Radiotherapy cures local cancer by repeatedly targeting a tumour with small doses of radiation in 'fractions'. Though healthy tissues are irradiated, image assisted pre-treatment planning keeps this to a minimum. CT scans allow the body surface, tumour and critical organs to be seen to scale, so that the optimum shapes and directions of a set of radiation beams can be calculated. These are used daily in a treatment regime that may last weeks. The corresponding dose distribution is estimated and radiobiology can be used to predict the probabilities of cure and complications. How a patient will move or change during treatment itself, is unknown. Hence, an expert specifies a tolerance margin around the tumour and assumes everything else will stay as seen in the pre-treatment CT scan. On this simplified basis the patient is positioned on each day of the treatment.When treatment is in progress, and radiation is being directed at the tumour, there is no monitoring of the patient's position or internal anatomy. Hence, a precisely planned treatment is delivered in a manner that is effectively blind. This situation persists, despite complex new treatments and image guided radiotherapy (IGRT) that now includes 'cone beam' imaging (CBI), which the investigators helped to develop. IGRT radiation dose and CBI practical limitations are new causes for concern. MEGURATH introduces metrology guided radiotherapy (MGRT), where the patient is measured, imaged and modelled during treatment delivery. It researches non-invasive, radiation-free, real-time 3D patient positional monitoring based on optoelectronic sensors using structured light to map the body surface. A prototype system, with unrivalled performance, has been successfully piloted by the investigators in the treatment room. This will be developed to include radical concepts of multi-colour, adaptive sensing, where the structured light projected onto the body surface is first pre-adapted to the shape information available in patient's CT planning scan and then refined during use. The MEGURATH sensors will be synchronised with novel low radiation dose CBI based on acquiring images of the patient between treatment beams. This approach has been piloted by the investigators along with an innovative CBI collimator design that has the potential to halve patient dose, yet improve contrast in the reconstructed volume image. In a feedback loop, the CBI will then be optimally corrected for measured motion that is not necessarily periodic. Reconstructive imaging will then be combined with dynamic deformation modelling, to quantify changes in the shapes and positions of the tumour and nearby organs. Pilot work using sensor measurements to deform treatment plans has been reported by the investigators. Extending this approach across the irradiated part of the body will make it possible to describe the shape changes that occurred in the patient during irradiation. This will be the first time that a point by point model of the patient during treatment has been constructed from live measurements. In turn, this will finally make it possible to use radiobiology to calculate the probabilities of tumour cure and complications for the treatment actually delivered, and to compare this with the treatment that was planned.MEGURATH has strong, diverse theoretical components. It also has an ambitious programme for the translation of science and technology into the first purpose built IGRT research facility in the UK. It is materially supported by the manufacturers of IGRT and treatment planning equipment. Hence, it offers a unique opportunity to advance clinical practice beyond IGRT to MGRT and to use the skills of scientists, mathematicians and clinicians to address cancer treatment at some of the most significant and mobile disease sites, not least breast, lung and pelvis.

