Title: Precision surgery for glioblastomas: determining individualised tumour resection volumes using advance MR imaging
Funder: Department of Health and Social Care

Abstract: Background: Glioblastomas are the most malignant primary brain tumour and have a dismal prognosis. Virtually all patients die of local progressive disease. Although improvements in surgery allow removal of the tumour seen on MRI, we know that conventional MRI does not identify all of the tumour. This 'residual disease' leads to early progression and deterioration in quality of life. Advanced MRI methods are sensitive to this disease and my research has shown more extensive resection of these areas improves outcome. Even though surgery is the most toxic therapy , we do not know the impact it has on quality of life. Developing new cognitive or visual lesions has not been studied, yet would inform us what we should avoid removing during surgery. At present, neurosurgeons face a dilemma. If we don't take enough tumour, then the tumour progresses and the patient's quality of life deteriorates sooner and their survival is reduced. If we extend our resection to improve local control we risk causing neurological deficits that lead to deterioration in quality of life. This Fellowship aims to provide information to help this problem by developing individualised surgical treatment volumes. Research Questions: This Fellowship aims to answer the following questions: Can we identify likely 'residual tumour' pre-operatively as a surgical target to optimise extended resection? What is the impact of extended and targeted resection on visual and cognitive deficits on patient functioning and quality of life? Can we develop intra-operative surgical methodology to allow extended resections? Methods: This study will explore three work-packages: WP1: IDENTIFYING 'RESIDUAL DISEASE' AS SURGICAL TARGET: WP1 will recruit a cohort of patients undergoing radical surgery for glioblastomas. 'Residual disease' will be defined as areas with pre-operative advanced imaging outside of area with increased amino acid PET (current fluorescent target). The primary objective is will be the presence of high density tumour in biopsy samples from these regions.WP2: IMPACT OF SURGICALLY INDUCED NEUROLOGICAL DEFICITS: This work package will recruit a cohort of patients with tumours in different brain regions and involve imaging pre- and post-operatively to outline the area of 'injury' to normal brain. We will then correlate anatomical disruption with changes in measures of quality of life, visual functioning and visual fields and neuropsychology.WP3: USING IMAGING TO GUIDE SURGERY: This work package will develop an intervention that involves image processing, surgical planning before surgical resection of 'residual disease'. Once an intervention has been defined I will take this to an early phase surgical trial - IDEAL stage 1 will be the 'first in man' report. IDEAL stage 2a will document and understand the iterative changes in developing this technique until a stable technique has been established. Secondary outcomes will study safety.Anticipated impact and dissemination: By the end of this Fellowship I anticipate I will have developed an intervention and a training package that will allow other surgeons to use this technique. I will have worked with the Papworth Clinical Trials unit to develop an adaptive trial design to explore efficacy of this intervention.

Lay abstract: Glioblastomas are the commonest and most aggressive form of malignant brain cancer. Unfortunately, we rarely cure these tumours so our aim is to maintain quality of life for as long as possible. As no new treatments are on the horizon we need to improve our current treatments.Surgery is a key treatment for brain tumours. Removing the entire tumour visible on MRI scans improves survival and maintains good quality of life. But virtually all patients will progress at the edge of the area removed at surgery. This is because these tumours spread into the surrounding normal brain. This invasion cannot be seen on normal MRI. If we knew where these invading areas are we might be able to extend surgery to prevent local spread into nearby brain.My research has used advanced MRI scans to identify these areas of tumour spread. We have developed methods that can show abnormalities that cannot be seen on normal MRI. Biopsies of these areas have been shown to be cancer. These areas are also the sites where tumours first progress. When we remove more of these areas we see better survival in patients.Unlike other parts of the body, in the brain we can't remove an area of normal tissue outside of the tumour. This can cause damage to the brain that will impact on the patient's function and quality of life. We know that damage to areas of the brain that control movement or are involved in speech and language cause serious problems for patients. Their quality of life is greatly affected. We don't know the effect on quality of life from damage to other brain functions - for example areas involved in vision and thinking. If we could show that damage to specific regions of the brain cause such problems with a person's ability to get about and look after themselves, we could avoid these areas. In this Fellowship I plan to study three areas: In a group of patients who need surgery to remove their tumour we will use our MRI scans to take samples at the end of surgery. This will show us if we can identify areas of cancer spread that has been left behind. This will help show what we need to remove. I will approach patients with brain tumours in areas near the vision and thinking pathways. Patients who agree to take part will have MRI scans of the brain (that look at these pathways and brain function) done before and after surgery. This will provide information on the exact location of any surgical damage. They will also have a series of tests of vision and mental function as well as questionnaires that test quality of life. We will then compare the site of brain injury (from the scans) with the effect on patients. We plan to use patients and carers to help interpret the impact of our results. I plan to use the data from the above stages to create an individualised map for each patient that shows the area of tumour that can be safely removed. I will develop methods that will allow this approach to be taken from the scanning room into the operating theatre. I will also develop the methods that will allow this to be used during surgery, that will allow me to use this in selected patients towards the end of this study. This study aims to allow us to improve planning of surgery for individuals. It will do so by working out the target for surgery for each patient, and then develop a method to use in the operating theatre.

Research activity codes: 6.4 SURGERY
Health categories: CANCER AND NEOPLASMS