Functional and Ultrasound Guided Resection of Glioblastoma

Study Overview
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Brief Summary
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Functional and ultrasound-guided resection of glioblastoma: assessing the use of additional imaging during surgery to improve outcomes for patients with glioblastoma brain tumours

Detailed Description
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Stage 1 (IDEAL IIB study) of the trial is observational only and all participants will receive all technologies during surgery. Stage 2 will be randomised. Randomisation will be via the web-based service provided by the Oxford Clinical Trials Research Unit (OCTRU), using the method of minimisation. Participants will be randomised 1:1 to either: Standard care surgery (neuronavigation based on preoperative imaging and intraoperative use of 5-ALA)(Control arm) Standard care surgery (neuronavigation based on preoperative imaging and intraoperative use of 5-ALA) AND of DTI neuronavigation and NiUS (Intervention arm) At baseline all participants will undergo a routine preoperative neuronavigation MRI scan. Those participants randomised to the experimental arm, will also have a DTI scan (additional 5 minutes in the MRI). All participants will then undergo the planned resection of their tumour, with the additional technologies if they are in the experimental arm. Following surgery, participants in both arms have the same follow up schedule and undergo standard clinical care for a total of 24 months.

Official Title
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FUTURE-GB Trial (Functional and Ultrasound-guided Resection of Glioblastoma) A 2-Stage Trial. A Learning Phase Evaluation of Participating Centres, Followed by a Randomised, Controlled Multicentre Phase III Trial.

Conditions
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Glioma Glioblastoma Multiforme

Intervention / Treatment
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* Other: Standard of Care
* Other: Additional pre- and intra-operative imaging


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18-70 years Neuro-oncology Multi-Disciplinary Team (MDT) decision that the imaging shows a primary GB tumour which is maximally resectable (attempted gross total resection of all enhancing tumour) Patient is suitable for concomitant adjuvant radiotherapy and Temozolomide (TMZ) chemotherapy or adjuvant TMZ at the time of MDT decision Able to receive 5-ALA Willing and able to give informed consent Able to complete trial questionnaires, this may be with support where English is not their first language. (Stage 2 only) Able to provide a proxy who is willing to complete questionnaires as requested (Stage 2 only). Exclusion Criteria: Midline/basal ganglia/cerebellum/brainstem GB Multifocal GB Recurrent GB Suspected secondary GB Contraindication to MRI