Radiotherapy is an important cancer treatment given to about 125,000 patients each year. It is typically delivered in daily doses (fractions) over a period of several weeks using multiple high energy X-ray (and now proton) "beams". The beams are individually shaped for each patient and designed to overlap at the precise location of the target disease. The intention is to give maximum dose to the cancer cells while minimising dose to nearby healthy tissues. Usual practice is to plan the arrangement and shape of these treatment beams based on CT images taken before treatment begins. Ensuring that the patient and their tumour target are in the correct position for treatment on each day of their therapy is challenging. Small changes (more than a few millimetres) could invalidate the pre-treatment planning leading to the target receiving too low a dose of radiation (and hence reduced chance of cure) or healthy tissues receiving too high a dose of radiation (and hence increased chance of side effects). The use of cone-beam CT (CBCT) imaging within the treatment room to check patient position, pose, and anatomy just before the radiation beams are switched on has recently become widespread. However, changes in patient shape can be complex, making it difficult to calculate whether the resulting change in radiation dose received will be significant - that is, will it be necessary to alter the pre-planned treatment to take account of the change? Our aim is to simplify this decision process. We will develop a computerised method that uses a patient's CBCT image to calculate changes from their prescribed and planned dose. Currently this is not possible because calculation of radiation dose requires accurate data on tissue density within the patient, in order to determine how X-rays (or protons) will interact with their anatomy. Unlike CT images, which are used to generate the initial treatment plan, CBCT images do not give accurate information on tissue density. This project will develop a method to "correct" the CBCT images so that the tissue density information that they contain can be used to directly compute delivered doses. This will be of significant benefit to radiotherapy patients since staff we be able to quickly check that the correct dose will be delivered, or if it is necessary to take action to avoid incorrect doses. Currently this process is very time consuming - tissue boundaries have to be manually drawn onto CBCT images and assumed density values assigned to each region. The technology we propose to develop will accelerate such assessments, estimated to be necessary for about one fifth of CBCT images. A further benefit is that our correction method not only restores accurate CBCT density values, but also markedly improves visual image quality. This makes images easier to interpret and more suitable for automatic analysis, with potential for further time savings. The project builds on our previous work, where we have developed a correction method that appears to be effective for pelvic or head and neck images. We have acquired a UK patent for this invention, ensuring that benefits and value to the NHS can be maximised. In this project we propose to extend our method for use in lung images. This site is challenging due to the large differences in tissue densities present (lung, soft-tissue, bone), and the inherent respiratory motion. We will additionally investigate the suitability of corrected CBCT images for the planning of proton radiotherapy, a looming challenge as we move towards the opening of the first high-energy proton therapy centres in the UK.

In this grant we will develop a more accurate way of processing medical images from patients receiving cancer therapy using radioactive materials that target their tumours, known as Targeted radionuclide therapy. These images are taken using a SPECT (Single Photon Emission Computed Tomography) scanner which typically produces images which are quite blurry and noisy. By modelling the SPECT scanner system on a computer we can create a range of corrections which will improve the accuracy of the information from these images. This information will ultimately be used to provide doctors treating patients with an accurate measurement of the radiation dose delivered to the tumours and also to the rest of the patient's body. Using current SPECT images, the uncertainties in dose estimation do not allow treatments to be optimised and consequently a significant proportion of patients do not receive the optimal therapy. Identification of these patients is problematic due to the current low accuracy of dose measurements, especially in the kidney and bone marrow which are often the dose limiting organs. Having this improved dose information can help doctors to improve their therapies and plan for treatments with reduced side effects and potentially reduced hospital stays. This will improve the patients' experience of this type of therapy and also improve the efficacy of the therapies by allowing the doctors to individualise the treatment for each patient. Only by improving the accuracy of the images obtained from the SPECT scanner can we provide this information. Accurate dose information is considered very important in countries across Europe and legislation is being written recommending this be done for every patient receiving this type of treatment. Our research will concentrate on improving the dose information for therapies using the isotope 177Lu. Recent work has shown that new treatments using this isotope can improve a patient's life expectancy by several years compared to congenital therapies, particularly for tumours effecting the hormonal and nervous systems. Our research will provide the basis for developing a commercial solution which will allow the techniques from this grant to be used in all clinical departments performing cancer therapy with these radioactive materials. It can be extended to cover the complete range of isotopes used for therapy and for images from different models of SPECT scanner. This will provide a significant improvement in the outcome of an estimated 201,000 such therapies performed annually in Europe.

