Technology in Radiotherapy Feasibility Studies

Lead Research Organisation: University of Central Lancashire
Department Name: Sch of Comput Engin and Physical Sci

Abstract

The context of the research:Approximately one in three people will develop cancer at some point in their lives. Technical improvements in diagnosis and treatment have significantly contributed to improved survival in recent years: the 5 year rate is now 50% and the 10 year rate has doubled in the last 30 years. It is in this context that our research group operates, particularly with reference to radiotherapy, which treats 40% of patients.Each proposing institute has an established track record of delivering innovative research, both individually and as a consortium. Indeed, we jointly created the Engineering & Computational Science for Oncology Network (ECSON), with the aim of establishing a basis for free exchange of cross-disciplinary expertise and knowledge to expedite technical solutions to problems in cancer therapy. Funded by the EPSRC Collaborating for success through people programme, ECSON is a formidable hub composed of 24 leading academic, research, commercial and clinical institutions from 6 European countries.Whilst the majority of physics/engineering activity in oncology is focused on delivering translational research that will be beneficial to patients in the short-term, this feasibility account presents an opportunity to explore some of the riskier ideas, with the potential to engender significant changes in long-term knowledge and treatment, that have emerged from the rich breeding ground of ECSON.The aims and objectives:The proposed research has the potential to open unexplored avenues of investigation of particular relevance to radiotherapy. However the tools and techniques we hope to create may provide the means for other investigators to conduct studies that could well be tangential to our aims.There are 4 themes to our proposal, drawing on different strengths of the proposing institutes:-We aim to investigate the bio-mechanical properties of healthy and cancerous cells when subjected to radiation exposure. We think this could provide evidence implicating the cellular structure as a whole in their response to radiation, as opposed to just the nuclear DNA.-We will investigate subtle structure in 3D/4D (i.e. moving 3D) medical images that we think clinicians may sub-consciously refer to when looking at images. This is particularly relevant to modern image guided radiotherapy where image quality is poor in comparison with diagnostic data.-We will model the complex cytoskeletal structure in cells. We believe this structure is implicit in a cell's mechanical strength, so understanding its structure fully will enable scientific, evidence-based analysis of its contribution. Also we will investigate how it varies in cancerous cells and cells exposed to radiation.-We will measure the 3D movement and articulation of head and neck radiotherapy patients' faces. We hope that we will be able to identify early predictors of treatment complications that can result in loss of facial function.Potential applications and benefits:Each of these themes constitutes an exciting, high-risk, but potentially very rewarding avenue of investigation. If realised, our research aims could, in the medium to long term, bring about very significant benefits in the radiotherapy process. We think they could lead to the introduction of new procedures, improvement in existing treatment methods, or even the dawn of a completely new ways of understanding the manner in which radiation interacts with healthy and diseased cells - i.e. the way in which radiotherapy works! Beyond radiation therapy, we hope that any tools we might develop, or discoveries we might make, during the proposed research could open up a number of new topics for academia. In this respect we are well placed, as the cross-disciplinary nature of the ECSON network provides the means to rapidly communicate findings outside our traditional subject areas. We believe that this work could provide immense gains across all medical fields.

Planned Impact

If successful the proposed research presents the medium to long term possibility of bringing about very significant benefits to the patients and clinical staff across the radiotherapy process, as well as to relevant manufacturing sectors. Who will benefit from this research and how ? Patient Beneficiaries: Nearly half of all cancer patients have radiotherapy and the proposed research has the potential to majorly impact this process. The research on biomechanical properties of cells can have significant future impact on the delivery of radiotherapy. If mechanical properties do indeed alter as a result of radiation insult for mammalian cells, as it is hypothesised, it would radically change the conventional views on how ionising radiation kills both healthy and pathological cells and as a consequence would lead to improved treatment procedures. Quantifying clinical image structural content, as proposed, will be instrumental in limiting the additional radiation dose delivered to patients. A formal, quantifiable, understanding of cytoskeletal structure would bring closer the goal of being able to model the cell as a chemo-mechanical system. Such a model would be a major tool in studying drug and radiation insult to cells, where structure change plays a significant role - e.g. cancer, and Alzheimers disease, etc. If the proposed feasibility studies show a potential for using facial scans to measure a radiation-induced damage, then this would be likely to open a completely new way of non-invasive monitoring of radiotherapy for head and neck patients. Furthermore, it would be of benefit to other patients, such as stroke patients, enabling early detection of symptoms and better patient care. Clinical Staff Beneficiaries: Clinical experts are pressed for time to accurately define tumour position during pre-treatment planning, let alone on each day of treatment. The clinically oriented image metrics investigated in the proposed research will provide the potential for simplified, automated procedures for treatment monitoring, freeing-up the valuable time of clinical staff. Drug design is one area in which biomolecular computer modelling is becoming more prevalent. For cellular diseases such as cancer, where therapeutic drugs often work by interaction with the cytoskeleton, e.g. tomoxifen, the ability to accurately model cytoskeletal structure in healthy and diseased cells would be of inestimable benefit. For facial dysfunction assessment, there exists no robust and quantitative measurement of facial articulation, other than subjective judgement. The proposed research will contribute to the development of objective standards, by discovering possible metrics for changes in facial symmetry and weakness, leading to a reduction in precious clinicians' time that currently spent in visual examination and diagnosis. Manufacturers: Radiotherapy is a technology driven activity, so with the proposed standardised clinical image quality measures, manufacturers of imaging modalities and treatment planning systems would be in a better position to respond to clinical needs. Research on cell biomechanics and facial scans, if successful, would have very significant effects on manufacturing industry, e.g. by opening completely new markets for dynamic 3D scanners, or atomic force microscopes. Action plan to ensure that beneficiaries will have the opportunity to benefit from the project As the proposed project consists of feasibility studies, it is very difficult to predict their outcomes and consequently plan for their exploitation, but whatever outcomes will be achieved, they will be communicated to the wider research community, clinicians, patient groups, and relevant manufacturing sectors, through dissemination of the results. Feasibility account results will also be presented at public events, open days, etc. This will include the creation of CDROM 'story-boards' to share scientific concepts and their clinical applications.

