E va l uation of I ntraoperative S urgical A djuncts and R esection of G lio b lastoma

(GB)

ELISAR-GB

Protocol Preparation:

NANSIG Neurosurgery Chair 2019-2020: Georgios Solomou, giorgossolomou@hotmail.com

NANSIG Research Lead 2019-2020 : Ali Gharooni, aag56@cam.ac.uk

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Contents1. Introduction...................................................................................................................................3

1.1. Summary..............................................................................................................................3

1.2. Background..........................................................................................................................4

2. Methods........................................................................................................................................5

2.1. Study Aim.............................................................................................................................5

2.2. Study Design.........................................................................................................................5

2.3. Inclusion and exclusion criteria............................................................................................6

2.4. Audit standards....................................................................................................................6

2.5. Outcome measures..............................................................................................................7

3. Data Collection..............................................................................................................................7

3.1. Local Registration and Data Governance..............................................................................7

3.2. Data collection......................................................................................................................7

3.4. Data Validation.....................................................................................................................8

3.5. Dataset.................................................................................................................................9

3.6. Data analysis.........................................................................................................................9

3.7. Project Timeline...................................................................................................................9

3.8 Authorship Eligibility..........................................................................................................10

3.9 Study Steering Committee..................................................................................................10

References...........................................................................................................................................12

Appendix A – Required data fields.......................................................................................................14

Appendix B – Neurosurgical centres and Local Data Collection Groups..............................................17

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1. Introduction1.1. Summary

Background

Glioblastoma is the most common and aggressive primary intrinsic brain tumour and despite optimal combinatorial operative and adjuvant therapies, it remains incurable with a median survival of 6.1 months and a 3.4% 5-year survival rate. Evidence suggests that gross total resection (GTR) of enhancing tumour improves survival and progression-free survival. The National Institute for Health and Care Excellence (NICE) in 2018 and the European Association of Neuro-Oncology (EANO) in 2017, recommend that neurosurgeons should consider using intraoperative adjuncts (intraoperative MRI (IoMRI), intraoperative ultrasound (IoUS), neuronavigation, electrophysiological stimulation) during surgery for high grade gliomas (HGG) including glioblastoma and 5-Aminolevulinic acid (5-ALA) to be used only if the tumour is deemed suitable for GTR as a baseline standard.

Objectives

The ELISAR-GB audit aims to evaluate the current service provision regarding the availability and usage of intraoperative surgical adjuncts for glioblastoma deemed suitable for resection and whether pre-operative surgical intent was achieved upon using the suggested (NICE 2018 and EANO 2017) intraoperative technologies.

Methods

We aim to conduct a national (UK), prospective audit and service evaluation, for a period of 4 months, between the 6th of January 2020 and 31st of April 2020. Local teams consisting of NANSIG and BNTRC collaborators will register the audit locally, obtain local approval if needed, identify eligible patients, collect and upload data on a secure online server.

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1.2. Background

Glia is a type of tissue that support the neurones in the brain and spinal cord. Tumours arising from these cells are called, gliomas. The categorisation of gliomas in the WHO classification 2016, has recently been updated and now incorporates both histological and molecular characteristics. In the United Kingdom it is estimated that there are 10,000 new cases of primary brain tumours. Gliomas are the most common morphological type of primary intrinsic brain tumour and account for<60% of the cases1,2.

Of all primary brain tumours in adults, glioblastoma, a WHO grade IV glioma, is the most common. Glioblastoma are aggressive3 and incurable. Recent evidence suggests that there has been a significant increase in the incidence of glioblastoma from 1995 to 2015 with the age-standardised rate per 100,000-people more than doubling from 2.4 to 5.04. Despite optimal operative and post-operative management, glioblastoma mortality rate remains significantly higher compared to other glioma subtypes. The five-year survival rate for glioblastoma is only 3.4%, compared to 27% for WHO grade-3 astrocytomas5 and 78% for oligodendrogliomas6.

