Exploring novel solutions of radiotherapy delivery and using biological imaging, new fractionations and radiobiological models to improve TCP/NTCP ratio

Lead Research Organisation: University of Oxford

Abstract

Cancers of the upper gastro-intestinal tract (oesophagus, pancreas) have a poor outcome if surgery cannot be undertaken. Radical radiotherapy combined with chemotherapy are the standard of care, however a significant number of patients have tumour recurrence in the radiotherapy field. In the past increasing radiotherapy dose caused severe toxicity. There are now several technological advances in radiotherapy that permits further individualization of treatment using either functional imaging such as MRI and PET to guide the areas that need more radiotherapy or focused radiotherapy (such as Stereotactic ablative radiotherapy) to areas of tumour that cannot be removed by surgery.
The aim of the research is to further personalise the way radiotherapy is delivered using characteristics specific to an individual patient and/or tumour. The ultimate impact in clinical practice would be improvement in local tumour control and reduction in toxicity caused by radiation.

Technical Summary

Despite several advances in techniques of radiotherapy planning (intensity modulated radiotherapy (IMRT), tumour imaging (PET, MRI); radiation delivery (rotational arc therapy, flattening filter free), image guided radiotherapy (IGRT), the techniques and doses used for radiotherapy treatments of gastro-intestinal malignancies cancers have remained unchanged. The outcomes of patients with tumours such as oesophagus; treated with chemo-radiotherapy in the radical setting have not improved over the last decades with local failure (in the radiotherapy target volume) being predominant. The causes of local failure are due to several aspects: inadequate radiation dose, hypoxia, failure to target areas that have an unfavourable micro-environment. The advances in technology offer an opportunity to explore novel approaches.
The aim of my research has 3 main themes with the ultimate aim of maximising clinical benefit in terms of better tumour control and reduction in toxicity.
1. Strategies of modulating radiotherapy (SMART). Radiotherapy dose escalation techniques using Simultaneous Integrated Boost (SIB) permits intensification of radiotherapy dose to predetermined volumes of the highly conformal target volume e.g. Tumour control probability/ normal tissue control probability (TCP/NTCP) models can be then used to refine the escalation further. The SIB could be derived from biological imaging such as PET or functional MRI. These techniques can incorporate imaging as a biomarker for outcome and toxicity with the aim to individualise dose and fractionation delivered. Combination with biological agents would be tested to further improve the therapeutic ratio.
2. Margin intense therapy concept. The use of stereotactic ablative radiotherapy to areas at risk of positive margin at surgery with the aim of achieving complete tumour resection in tumours such as pancreatic cancers.
3. Refining normal tissue toxicity modelling in thoracic malignancies. The objective of this work would be to characterise and corroborate lung, heart and oesophagus radiotherapy toxicity parameters and develop individualised RT delivery techniques to mitigate dose to susceptible cardiac and or lung substructures. Develop patient selection and specific cardiopulmonary optimisation when multimodality approach such as chemo-radiation followed by surgery is required. Novel MRI techniques would be tested to characterise changes and aid develop patient specific RT delivery.

Publications

10 25 50
 
Description IMRT Foundation Workshop RCR
Geographic Reach National 
Policy Influence Type Influenced training of practitioners or researchers
Impact Improvement of radiotherapy technique delivery with a reduction in morbidity of treatment
 
Description IMRT implementation for anal cancer radical radiotherapy
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
Impact the uptake in IMRT and related outcomes for anal cancer was audited by the Royal College of Radiologists Q4 2015. the results of the audit will hopefully confirm outcomes.
 
