over 730 people from 40 countries the 2nd in the series will be held in Barcelona Nov 30-Dec 2nd 2022.
the top 15 papers will be published in The Green Journal with further papers in Physica Medica where the abstracts will also be published
Year(s) Of Engagement Activity 2020,2021,2022
URL https://frpt-conference.org/
 
Description Netwok on AI in radiotherapy 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Radiotherapy and Machine Learning Network was established led by Dr Robert Lyons. The network brought together expertise in ML from physics and computer science with clinical expertise in radiotherapy. Three meetings took place and initiated: 7 unique ML projects. An MRC/NIHR methodology grant application (initiated at event two) entitled "Developing a fully automatic, quantitative biomarker for assessing patient frailty from A successful sandpit project on data sharing, awarded to Dr (now Prof) Jamie McClelland UCL, looks at the need to share data between different treating centres and radiotherapy modalities, while maintaining confidentiality. The prototype system developed with funding from ARN+ was used to transfer data (both dicom and non-dicom) between UCL and KCL. Following further discussions with UCLH it was decided to alter the design and components of the system, so the prototype system was not tested at UCLH. However, a new improved prototype system has now been developed and further funding for this was provided by UK Radiotherapy Trials Quality Assurance RTTQA and CRUK ART-NET grant £4.5M. This new system will soon be deployed in a number of clinical sites for testing, with more widespread deployment expected later this year. While this new system was developed after the STFC network funded work had finished, the initial prototype and the work undertaken in developing and testing it has been invaluable in developing the new system.

Following the Big data sandpit the Radiotherapy and Machine Learning Network was established led by Dr Robert Lyons. The network brought together expertise in ML from physics and computer science with clinical expertise in radiotherapy. Three meetings took place and initiated: 7 unique ML projects. An MRC/NIHR methodology grant application (initiated at event two) entitled "Developing a fully automatic, quantitative biomarker for assessing patient frailty from routine cancer imaging" led by Dr. A. McWilliam; Three successful data access requests submitted to the REQUITE consortium:

REQUITE Proposal #46 Approved March 2019: "Machine Learning Approach to Auto-contouring tumour and organs at risk in prostate radiotherapy", PI: Dr. C. S. Boon CI: Dr. T. Rattay & Dr. M. H. Yap; REQUITE Proposal #47 Approved March 2019: "Predicting radiotherapy treatment plan metrics from patients' geometrical properties", PI: Dr. A. Green CI: Dr. E. Stubington & Prof G. Shentall; REQUITE Proposal Approved March 2019: "Predicting acute desquamation after surgery & breast cancer radiotherapy", PI: Dr. T. Rattay, CI: M. Aldraimli et. el.
The following paper has been submitted
1. Aldraimli, M., Osman, S., Grishchuck, D., Ingram, S., Lyon, R., Mistry, A., Oliveira, J., Samuel, R., Shelly, L.E.A., Soria, D., Dwek, M. V., Azria, D., Chang-Claude, J., Dunning, A., Gutiérrez-Enríquez, S., Müller, A., Rancati, T., Rosenstein, B. S., De Ruysscher, D., Seibold, P., Sperk, E., Symonds, R. P., Stobart, H., Vega, A., Veldeman, L., Webb, A., Talbot, C. J., West, C. M., Chaussalet, T. J., Rattay, T., on behalf of the REQUITE consortium* and the UK Radiotherapy Machine Learning Network** , "Development and optimisation of a machine-learning prediction model for acute desquamation following breast radiotherapy in the multi-centre REQUITE cohort", submitted to the International Journal of Radiation Oncology, Biology, Physics.
And the following paper is now published
2. Aldraimli, M et al"A Data Science Approach for Predicting Patient's Susceptibility to Acute Side Effects of advanced radiotherapy Computers in Medicine and Biology 135, 2021 https://doi.org/10.1016/j.compbiomed.2021.104624
With the following book chapter due to be published in 2021/22
o Lyon, R. and Rattay T., "Introduction to Machine Learning", in ML in Radiation Oncology, Springer, to be published in 2021-2022.
There are also non-tangible outputs produced by the RTML network not listed above. Some of the research projects initiated during our workshops are still being actively worked upon, with the potential for them to yield papers and research proposals. Whilst the connections and collaborations formed during are workshops are proving beneficial for helping initiate new avenues of research, in addition to research proposals.

Sam Ingram went on to be a HEE Topol Digital Fellowship
Year(s) Of Engagement Activity 2021
 
Description On cancer UoM and The Christie 
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 On Cancer is a new 44-page collection of research-led policy recommendations authored by academics from The University of Manchester, and The Christie which aim to highlight areas where research can inform policy changes and improve the lives of patients living with cancer. It is a collaboration between the Manchester Cancer Research Centre, the Cancer Beacon, and the Policy@Manchester team at The University of Manchester and involves the thoughts and research activities of four CRUK RadNet Manchester affiliated radiotherapy researchers.

Specific relevant examples included in On Cancer relate to work by Professor Karen Kirkby and Professor Ananya Choudhury (Advanced radiotherapies: what are the challenges and opportunities). Here, Ananya and Karen argue that researchers need to work with policymakers to produce a cost-benefit analysis of MR-Linac and Proton Beam Therapies and engage with leadership to determine opportunities for informed and enhance patient consent.
As the recommendations have only been recently published, direct influence on policy is still unknown. The authors involved are all committed to helping to promote the activities of the articles further, and we are continuing to work with Policy@Manchester a team dedicated to connecting policymakers and researchers to further expand on these recommendations.
Year(s) Of Engagement Activity 2022
 
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 Talks for GM Cancer 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact GM cancer conference talking about proton therapy
link to the new PRECISE YouTube channel:
https://www.youtube.com/channel/UCTAyoUeLIYQu5Gokqle4-Pg/featured

And to the video:
https://www.youtube.com/watch?v=j2QR4PQvaeI
Year(s) Of Engagement Activity 2021
URL https://www.youtube.com/watch?v=j2QR4PQvaeI
 
Description Webinar on UK Ion Therapy Research Facility 
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 First of a meeting to engage the community in UK ITRF
Year(s) Of Engagement Activity 2022
 
Description You tube channel 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact You tube channel to promote research
Year(s) Of Engagement Activity 2021
URL https://www.youtube.com/channel/UCTAyoUeLIYQu5Gokqle4-Pg/featured