The aim of the management of glioblastoma is to maintain each patient’s quality of life for as long as possible. The current gold standard management of gliomas includes a combination of chemotherapy, radiotherapy and surgery7. Whilst complete or near-complete safe resection is very challenging due to the a risk of neurological morbidity, it can lead to increased overall survival and progression free survival8,9. To increase complete safe resection margins and minimise post-operative neurological morbidity, adjuncts in neurosurgery have been introduced, such as IoMRI 10, IoUS11, fluorescence guided surgery (e.g. 5-ALA)12 and awake craniotomy with electrophysiological stimulation.

Data from randomised controlled trials (RCTs) have shown favourable outcomes in using 5-ALA 12

and IoMRI in achieving complete safe resection vs standard microscopic resection, which was statistically significant (P<0.05)13. Despite this, a recent Cochrane review found notable risks of bias in those studies highlighting uncertainty in our estimates of benefit with these adjuncts 14. Furthermore, whilst efficacy in trial conditions has been demonstrated, there is great variation in GTR in prospective and retrospective cohort studies ranging from 47.6 - 98.5% 15. Further, IoUS has been utilised in neurosurgery since 198216 and numerous enhancements to this adjunct have been introduced which has improved imaging quality17. Whilst no RCT has been performed, various studies have demonstrated its utility in achieving GTR, with a recent meta-analysis showing the rate of GTR of HGG with IoUS to be 71.9% (95% CI, 64%-79.7%)11, similar to other intraoperative adjuncts presented. Furthermore, there is some evidence to suggest the synergistic effects of combining these adjuncts in achieving GTR18,19.

In the context of the current evidence base, the NICE and EANO recommend the consideration of using intraoperative adjuncts during initial surgery for HGG including glioblastoma1,20,21. Since July 2018, NICE has specifically recommended that HGG, which are amenable to total surgical resection should be offered 5-ALA, whilst other forms of adjuncts (i.e. IoMRI, IoUS, awake craniotomy) should be ‘considered’.

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In addition, in 2017 the EANO reflected on the increasing evidence that having no residual enhancing disease after operation of glioblastoma is related to improved survival. Therefore, suggesting that if agreed to be feasible, surgery for glioblastoma should be complete resection of enhanced disease or GTR. Thus, in this audit, GTR is defined as no residual enhancing disease on T1-weighted MRI with contrast12 i.e. close to >90% resection of enhancing tumour. To assess the extent of resection, NICE recommends the use of post-operative T1-weighted MRI within 72hrs post-operatively1.

Prior to the NICE guidelines 2018 update1, a British Neurosurgical Trainee Research Collaborative study (BNTRC) by Ma et al, 2017, reported that only 44% of surgeons had routine access to 5-ALA and it was used in only 15.9% of potential cases. Since then no audit was conducted to re-evaluate these findings and the impact of the new guidelines. The study also showed that post-operative MRI was performed within 72hrs in only 70.8% of cases, and that GTR was achieved in only 55%. The rate of GTR was statistically significantly better only when all adjuncts were taken into account suggesting “the use of surgical adjuncts to increase GTR rates”. Notably, despite the accumulation of evidence, Ma et al discuss that variation in surgical practice was representative of the lack of consensus on best practice22. This was compounded by variation in the availability of each technology across centres, surgeon training in each technology, and the perceived time needed to use these adjuncts within an operation. Further, one unit showed that use of IoMRI added 105 minutes to an operation, and when the patient was awake it added another two hours to the operating time23. Since the implementation of the new NICE 2018 and EANO 2017 guidelines, no further evaluation of service provision was conducted.

In light of this rationale, the Neurology and Neurosurgery Student Interest Group (NANSIG) in collaboration with the British Neurosurgical Trainee Research Collaborative (BNTRC), propose to audit the current service provision regarding the availability and the usage of intraoperative surgical adjuncts for glioblastoma deemed suitable for resection.

2. Methods2.1. Study Aim

1. To prospectively audit the availability and usage of surgical adjuncts in the UK for glioblastoma according to the NICE and EANO guidelines: 5-ALA, intraoperative MRI, intraoperative US, awake craniotomy, neurophysiology and tractography.

2. To evaluate whether GTR was planned and achieved in each case.

2.2. Study Design

To prospectively collect national data from all centres offering neurosurgical oncology service in the UK, for a period of four months comparing current practise to current guidance and to assess

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preoperative resection intent using combination of adjuncts suggested by NICE. Cases to be collected will include those patients with a diagnosis of suspected HGG including glioblastoma (grade IV) on MRI scan who are deemed suitable for resection (GTR or not) by the operating surgeon/consultant.

