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

Stage 1:
Feasibility of using DTI and NiUS in addition to standard of care for neurosurgery assessed using:
1. Operation length measured using patient records, analysed post-operatively
2. Successful use of the technology measured using operating surgeon theatre reports completed during surgery and analysed post-operatively
3. Tumour resection shown by pre and post-op MRI scan
4. Surgical complications measured using number of return visits to theatre, and other medical complications and analysed at discharge

Stage 2:
Deterioration Free Survival (Global Health Status) measured using a composite measure obtained from the QLQ-C30 patient and proxy questionnaire at baseline, 5 days post-op/discharge, 6 weeks post-op, 3 month post-op, then every 3 months subsequently up to 24 months post-op, Progression-Free Survival (PFS) and Overall Survival (OS) measured using patient records

Updated 05/04/2022:
Deterioration Free Survival (Global Health Status) measured using a composite measure obtained from the QLQ-C30 patient and proxy questionnaire at baseline, 6 weeks post-op, 3 months post-op, then every 3 months subsequently up to 24 months post-op, Progression-Free Survival (PFS) and Overall Survival (OS) measured using patient records

Current secondary outcome measures as of 19/08/2022:

Secondary Outcomes (In Stage 2 only)
1. To assess whether additional intraoperative imaging (DTI and iUS*) to standard of care (Neuronavigation and intraoperative 5-ALA) improves DFS where deterioration relates to physical functioning, social functioning from the QLQ-C30, and motor dysfunction and communication deficit. Measured using 4 composites using the respective domain of QLQ-C30 (physical functioning and social functioning) and BN20 (motor dysfunction and communication deficit) combined with PFS and OS. To be recorded at baseline; 6wks post-op., 3mths post-op., and then 3mthly up to 24 months
2. To assess whether additional intraoperative imaging (DTI and iUS*) to standard of care (Neuronavigation and intraoperative 5-ALA) improves time to deterioration. Measured similarly 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. To be recorded at 6wks post-op., 3mths post-op., and then 3mthly up to 24 months
3. To assess whether additional intraoperative imaging (DTI and IUS*) to standard of care (Neuronavigation and intraoperative 5-ALA) improves Overall Survival (OS). Measured by OS (time from randomisation to death or trial closure). To be recorded at 24 months
4. To assess whether additional intraoperative imaging (DTI and iUS*) to standard of care (Neuronavigation and intraoperative 5-ALA) improves Progression Free Survival (PFS). Measured by PFS (time from randomisation to radiological tumour progression on imaging, as agreed in
local MDT). To be recorded from MRI at 6 months post-op., and then 3mthly up to 24 months
5. To assess whether additional intraoperative imaging (DTI and iUS*) to standard of care (Neuronavigation and intraoperative 5-ALA) improves the extent of tumour resection. Measured by extent of resection as % of pre-operative tumour volume on postoperative contrast
enhanced MRI. To be recorded at post-operative review
6. To assess whether additional intraoperative imaging (DTI and iUS*) to standard of care (Neuronavigation and intraoperative 5-ALA) improves the incidence of surgical complications. Measured by number and type of surgical complications. To be recorded at 5 days post-op, or discharge date (whichever is soonest); 6wks post-op., 3mths post-op., and then 3mthly up to 24 months
7. To assess whether additional intraoperative imaging (DTI and iUS*) to standard of care (Neuronavigation and intraoperative 5-ALA) improves the number of patients eligible for adjuvant treatment following surgery. Measured by number of patients eligible for adjuvant treatment at 3mths post-op.
8. To assess whether additional intraoperative imaging (DTI and iUS*) to standard of care (Neuronavigation and intraoperative 5-ALA) improves functional outcome postoperatively. Measured by WHO performance status, mini-MoCA (Montreal Version), Barthel Index, and MRC grading of power in all 4 limbs. To be recorded at baseline, 5 days post-op., or discharge date (whichever is soonest); 6wks postop., 3mths post-op., and then 3mthly up to 24 months (MRC grading to be assessed at baseline and 5 days post-op., or discharge date only)
9. Assess the correlation of proxy to participant classification assessment of quality of life. Measured by answers to questions 29 and 30 of the QLQ-C30. Ideally answers will be provided to all of the QLQ-C30 and BN20. To be recorded at baseline, 6wks post-op., 3mths post-op., and then 3mthly up to 24 months. Proxy will not complete questionnaires when participant stops completing them.

Tertiary Mechanistic Study Objectives (in Stage 2 and on a sub set of participants only)
1. To assess the sensitivity and specificity of the anatomico-spatial location of DTI fibre tracts compared with intraoperative direct electrical stimulation/behavioural change without stimulation but related to adjacent white fibre tract in patients undergoing awake surgery, or
motor evoked potential changes in patients undergoing surgery. Measured by sensitivity and specificity calculation using pre- and post-surgery MRI images. Analysis will be undertaken post-surgery.
2. To assess the sensitivity and specificity of iUS* to identify the tumour boundary when compared with 5-ALA, navigated biopsies will be taken from tumour boundary tissue planned for resection. Measured by intra operative iUS* images and post-operative MRI scans and intraoperative biopsy sample. Analysis will be undertaken post-surgery when biopsy results are available.

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Previous secondary outcome measures:

Measured at baseline, 5 days post-op/discharge, 6 weeks post-op, 3 month post-op, then every 3 months subsequently up to 24 months post-op (unless otherwise mentioned):
1. Physical functioning, social functioning measured using the QLQ-C30
2. Motor dysfunction and communication deficit measured using the QLQ-BN20
3. Time to deterioration measured using a composite measure obtained from the QLQ-C30 patient and proxy questionnaire, progression-free survival (PFS) and overall survival (OS) measured using patient records
4. Progression Free Survival (PFS) measured as time from randomisation to radiological tumour progression on imaging
5. Extent of tumour resection measured as % of pre-operative tumour volume on postoperative contrast enhanced MRI at post-op review
6. Incidence of Surgical Complications measured using patient records
7. Number of patients eligible for adjuvant treatment (for radiotherapy and/or chemotherapy) following surgery measured using patient records
8. Functional Outcome measured by results from standardised assessments:
8.1. Activity ability measured using WHO performance status
8.2. Cognitive function measured using Montreal Cognitive Assessment (MOCA)
8.3. Performance in activities of daily living measured using the Barthel Index
8.4. Muscle power measured using MRC grading of power in all 4 limbs
9. Participant classification assessment of quality of life, measured by answers to QoL questions provided by the participant and their proxy

Stage 2 tertiary outcome measures:
1. Location of nerve tracts measured using DTI imaging pre and post-surgery
2. Location of nerve tracts measured using intraoperative direct electrical stimulation or motor evoked potential changes during surgery
3. Location of tumour boundary measured using intraoperative NiUS images
4. Location of tumour boundary measured using post-operative MRI scans
5. Location of tumour boundary measured using intraoperative biopsy samples