Description SABR Consortium Radiotherapy Guidance
Geographic Reach National 
Policy Influence Type Citation in other policy documents
 
Description ATR inhibitor and radiotherapy in oesophageal cancer Phase I trial (CHARIOt)
Amount £13,555,316 (GBP)
Funding ID C43735/A20874 
Organisation Cancer Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2016 
End 02/2020
 
Description Human Immune Discovery Initiative (HIDI
Amount £12,500 (GBP)
Funding ID Initial assessment of circulating immune cell populations in response to stereotactic body radiotherapy in patients with borderline resectable pancreatic cancer Reference Number: 0005924 
Organisation University College Oxford 
Sector Academic/University
Country United Kingdom
Start 10/2018 
End 10/2020
 
Description Lead: 2017 CRUK/17/015 CEDAR: Chemoradiation with Enadenotucirev as a radiosensitiser in locally advanced colorectal cancer
Amount £400,000 (GBP)
Funding ID CRUK/17/015 
Organisation Cancer Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start  
 
Description Merck CGAA colab 
Organisation Merck
Country Germany 
Sector Private 
PI Contribution discussion regarding potential development of Phase II study with the ATR-i once trial completed
Collaborator Contribution discussion regarding supply of investigational agent
Impact none
Start Year 2019
 
Description Refining radiotherapy in oesophageal cancer 
Organisation Cancer Research UK
Department Wales Cancer Trials Unit
Country United Kingdom 
Sector Academic/University 
PI Contribution developed radiotherapy dose escalation models estimating improvement in outcomes for definitive chemo radiation in inoperable oesophageal cancer
Collaborator Contribution provided database and data interpretation, visiting PhD student
Impact Early collaboration so abstract submitted to ESTRO 2014 and manuscript published Trial successfully funded by CTAAC
Start Year 2013
 
Description Refining the normal tissue parameters for radiotherapy treatments in lung cancer 
Organisation University College London
Country United Kingdom 
Sector Academic/University 
PI Contribution data analysis of radiotherapy delivered part of a CRUK funded trial
Collaborator Contribution provided data (UCL) stats support (Liverpool)
Impact abstracts and oral presentations at international meetings
Start Year 2015
 
Description Refining the normal tissue parameters for radiotherapy treatments in lung cancer 
Organisation University of Liverpool
Country United Kingdom 
Sector Academic/University 
PI Contribution data analysis of radiotherapy delivered part of a CRUK funded trial
Collaborator Contribution provided data (UCL) stats support (Liverpool)
Impact abstracts and oral presentations at international meetings
Start Year 2015
 
Title A phase I dose escalation safety study combining the ATR inhibitor M6620 with chemoradiotherapy in oesophageal cancer & other solid cancers using time to event continual reassessment method 
Description To determine the best tolerated M6620 treatment schedule (or phase II recommended dose (RPTD)) administered concomitantly with radiotherapy (RT) only in the palliative treatment of oesophageaL cancer. trail activated and recruiting patients 
Type Therapeutic Intervention - Drug
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2018
Development Status Under active development/distribution
Impact this is a phase I trial 
URL https://www.oncology.ox.ac.uk/trial/chariot
 
Title Addition of stereotactic body radiotherapy to systemic chemotherapy in locally advanced biliary tract cancers(Cancer Research UK & UCL Cancer Trials Centre) 
Description CRUK funded trial 
Type Therapeutic Intervention - Radiotherapy
Current Stage Of Development Refinement. Clinical
Year Development Stage Completed 2015
Development Status Under active development/distribution
Impact none at present 
 
Title Clinical Trial: CORE Conventional Care Versus Radioablation (Stereotactic Body Radiotherapy) for Extracranial Oligometastases 
Description TBA 
Type Therapeutic Intervention - Radiotherapy
Current Stage Of Development Refinement. Clinical
Year Development Stage Completed 2016
Development Status Under active development/distribution
Clinical Trial? Yes
Impact TBA 
URL http://www.isrctn.com/ISRCTN45961438
 
Title Clinical Trial: PLATO - Parsonalising Anal Cancer Radiotherapy Dose 
Description TBA 
Type Therapeutic Intervention - Radiotherapy
Current Stage Of Development Refinement. Clinical
Year Development Stage Completed 2016
Development Status Under active development/distribution
Clinical Trial? Yes
Impact TBA 
URL http://www.isrctn.com/ISRCTN88455282
 