2.3. Inclusion and exclusion criteria

Inclusion:

1. All Patients with first diagnosis of suspected glioblastoma/HGG on MRI:1.1. Aged 18 years and above1.2. Receiving neurosurgical intervention with intention to achieve complete resection or

subtotal resection (debulk) of enhancing component on post-operative T1-weighted MRI with contrast, as decided by the operating surgeon

2. Supratentorial tumours

Exclusion:

1. Emergency/unplanned procedures 2. No MRI data available (i.e. MRI contraindicated in patient)3. Infratentorial tumours4. Biopsy surgery5. Prior operative or non-operative management of index glioma 6. Previous diagnosis and treatment (operative or adjuvant) of primary or secondary brain

tumour

2.4. Audit standards

The audit criteria are based on current NICE guidance and the EANO recommendations and are the following:

Patients deemed suitable for GTR of HGG including glioblastoma should be offered 5-ALA (100%)

Patients deemed suitable for surgical resection (GTR or debulk) of a glioblastoma should be considered to be offered any of the following intraoperative adjuncts:

a. IoMRIb. IoUSc. Tractographyd. Awake craniotomye. Involvement of other specialists (e.g. physiotherapist)

Post-operative MRI should occur within 72hr (100%) Surgery for glioblastoma should aim for GTR when deemed feasible

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2.5. Outcome measures

Primary outcomes:a. Percentage of centres offering the surgical adjuncts as per NICE guidelines1 1.2.36-

1.2.42b. Percentage of resections of glioblastoma where each or combination of

intraoperative surgical adjuncts suggested by NICE were usedc. Percentage of patients that underwent resection who have had MRI within 72hours

post-operatively d. Percentage of patients with glioblastoma intended to have GTR that have RED with

each combination of adjuncts on post-operative MRI

Secondary outcomese. Percentage of patients with glioblastoma intended to have GTR that have RED based

on location, eloquence and molecular characteristics f. Percentage of glioblastoma with successful uptake of 5ALA (5ALA +ve)g. Resource use in terms of operation length, requirement for level 2 or 3 critical care

beds, length of inpatient stay, place of dischargeh. Change in neurological function or adverse effects with each combination of surgical

adjunctsi. Overall survival/PFS in two years

3. Data Collection3.1. Local Registration and Data Governance

The project should be registered as a clinical audit with each local audit department. Caldicott Guardian approval and local supervising consultant neurosurgeon approval should be in place if necessary, prior to data collection.

3.2. Data collection

No identifiable patient information will be stored or uploaded. If collaborators wish to use the paper copies of the collection proforma, these must be stored securely at the centre and destroyed using confidential waste disposal once the data have been uploaded.

Each Neurosurgical centre will have a local collaborative team formed by the NANSIG university representative, a neurosurgical trainee/registrar, a local consultant and additional medical

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students/Junior doctors. Data will be collected by the team over a period of four months from January 6th to 31st of April 2020. The NANSIG university representative will be responsible for data entry on the online database. All eligible cases should be included. Data collection fields are outlined in Appendix A. Some of the data will require some expertise in radiological imaging interpretation, (i.e. tumour location) and if not clear from neuroradiology report, should be referred to the neurosurgical trainee and reviewed by the consultant neurosurgeon. In cases where further advice is needed the local team can decide whether the advice of a local neuroradiologist is needed.

Data is collected locally and submitted to an online secure central database – Castor 24. Any locally collected data must be stored in a secure locked room on-site, or on a password protected NHS hospital site as per local research and audit department policy.

Sources of data for case ascertainment can include local hospital online portals, theatre logbook/lists, neuro-oncology MDT lists and pathology departments. Once a case is identified, useful sources of data will include pre-operative and post-operative notes, patient clinical notes, pathology reports and radiological scans.

The operating surgeon must clearly state prior to data collection their intention regarding extent of resection i.e. GTR Or subtotal resection (STR), either during the MDT or otherwise.