Publications

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Emsley HC (2011) A new way of looking at the face? in British journal of hospital medicine (London, England : 2005)

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Hedley C A Emsley (Author) (2011) A new way of looking at the face? in British journal of hospital medicine (London, England : 2005)

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Matuszewski B (2012) Hi4D-ADSIP 3-D dynamic facial articulation database in Image and Vision Computing

 
Description Technological research into improving cancer treatment continues to develop new devices to bring about patient benefits. But typically it deals with fairly mature ideas. In order to have a good supply of such mature ideas it is important to "feed the other end of the pipe" by sometimes looking at new ideas that are radical, new and often highly speculative. TeRaFS is a project which looked at four such new ideas and carried out the basic groundbreaking research necessary to evaluate whether these ideas could eventually become clinically useful. While the investigation of such speculative ideas is clearly risky, they also hold out the prospect of huge potential benefits.
TeRaFS looked at four such ideas:
Theme 1: The mechanisms by which cells, both cancerous and normal, react to radiation are not fully understood. In particular how does radiation affect the mechanical strength and integrity of cells? Could it be that cancer cells, which are already compromised in their structure, are particularly vulnerable to further mechanical damage caused by radiation? Is that why they die more readily under radiation insult than normal cells? If so, is this an opportunity to further "fine tune" radiation delivery to patients? Work in this theme developed new experiments to answer these questions and found that the mechanical properties of cells are indeed affected by radiation. It also found that cancer cells are more likely to exhibit this behaviour than normal cells. Next step is to answer how this new knowledge can be exploited to provide better treatments.
Theme 2: Radiotherapists use their expertise to visually analyse medical images and decide where boundaries between tumours and organs lie. This is a subjective process in which we hypothesise that the clinical expert may be subconsciously using information that is very subtly held within the medical images. This theme aimed to work out how useful a clinical image is in terms of putting hard parameters upon this process and therefore standardising the procedure in clinical use. The work has developed new parameters for assessing image quality and the theoretical work here may form the basis for a whole new outlook offering a 'quantitative' approach to many aspects of practical medical imaging.
Theme 3: Much of the mechanical strength and integrity of a cell stems from a fabulously complex mesh that occupies the interior of the cell. It can be imaged via a technique known as confocal microscopy and our task here was to develop analytical tools that could be used to make sense of this structure. We found that it is indeed possible to make some sense of it, with the development of fully automatic methods for delineation of complex structures from microscopy images opening ways for mass scale statistical analysis of cell data. We have also shown that the newly proposed measure of structural data disorder from theme 2 can indicate cell well-being. This may open the way to fully automatic quantifiable characterisation of cells into those with normal internal structures and those like cancer cells with disrupted internal structures.
Theme 4: New methods for the early detection of facial dysfunctions were studied here by using dynamic optical scanning of patient's faces. This theme developed tools for assessing facial dysfunctions using probably the most comprehensive 3D dynamic facial articulation database to date. This work has provided a genuine foothold for introducing such optical 3D technology to wide clinical practice and has demonstrated a real potential for assessing neurological patients. The next step is to apply these tools in different clinical setting, including dysfunctions caused by head and neck radiotherapy.