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: FUTURE-GB is a 2-Stage trial: Stage 1 is a non-randomised multicentre learning and evaluation Stage (IDEAL IIB study), and Stage 2 a prospective, multicentre definitive randomised controlled trial.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Additional pre- and intra-operative imaging<br>Surgery to resect the GB using Diffusion Tensor Imaging (DTI) and intraoperative Ultrasound (iUS) (navigated iUS where available) in addition to standard care (i.e. neuronavigation based on preoperative MRI and intraoperative use of 5-aminolevulinic acid (5-ALA)) | Other: Additional pre- and intra-operative imaging<br>* Additional DTI scan during routine pre-operative tumour MRI scan, additional use of intraoperative ultrasound in addition to normal to standard of care (Neuronavigation and intraoperative 5-ALA)<br>* Other names: IUS;|
| Active Comparator: Standard of Care<br>The comparator is standard care as per current NICE guidelines (i.e. neuronavigation based on preoperative MRI and intraoperative use of 5-ALA). | Other: Standard of Care<br>* Neuronavigation and intraoperative 5-ALA<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Stage 1 Primary Outcome: to demonstrate the feasibility of using DTI and iUS in addition to standard of care for neurosurgery using a combination of qualitative and quantitative data to prove workflow capability at each site. | Sites are qualitatively assessed through a standardisation stage, providing feedback to enable learning and ensure the workflow is followed. Sites with satisfactory data will progress and pass into Stage 2. The measures assessed in combination are: Operation length, in normal range for this surgery. Use of DTI neuronavigation & iUS to achieve maximal safe tumour resection without major neurological deficit, measured by getting clear, relevant images for the DTI & US scans, and accurate pre-operative tractography. Extent of tumour resection (cm³ remaining) on postoperative MRI scan. Surgical Complications/Serious Adverse Events-measured from recorded post-operative complications and a 6-month notes check to ensure patient safety. If the assessment panel is satisfied with the data after  3 recruits, a site will progress into Stage 2 of the trial, the RCT. Data will be analysed for Stage 1 once all sites have progressed through into Stage 2 of the trial. | Measured 6 weeks post-surgery | 
| Stage 2 Primary Outcome: to assess whether additional imaging to standard of care changes Deterioration Free Survival (DFS) (Where deterioration relates to global health status only) | This is measured by a composite of: Change in global health status domain of the QLQ-C30 questionnaire (Quality of Life Questionnaire Cancer) from baseline to final questionnaire completion. Questionnaires are administered at baseline, 6 weeks, then every 3 months until 24months. Progression Free Survival (PFS). This is measured by radiological tumour progression on imaging, which is taken 3-months post-op and 3-monthly thereafter. Overall Survival (OS) with an event defined as either deterioration, progression or death. | Measured from baseline up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Stage 2: To assess if additional intraoperative imaging changes DFS where deterioration relates to physical and social functioning, and motor and communication dysfunction | This is measured using a combination of specific questions (physical functioning and social functioning) in the QLQ-C30 (Quality of Life Questionnaire Cancer) and BN20 questionnaire (Quality of Life Questionnaire Brain) (motor dysfunction and communication deficit questions), combined with the values of Progression Free Survival (PFS) and overall survival (OS) taken from the primary outcome. Questionnaires are administered at baseline, 6 weeks, then every 3 months until 24months. | Measured from baseline up to 24 months | 
| Stage 2: To assess whether additional intraoperative imaging to standard of care changes time to deterioration | Defined similar to DFS with the exception that progression is excluded as an event (i.e. only deterioration or death are considered). There will be five time to deterioration outcomes, one for each of the domains utilised in the primary and secondary DFS outcomes, used in turn to define deterioration | Measured from baseline up to 24 months | 
| Stage 2: To assess whether additional intraoperative imaging to standard of care improves Overall Survival (OS) | OS (time from randomisation to death or trial closure) | To be recorded at 24 months | 
| Stage 2: To assess whether additional intraoperative imaging (DTI and iUS*) to standard of care (Neuronavigation and intraoperative 5-ALA) changes Progression Free Survival (PFS) | PFS (time from randomisation to radiological tumour progression on imaging, as agreed in local MDT This involves using the post-operative MRI scan as a reference point and making comparisons will the ensuing MRI reports that are recieved 3 months post-surgery and 3 monthly thereafter until 24 months post-surgery. | MRI at 6 months post-op., and then 3 monthly up to 24 months or an MRI performed outside protocol if patient is symptomatic | 
| Stage 2: To assess whether additional intraoperative imaging (DTI and iUS*) to standard of care (Neuronavigation and intraoperative 5-ALA) changes the extent of tumour resection | Extent of resection as percent of pre-operative tumour volume on postoperative contrast enhanced MRI | Measured 1 week post-surgery | 
| Stage 2: To assess whether additional intraoperative imaging (DTI and iUS*) to standard of care (Neuronavigation and intraoperative 5-ALA) changes the incidence of surgical complications | Number and type of surgical complications | Measured from surgery up to 24 months | 
| Stage 2: To assess whether additional intraoperative imaging (DTI and iUS*) to standard of care (Neuronavigation and intraoperative 5-ALA) changes the number of patients eligible for adjuvant treatment following surgery | Number of patients eligible for adjuvant treatment | Measured 3 months post surgery | 
| Stage 2: To assess whether additional intraoperative imaging (DTI and iUS*) to standard of care (Neuronavigation and intraoperative 5-ALA) changes functional outcome postoperatively | Measured by any change in the functional performance assessment which consistes of a combination of: The WHO (World Health Organisation) performance status A 5-minute telephone mini-MoCA (The Montreal Cognitive Assessment, Montreal Version) Barthel Index MRC (Medical Research Council) grading of power in all 4 limbs Assessments are made at baseline, at hospital discharge, 6 weeks post-op, 3 months post-op, then 3 monthly thereafter until 24 months. | Measured from baseline up to 24 months | 
| Stage 2: Assess the correlation of proxy to participant classification assessment of quality of life | Assessed using comparisons between the patient and proxy responses to the Quality of Life questionnaires administered. Specifically comparisons between the answers to questions 29 and 30 of the QLQ-C30. | Measured from baseline up to 24 months. Proxy will not complete questionnaires when participant stops completing them. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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DTI, iUS