3.4. Data Validation

Data validation will be performed in two centres in the UK. Data validators should be trainees/registrars/junior doctors not involved in the initial data collection. The validator will select a single 1-month study period at a local centre to validate and will take place after completion of data collection. The validator will send a summary of how many records were reviewed and error rates to the study management group. There are two components of validation:

Case ascertainment

Validators will independently identify all patients eligible for inclusion over the one-month study period. The target for data ascertainment is >95%.

Data accuracy

Validators will independently collect data for five key data fields relating to operative and 5 for non-operative measures. The selection of fields will only be made available to validators. Conflicts with the data originally submitted by the relevant local team will be resolved by discussion between the validator and local team. The target for accuracy of collected data is >98%.

The outcome of data validation (case ascertainment and data accuracy) and error rates will not affect the inclusion of data in the pooled analysis.Data accuracy will be determined for the data fields for selected cases. The target for data accuracy is >95%.

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3.5. Dataset

Data domains that relate to patient, tumour, surgical adjunct and post-operative period will be collected. No patient identifiable confidential information collected will be submitted onto Castor. No information in additional to routinely collected clinical information will be collected. All patients will have a unique Castor ID number traceable to the identifiable patient information only through securely stored forms physically on NHS sites or on password-protected NHS computers and servers. A full list of data fields is provided in appendix A. Data will be stored on a secure server using the Castor platform. If data collectors upload data on an Excel sheet or proforma it should be stored on an NHS trust computer or locked room that is only accessible by a student or doctor registered with the NHS trust. Errors in data entry will be resolved with local data collection teams prior to any analysis.

3.6. Data analysisAnalysis will be performed on anonymised data. Data will be analysed using descriptive statistics on participant characteristics and outcomes as outlined in appendix using an appropriate software such as SPSS or R.

3.7. Project TimelineData collection will start on Monday 6st of January 2020 and is to include data until Thursday 31st of April 2020. Below is a chart outlining the study timeline:

Apr-Sept2019

Oct Nov Dec Jan 2020

Feb Mar Apr

May June

July Aug Sept

Oct Nov

Protocol development and approvalLocal team sign up

Local project registrationData collection periodData submission deadline

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Data cleaning and validationStatistical AnalysisPreparing Manuscript(s)Publication and presentation back to local departments

3.8 Authorship Eligibility

The contribution to all participants who are NANSIG local representatives, medical students and junior doctors will be recognised with PubMed citable collaborator-status authorship under the group entitled “NANSIG collaborators”. PubMed citable collaborator-status authorship will also be given in recognition of the supporting trainees and local supervising consultant neurosurgeons, under the group :BNTRC”

Fully named authors must satisfied the International Committee of Medical Journal Editors’ conditions for authorship as follows:

(i) Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; AND

(ii)Drafting the work or revising it critically for important intellectual content; AND

(iii)Final approval of the version to be published; AND

(iv) Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

3.9 Study Steering Committee

NANSIG: Georgios Solomou, Ali Gharooni, Danyal Zaman Khan, Melissa Gough

BNTRC: Mr Dan Fountain, Mr Rory J Piper, Mr Michael Tin Chung Poon, Mr Angelos G Kolias

Consultants: Prof. Colin Watts, Prof. Keymouras Ashkan, Mr. Stephen Price, Mr. Puneet Plaha, Mr. Michael D Jenkinson, Miss Kathrin Whitehouse 10

Roles

Project Leads: Georgios Solomou & Ali Gharooni

Protocol preparation: Georgios Solomou, Ali Gharooni

Data collection Team: Ali Gharooni, Melissa Gough

Manuscript Preparation Lead & Corresponding author: Georgios Solomou

BNTRC Coordination: NANSIG Chair (Georgios Solomou)

Senior advisor committee:

Prof. Colin Watts – Honorary Consultant Neurosurgeon and Professor in Neurosurgery, University Hospitals Birmingham

Prof. Keyoumars Ashkan – Professor of Neurosurgery and Consultant Neurosurgeon, King’s College Hospital NHS Trust

Mr. Stephen Price – Honorary Consultant Neurosurgeon and Clinician Scientist, Cambridge University Hospitals Trust

Mr. Puneet Plaha – Consultant Neurosurgeon, Oxford University Hospitals NHS Trust