The research team has been supported in their investigations by a research network previously created the Engineering & Computational Science for Oncology Network (ECSON), providing platform free exchange of cross-disciplinary expertise and knowledge to expedite technical solutions to problems in cancer therapy.
Exploitation Route The research on biomechanical properties of cells can have significant future impact on the delivery of radiotherapy. During the project it has been shown that mechanical properties of cells do indeed alter as a result of radiation. This could radically change the conventional views on how ionising radiation kills both healthy and pathological cells and as a consequence could lead to improved radiotherapy treatment procedures. A formal, quantifiable, understanding of cytoskeletal structure could enable to model the cell as a chemo-mechanical system. Such a model can be a major tool in studying drug and radiation insult to cells, where structure change plays a significant role - e.g. cancer, and Alzheimers disease, etc.
Clinical experts are pressed for time to accurately define tumour position during pre-treatment planning, let alone on each day of treatment. The investigated clinically oriented image metrics has shown potential for simplified, automated procedures for treatment monitoring, freeing-up the valuable time of clinical staff. Indeed the Approximated Entropy Metric tools developed during the TeRaFS project will be utilised on the recently awarded MRC project "Making cone beam CT imaging fit for aggressive targeting & adaptive re-planning of photon and proton radiotherapy".
The research has demonstrated potential for using 3D dynamic facial scans to measure objectively facial dysfunctions, using metrics assessing changes in facial symmetry and face articulation. These findings can lead to a reduction in clinicians' time that currently is spent on visual examination and diagnosis. Indeed it seems that a fully automated assessment procedure could be possible. These findings have been influential for the currently awarded FP7 project "Semitic Oriented Technology for Individual's Cardio Metabolic Risk Self-assessment and Self-Monitoring".
Sectors Digital/Communication/Information Technologies (including Software),Healthcare

 
Description The investigations that have been carried out into the biomechanical effects of subjecting various types of living human cells to ionizing radiation insult have formed a valuable foundation for future research in that they have set the groundwork in this newly emerging area. The work by GERI at Liverpool John Moores University here is perhaps the most speculative of the TeRaFS research themes and is truly blue sky research. Impact here is in the form of the basic research that has set up new protocols and experimental methods in this area, along with the corresponding early sets of results, with this body of data itself representing a world first. Methodologies such as the experimental protocols for controlled irradiation of monolayer cell samples and the analysis, modelling, visualisation and future-proofed database tools that have been developed all form a directly relevant and usable set of resources upon which future research can be built. Current clinical practice in radiotherapy tailors spatial radiation beam volume geometries to the patient's physical form, but does not customise the treatment in terms of individual radio-sensitivity. This research may represent the very first steps towards truly customising radiotherapy treatments to individual patients. Impact is also shown by way of the growth of the GERI Cell Mechanics Group and the recent investment by LJMU in recruiting a new Professor in this area. In the current clinical practice the assessment of facial dysfunction is based on direct observations performed by clinicians, which inevitably can be somewhat subjective. The results of the conducted feasibility study based on the preliminary quantitative metrics developed for 3D dynamic facial scans show an excellent prospect for measurement of small changes in facial symmetry and weakness. This can impact on the way patients are assessed and monitored, as well as reduce precious clinicians' time currently spent on visual examination and diagnosis. This also opens a completely new way for effective and non-invasive monitoring of patients with facial dysfunctions either due to side effects of the treatment (radiation therapy), trauma (stroke) or neurodegenerative diseases (Parkinson's disease). Furthermore, the work on quantitative facial assessment has great potential to form a basis for practical implementation of a novel measurement tool in wider clinical practice including GP. To compactly parameterise real-world clinical images, we have succeeded in producing the first two and three dimensional extensions of the approximate entropy regularity measure. This retains the vital link between spatial and grey scale content. By applying the dimensionally extended approximate entropy metric to real clinical CBCT image volumes of cancer patients and confocal microscopy image stacks of normal and cancer cells, we have been able to produce compelling initial evidence that the new metric can be used to indicate structural boundaries in tissues, and malignant changes to cytoskeletal arrangement. The extended metrics that we have developed during this project will provide additional information to assist in delineation of target volumes in radiotherapy, a notoriously difficult problem acknowledged being a significant factor limiting treatment accuracy.
First Year Of Impact 2011
Sector Digital/Communication/Information Technologies (including Software),Healthcare
Impact Types Economic

 
Description ENSEA Scientific Council
Amount € 10,000 (EUR)
Funding ID BIO MICMAC Project 
Organisation National School of Electronics and Applications (ENSEA) 
Sector Academic/University
Country France
Start 04/2011 
End 12/2012
 
Description ENSEA Scientific Council (3DCell)
Amount € 5,000 (EUR)
Funding ID 3DCell 
Organisation National School of Electronics and Applications (ENSEA) 
Sector Academic/University
Country France
Start 06/2012 
End 12/2013
 
Description MRC Developmental Pathway Funding Scheme (DPFS)
Amount £285,000 (GBP)
Funding ID MR/L023059/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 10/2014 
End 09/2017
 
Description SEMEiotic Oriented Technology for Individual's CardiOmetabolic risk self-assessmeNt and Self-monitoring (SEMEOTICONS)
Amount £251,000 (GBP)
Funding ID FP7-ICT-2013-10, Project No. 611516 
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 11/2013 
End 10/2016
 
Description The Royal Society Travel Grant
Amount £5,200 (GBP)
Funding ID IE140026 
Organisation The Royal Society 
Sector Charity/Non Profit
Country United Kingdom
Start 08/2014 
End 08/2015