Title Clinical Trial_SBRT pre-operatively for borderline resectable pancreatic cancer (OCTO) 
Description phase I trial to find the maximum tolerated dose of margin intense stereotactic ablation radiotherapy for borderline resectable pancreatic cancer 
Type Therapeutic Intervention - Radiotherapy
Year Development Stage Completed 2015
Development Status Under active development/distribution
Clinical Trial? Yes
Impact trial ongoing 
URL http://www.oncology.ox.ac.uk/trial/sparc
 
Title Clinical trial: SCOPE2 - Study of chemoradiotherapy in oesophageal cancer including PET response and dose escalation 
Description TBA 
Type Management of Diseases and Conditions
Current Stage Of Development Refinement. Clinical
Year Development Stage Completed 2015
Development Status Under active development/distribution
Clinical Trial? Yes
Impact TBA 
URL http://www.isrctn.com/ISRCTN97125464
 
Description presented poster with trial update at patients meeting during AMMF Conference May 2018 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Patients, carers and/or patient groups
Results and Impact discussion about potential benefits to patients if they would consider participation int he trial
Year(s) Of Engagement Activity 2018
 
Description A Witztum_Oxford Science Fair (Jun 2016) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Supporters
Results and Impact presenting public opportunities and challenges in undertaking basic research
Year(s) Of Engagement Activity 2016
 
Description Ben George_Talk about radiotherapy to Sixth Form students at a local secondary school in January. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact TBC
Year(s) Of Engagement Activity 2018
 
Description CRUK Grand Challenge Meeting (London, Jan 2015) 
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 brainstorming meeting to propose research idea for forthcoming CRUK grand challenge proposal
Year(s) Of Engagement Activity 2015
 
Description D Holyoake_CRUK Shine Night Walk 2016 "Thank-you" video (national coverage) (2016) 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact video to thank supporters and participants to a CRUK event
Year(s) Of Engagement Activity 2016
URL https://www.youtube.com/watch?v=JEgfhwV1D_Y
 
Description L Bendall_MRC festival of medical research roadshow (UK, June) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact Louise helped out during the MRC science festival. She spent the day in Banbury as part of the MRC festival of medical research roadshow around Oxford. It aimed to engage with the public and explain to them some of the research currently undertaken by the MRC in the "fight against cancer" using the immune system. I did the Banbury stint, but the outings aimed to reach members of the public in and around Oxford (particularly small local towns).
Year(s) Of Engagement Activity 2016
 
Description Louise Bendall_Volunteering with a summer school (UNIQ), 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Louise did some volunteering with a summer school (UNIQ), teaching year 12 students about Radiotherapy physics. (two 1.5 hour sessions) on 24-27th July.
Year(s) Of Engagement Activity 2017
 
Description M Hawkins_reviewing Macmillan Cancer Support's booklet on Understanding primary liver cancer 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Received a request from Macmillan Cancer Support to review/comment on their booklet "Understanding primary liver cancer" as a specialist reviewer.
Year(s) Of Engagement Activity 2016
 
Description Maria Hawkins_SABR talk for Royal Berkshire Hospital 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact TBA
Year(s) Of Engagement Activity 2018
 
Description Pancreatic Cancer UK Anniversary Event (Feb 2016) 
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 The event celebrated 10 years of PCUK charity work and highlighted the research and other improvements made in pancreatic cancer
Year(s) Of Engagement Activity 2016
 
Description Talk re: stereotactic radiotherapypancreatic cancer 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Pancreatic Cancer UK Summit on Survival
Stereotactic body radiotherapy in pancreatic cancer

Discussion re access to novel radiotherapy techniques
Year(s) Of Engagement Activity 2013
URL http://www.pancreaticcancer.org.uk/campaigning/annual-summit/2013-summit-on-survival
 
Description promoting trial at conference 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Patients, carers and/or patient groups
Results and Impact poster presentation of the trial at the conference. I have discussed with other researchers the rationale of the trial and interventions. I have discussed with PPI how the trial adds to current knowledge
Year(s) Of Engagement Activity 2017