Mr. Michael D Jenkinson – Honorary Consultant Neurosurgeon and Senior Clinical Lecturer in Neurosurgery, University Hospitals Liverpool (SBNS Academic Chair)

Miss Kathrin Whitehouse – Senior Fellow in Neurosurgery, Southampton University Hospitals

Mr. Angelos G Kolias - Clinical Lecturer in Neurosurgery, Cambridge University Hospitals Trust & the University of Cambridge

Mr Michael Tin Chung Poon – Cancer Research UK Clinical PhD Fellow, University of Edinburgh

Mr. Rory J Piper – Academic Clinical Fellow in Neurosurgery, Oxford University Hospitals NHS Trust (BNTRC 2019-2020 Chair)

Mr. Dan Fountain – Academic Clinical Fellow in Neurosurgery, Salford Royal NHS Foundation Trust

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References

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2. Cancer Research UK. Brain, other CNS and intracranial tumours statistics | Cancer Research UK [Internet]. [cited 2019 Mar 23]. Available from: https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/brain-other-cns-and-intracranial-tumours#heading-Zero

3. Burnet NG, Jefferies SJ, Benson RJ, Hunt DP, Treasure FP. Years of life lost (YLL) from cancer is an important measure of population burden—and should be considered when allocating research funds. British journal of cancer. 2005 Jan;92(2):241.

4. Philips A, Henshaw DL, Lamburn G, O’Carroll MJ. Brain tumours: rise in Glioblastoma Multiforme incidence in England 1995–2015 suggests an adverse environmental or lifestyle factor. Journal of environmental and public health. 2018;2018.

5. Astrocytoma Prognosis | Brain Tumour Survival Rates [Internet]. [cited 2019 Mar 23]. Available from: https://www.thebraintumourcharity.org/brain-tumour-information-treatment/types-of-brain-tumour-adult/astrocytoma/astrocytoma-prognosis/

6. Oligodendroglioma Prognosis | Brain Tumour Survival Rates [Internet]. [cited 2019 Mar 23]. Available from: https://www.thebraintumourcharity.org/brain-tumour-diagnosis-treatment/types-of-brain-tumour-adult/oligodendroglioma/oligodendroglioma-prognosis/

7. Stupp R, Mason WP, Van Den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. New England Journal of Medicine. 2005 Mar 10;352(10):987-96.

8. Bloch O, Han SJ, Cha S, Sun MZ, Aghi MK, McDermott MW, Berger MS, Parsa AT. Impact of extent of resection for recurrent glioblastoma on overall survival. Journal of neurosurgery. 2012 Dec 1;117(6):1032-8.

9. Sanai N, Polley MY, McDermott MW, Parsa AT, Berger MS. An extent of resection threshold for newly diagnosed glioblastomas. Journal of neurosurgery. 2011 Jul 1;115(1):3-8.

10. Coburger J, Wirtz CR, Koenig RW. Impact of extent of resection and recurrent surgery on clinical outcome and overall survival in a consecutive series of 170 patients for glioblastoma in intraoperative high field magnetic resonance imaging. Journal of neurosurgical sciences.

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2017 Jun;61(3):233-44.

11. Mahboob S, McPhillips R, Qiu Z, Jiang Y, Meggs C, Schiavone G, Button T, Desmulliez M, Demore C, Cochran S, Eljamel S. Intraoperative ultrasound-guided resection of gliomas: a meta-analysis and review of the literature. World neurosurgery. 2016 Aug 1;92:255-63.

12. Stummer W, Pichlmeier U, Meinel T, Wiestler OD, Zanella F, Reulen HJ, ALA-Glioma Study Group. Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. The lancet oncology. 2006 May 1;7(5):392-401.

13. SSenft C, Bink A, Franz K, Vatter H, Gasser T, Seifert V. Intraoperative MRI guidance and extent of resection in glioma surgery: a randomised, controlled trial. The lancet oncology. 2011 Oct 1;12(11):997-1003.

14. J Jenkinson MD, Barone DG, Bryant A, Vale L, Bulbeck H, Lawrie TA, Hart MG, Watts C. Intraoperative imaging technology to maximise extent of resection for glioma. Cochrane Database of Systematic Reviews. 2018(1).

