Title: Histopathological validation and optimisation of hypoxia and perfusion imaging
Funder: Health Education England

Abstract: Solid tumours often have a highly disorganised microvasculature resulting in poor perfusion and oxygen delivery; combined with their high metabolic rates, this often leads to oxygen demand outstripping oxygen supply causing tumour hypoxia. Hypoxia is one of the hallmarks of cancer and is integral in the pathophysiology of tumour biology, driving malignant progression. This research will determine an optimised method to image hypoxia and perfusion allowing:Stratification of patients, enabling hypoxia or perfusion modifying treatment to be targeted to the most appropriate patientsEarly assessment of treatment response, enabling clinicians to determine the effectiveness of the interventions targeted to alter the hypoxia or perfusion status of the patient's tumourSpatial distribution of hypoxia or perfusion to be mapped, enabling radiotherapy (RT) patients to receive additional radiation to those areas to overcome the radioresistance An open clinical trial, ATOM, will provide the underlying imaging data that will be used in the research. This is a phase 0 window of opportunity' study investigating whether a short course of atovaquone reduces tumour hypoxia in patients with non-small cell lung cancer (NSCLC) prior to surgical resection. The imaging funded in the trial includes:fluoromisonidazole (FMISO, a hypoxia tracer) positron emission tomography (PET)perfusion computed tomography (pCT)dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) These images are analysed to obtain derived parameters, calculated on the basis of models. This data will be compared to tumour histology samples (considered the ground-truth) to validate the imaging techniques and determine the derived parameter that correlates most strongly with hypoxia or perfusion histology. To achieve this overall goal, the research plan has been sub-divided into four aims.Aim 1 Histopathological validation and optimisation of clinical hypoxia imaging Identify the optimal methods for imaging hypoxia by comparing derived parameters from advanced image analysis with NSCLC hypoxia histology samples. Additionally, the minimum effective timing schedule will be investigated for FMISO PET scans.Aim 2 Histopathological validation and optimisation of clinical perfusion imaging Establish the optimal methods for imaging perfusion by comparing derived parameters from advanced image analysis with NSCLC perfusion histology samples. Additionally, the optimal model to analyse time-courses of tracer uptake in DCE-MRI and pCT data will be determined.Aim 3 Evaluate test-retest reproducibility of derived parameters from imaging tests Determine the reproducibility of derived parameters from FMISO PET, DCE-MRI, and pCT including the optimal methods found in Aims 1 and 2.Aim 4 Assessment of drug response from optimal imaging tests Determine whether the optimum hypoxia and perfusion derived parameters can detect changes due to the action of atovaquone. Benefit to NHS and patients The optimal hypoxia and perfusion imaging technique (Aims 1 and 2) can be utilised within the NHS to stratify patients to receive appropriate treatment. In the oncology setting, for example, this could be achieved through additional RT dose delivered to hypoxic sub-regions of the tumour, in order to improve outcomes.In the context of using these imaging techniques to assess hypoxia or perfusion response to an intervention, Aim 3 will provide knowledge of the reproducibility for various derived parameters and so provide the threshold that the intervention being tested must pass to be shown to cause a significant difference.Aim 4 will determine the impact of atovaquone on a range of derived parameters. If atovaquone is shown to result in a reduction in tumour hypoxia, larger clinical trials will be conducted to determine whether this well-tolerated and inexpensive agent improves RT efficacy and clinical outcomes.

Lay abstract: Background Imaging plays a vital role in managing patients with cancer. Imaging can allow doctors to improve patient outcomes when they are treated with radiotherapy. Radiotherapy is a treatment that focuses radiation to kill tumour cells. However, radiotherapy is less successful when parts of the tumour are in a state called hypoxia. Hypoxia is a lack of oxygen. Hypoxia can be caused by poor perfusion. Poor perfusion means an irregular blood supply. More oxygen in tumours can make radiotherapy three times more effective, but first the hypoxia or poor perfusion must be identified. A recent independent UK cancer report recommended more research into radiotherapy based on advanced imaging. Research This research will compare how accurately different types of imaging measure hypoxia and perfusion. Calculations from the images before surgery will be compared against tumours once removed. This will confirm which hypoxia and perfusion image values are closest to the real tumour information Knowing this will mean: future patients can be screened for hypoxia and poor perfusion, when appropriate, patients can be treated to improve their hypoxia and perfusion, response to this treatment can be monitored, treatment can be targeted to specific tumour areas, and patients are needed for the minimum imaging time due to better procedures. Patient and Public Involvement The research is mainly focused on technical aspects of clinical work, but Patient and Public Involvement (PPI) has been included in as many aspects as possible, including this application. There is a PPI panel that will review research progress, advise on future work, and assist in the dissemination of results. Dissemination This research will be presented at conferences to inform professional and industry colleagues about my work. Research publications will also be submitted to journals. Together with the PPI team, we will inform patients and the public about the research through charities such as Cancer Research UK (CRUK). We would also aim to present the PPI involvement in this work at a suitable conference.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS