Title: FUT U RE – GB Trial (Functional and Ultrasound guided Resection of Glioblastoma) A 2-Stage trial. Stage 1 Non-randomised learning phase evaluation of participating centres (an IDEAL study), followed by Stage 2 which is randomised,controlled Multicentre Phase III trial with 2 mechanistic substudies
Funder: Medical Research Council

Abstract: AIMS AND BACKGROUND: This project asks: What is the best technology a surgeon can use to remove as much brain tumour as possible, whilst minimising risk of damaging brain function? _x000D_ Glioblastoma (GB) is the most common primary brain tumour and is incurable. It grows very quickly from the brain tissue itself, rather than from a cancer elsewhere in the body. It is expected that the number of people with a brain tumour will rise by 6% in the UK between 2014 and 2035. Furthermore, the number surviving for 5 years or more has increased in the last 10 years, as new treatments develop. Therefore we need to ensure quality of life, which remains difficult. _x000D_ The main treatments for GB are surgery, radiotherapy and chemotherapy, given in combination. For patients where it is thought that surgery will benefit, a surgeon often removes as much tumour as possible, whilst limiting the risk of causing damage, such as weakness, speech, or cognitive difficulties. However, which equipment a surgeon should use during surgery to remove the tumour safely is unclear. This can affect how soon the cancer returns, what symptoms the patient has, and how a patient feels. High frequency sound waves which create an image, called Ultrasound (US), is one of the tools a surgeon can use during the operation to see the tumour and see how much is removed. Another, Diffusion Tensor Imaging (DTI), allows important nerve pathways involved in certain functions, for example, speech/language, vision and movement, to be avoided in surgery. This trial aims to see if GB surgery with these extra tools added to the standard ones, increases a patient’s good functioning quality of life, so-called Deterioration Free Survival (DFS). _x000D_ DESIGN: Future-GB is a randomised control trial. This means those who agree to take part will be allocated by chance (like the tossing of a coin). The trial plans to enrol 357 newly diagnosed patients to have either surgery with standard methods, or surgery using the extra tools (US and DTI) as well. Patients will not know into which group they have been placed. Patients will be recruited from 15 NHS hospitals which routinely undertake GB surgery and have access to these tools. The trial will result in only minor changes to the present care pathway. After agreeing to take part, patients will be asked to fill in questionnaires about their quality of life, such as: their walking, ability to look after their personal hygiene, how they feel. They will also have a brief physical and cognitive/functional assessment before their surgery. Afterwards, the questionnaires and assessments will be repeated, before discharge, and at 3 monthly intervals until 24 months following surgery. These will be combined with planned hospital visits. How long a patient lives will also be recorded._x000D_ PPI: The trial focuses on keeping good quality of life for people living with a GB. It has been designed with the help of patient support groups at the Brain Tumour Charity and Brainstrust, the patient relative advisory group at the Oxford Clinical Trials Research Unit and the Brain Tumour PPI Group at Imperial College Healthcare NHS Trust. Dr Helen Bulbeck (Brainstrust’s Director) has been part of the trial proposal. _x000D_ _x000D_ DISSEMINATION: Trial results will be published and widely shared via a variety of channels. If this research shows that patients benefit, it is expected that the tools will become standard care and help GB patients in all 24 UK NHS neurosurgery units, and worldwide.

Lay abstract: RESEARCH QUESTION: During glioblastoma (GB) tumour resection, does the addition of the intraoperative technologies Diffusion Tensor Imaging (DTI) and Navigated intraoperative UltraSound (NiUS), to standard care (neuronavigation based on preoperative MRI and intraoperative use of 5-aminolevulinic acid, 5-ALA), improve Deterioration Free Survival (DFS)?_x000D_ BACKGROUND: GB is incurable and the most frequent and aggressive form of brain cancer, with an extremely poor prognosis. Patients experience a decline in health-related quality of life (HRQoL), and caregivers report high levels of distress and carer burden. Surgery is the most effective treatment and maximal surgical resection improves survival, but carries a potential risk of morbidity. _x000D_ AIMS AND OBJECTIVES: The aim of FUTURE-GB is to evaluate whether the use of DTI and NiUS, in addition to standard intraoperative tools, during GB tumour resection, improves DFS. The research objectives are to assess the patient impact of using these supplementary surgical technologies during GB resection, with reference to DFS, overall and progression free survival, extent of tumour resection, surgical complications/adverse events, number of patients eligible for adjuvant therapy following surgery, and functional outcome (cognitive/physical/performance status) post surgery. In addition, there are two mechanistic components which asses the sensitivity and specificity of the anatomical location of fibre tracts on preoperative DTI compared with intraoperative direct electrical stimulation in patients undergoing awake surgery, and, NiUS to identify the tumour boundary when compared with 5-ALA._x000D_ METHODS: Future-GB is a two stage trial. Stage 1 is a non-randomised multicentre learning and evaluation phase (IDEAL Phase 2B study), and Stage 2 a prospective, phase III, multicentre randomised controlled trial. It aims to recruit 357 newly diagnosed GB patients to receive either standard techniques during surgery, or surgery that uses NiUS and DTI as well. Patients and assessors will be blinded to study arm. The trial will result in only minor changes to the present care pathway for patients with a suspected GB. Participating patients will complete HRQoL questionnaires (EORTC QLQ-C30 and BN20), and undergo a brief preoperative physical (Barthel Index and MRC power grading in all 4 limbs) and functional/cognitive assessments (WHO performance status and Montreal Cognitive Assessment, MOCA). These measures will be repeated postoperatively (prior to discharge), and at regular intervals over the following 24 months, combined with planned hospital visits. The mortality of participants, and any complications will also be recorded._x000D_ TIMELINES FOR DELIVERY: The study duration is 60 months, commencing in September, 2019. Months 1-9 comprise the IDEAL IIb. Recruitment will continue until month 33. In months 10 to 51, follow-up will be completed, and months 55 to 60 are reserved for the analysis and final report._x000D_ ANTICIPATED IMPACT AND DISSEMINATION: It is anticipated that the two additional surgical techniques will prolong DFS. Increased survival without functional compromise has obvious benefit for patients and relatives, substantial health gains for society, and significant economic implications. Proven intraoperative techniques would be applied as standard care across the NHS, in all 24 adult UK neurosurgical trusts. In addition, such surgical technologies have clear global appeal and worldwide impact

Research activity codes: 5.4 SURGERY;6.4 SURGERY
Health categories: CANCER AND NEOPLASMS