Molecular Radiotherapy (MRT) is a relatively common procedure in counties with developed healthcare systems. In this procedure, a labelled radioisotope is administered to the body in order to irradiate and kill tumour cells whilst sparing the surrounding healthy organ tissue. In the UK alone, there are some 200 departments performing over 11000 MRTs annually and ~200,000 therapies in some 28 EU countries. In a recent development towards personalised healthcare, a new EU directive 2013/59 was introduced which requires that all Member states performing any form of radiotherapeutics (including MRT) must provide dosimetry treatment planning for each patient by 6th February 2018. Although this may sound like an obvious situation, MRT has in fact been used clinically for around 75 years with no fully established dosimetry practice for calculating the absorbed dose delivered to tumour targets or to organs at risk. Even though the general steps have been agreed, there still exists a wide variation in the current acquisition, quality and treatment of images used to determine dose. As a result, treatment protocols have often evolved locally, based on experience with a relatively small numbers of patients. Although such patients would all have received similar administered activities, the actual dose received to particular organs could have large variations. As a consequence of the complexities involved, the application of radionuclide dosimetry has been restricted to those academic groups with the facilities to develop in-house techniques. Very few therapy centres currently can validate dose calculations to a known level of accuracy and only a few academic therapy centres can perform MRT Monte Carlo (MC) calculations. Our group, established between The University of Manchester and The Christie, has developed the ability to deliver this within a very large MRT practice. We were recently selected to lead the EU work on validating dose calculations from simulated patient phantoms and physical 3D printed phantoms in the EMPIR MRTDosimetry project (2016-19). The project will provide a standardised European framework for clinical implementation of MRT dose planning. In our approach, developed with an STFC Mini-IPS grant, 3D-printed patient analogues (phantoms) are constructed based on patient CT images. This novel technique has clear potential to provide the foundation of a clinical service to provide a basis for improved activity quantification to all clinical centres and MRT patients in the UK. We are uniquely positioned to deliver this work, having access to a large data base of MRT patient data at The Christie. Working with these data, we can provide the foundation for establishing a future national clinical service. The Christie has the experience in both MRT dosimetry research and in providing training and support for a national clinical service (PET/CT) required to provide a MRT dosimetry service. In addition our collaboration has strong links with industry, in particular Hermes Medical Solutions Ltd, a leading provider of nuclear medicine workstation software. By developing a comprehensive validation methodology for clinical dosimetry systems, and thereby demonstrating that the HERMES dosimetry system meets this standard, our collaboration will be able to provide a de-facto validation standard for clinical dosimetry systems and a market leading package. These links provide a pathway to distribute the techniques to the wider EU and international nuclear medicine market. In turn, this improves patient outcomes by allowing modification of therapy based on disease response and also benefits the healthcare provider by maximising outcome for the same or reduced resource.

With this grant we will develop a far more accurate way of processing medical images from patients receiving cancer therapy using radioactive materials that target their tumours, known as Targeted Radionuclide Therapy (TRT). These images, taken using a hospital SPECT (Single Photon Emission Computed Tomography) scanner, are typically quite blurry and it is often difficult to distinguish tumours from normal healthy tissue. Based on our previous findings, by modelling the SPECT scanner system on a computer we will create a range of corrections that improve the accuracy of the information from these images. Our collaboration has successfully shown that we can significantly improve this accuracy for a variety of simple models representing the human body. We now wish to use this work as the basis of an advanced technique which will provide the same improvements for data from more detailed models of the human body and ultimately for actual patients receiving cancer therapy. This information will be used to provide doctors with an accurate measurement of the radiation dose delivered to the tumours and critical organs in the patient's body. Using current commercial SPECT images, the uncertainties in dose estimation do not allow treatments to be optimised and consequently a significant proportion of patients do not receive the optimal therapy. Identification of these patients is problematic due to the current low accuracy of dose measurements. Having this improved dose information will help doctors to improve their therapies, potentially reducing side effects and hospital stays. This will improve the patients' therapy experience and also improve the efficacy of the therapies by allowing the doctors to optimise the treatment for each patient. Only by improving the accuracy of the images obtained from the SPECT scanner can we provide this information. Accurate dose information is considered very important in countries across Europe. Legislation is currently being written recommending accurate dosimetry for every patient receiving Targeted Radionuclide Therapy treatment. Our research will concentrate on improving the dose information for therapies using the isotope 177Lu. Recent work has shown that new treatments using this isotope can improve a patient's life expectancy by several years compared with other therapies, particularly for tumours affecting the hormonal and nervous systems. Our research will provide the basis for developing a commercial solution that will allow the techniques developed from this grant to be used in clinical departments performing cancer therapy with 177Lu. However, it can be extended to cover the complete range of isotopes commonly used for therapy and for images from different models of SPECT scanner. We have already approached two commercial companies who are interested in helping bring this research to market. This has the potential to provide a significant improvement in the outcome of an estimated 201,000 such therapies performed annually in Europe.