15. Gandhi S, Tayebi Meybodi A, Belykh E, Cavallo C, Zhao X, Pasha SM, Borba Moreira L, Lawton M, Nakaji P, Preul M. Survival outcomes among patients with high-grade glioma treated with 5-aminolevulinic acid–guided surgery: a systematic review and meta-analysis. Frontiers in oncology. 2019;9:620.

16. Chandler WF, Knake JE, McGillicuddy JE, Lillehei KO, Silver TM. Intraoperative use of real-time ultrasonography in neurosurgery. Journal of neurosurgery. 1982 Aug 1;57(2):157-63.

17. Sastry R, Bi WL, Pieper S, Frisken S, Kapur T, Wells III W, Golby AJ. Applications of ultrasound in the resection of brain tumors. Journal of Neuroimaging. 2017 Jan;27(1):5-15.

18. TTsugu A, Ishizaka H, Mizokami Y, Osada T, Baba T, Yoshiyama M, Nishiyama J, Matsumae M. Impact of the combination of 5-aminolevulinic acid–induced fluorescence with intraoperative magnetic resonance imaging–guided surgery for glioma. World neurosurgery. 2011 Jul 1;76(1-2):120-7.

19. Gessler F, Forster MT, Duetzmann S, Mittelbronn M, Hattingen E, Franz K, Seifert V, Senft C. Combination of intraoperative magnetic resonance imaging and intraoperative fluorescence to enhance the resection of contrast enhancing gliomas. Neurosurgery. 2015 Mar 23;77(1):16-22.

20. Weller M, van den Bent M, Hopkins K, Tonn JC, Stupp R, Falini A, Cohen-Jonathan-Moyal E, Frappaz D, Henriksson R, Balana C, Chinot O. EANO guideline for the diagnosis and treatment of anaplastic gliomas and glioblastoma. The lancet oncology. 2014 Aug 1;15(9):e395-403.

21. Weller M, Van Den Bent M, Tonn JC, Stupp R, Preusser M, Cohen-Jonathan-Moyal E, Henriksson R, Le Rhun E, Balana C, Chinot O, Bendszus M. European Association for Neuro-Oncology (EANO) guideline on the diagnosis and treatment of adult astrocytic and oligodendroglial gliomas. The lancet oncology. 2017 Jun 1;18(6):e315-29.

22. Ma R, Chari A, Brennan PM, Alalade A, Anderson I, Solth A, Marcus HJ, Watts C. Residual enhancing disease after surgery for glioblastoma: evaluation of practice in the United Kingdom. Neuro-Oncology Practice. 2017 Sep 27;5(2):74-81.

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23. Pichierri A, Bradley M, Iyer V. Intraoperative Magnetic Resonance Imaging–Guided Glioma Resections in Awake or Asleep Settings and Feasibility in the Context of a Public Health System. World neurosurgery: X. 2019 Jul 1;3:100022.

24. Castor Electronic Data Capture 2019 [Available from: https://www.castoredc.com/.

Appendix A – Required data fields.

Pre-operative data 1. DoB Dd/mm/yyyy2. Gender Male, Female3. Site of tumour (tick >1 if

applicable)Right frontal, Right Temporal, Right Parietal, Right OccipitalLeft Frontal, Left Temporal, Left Parietal, Left Occipital, Insula

4. Eloquent* Yes, No5. If yes to the above then

please tick which function (please tick all that apply)

Motor, sensory, language, vision, other (please specify)

6. WHO Performance status– Prior to surgery

0, 1, 2, 3, 4 or 5

7. Was there a contrast enhancement on the pre-operative T1W MRI with contrast?

Yes, No

8. Regarding surgical adjuncts, please tick which of the following are available at your centre (select all that apply)

5ALA, Neuronavigation, intraoperative MRI, intraoperative US, awake craniotomy, Direct Electrical Stimulation/neurophysiology, tractography, other (Please specify)

9. Was tractography done as part of the pre-operative planning?

Yes, No

10. Is this suitable for complete resection (GTR), according to the MDT and the operating surgeon?

Yes, No

11. If no to above (n.10) then why?

To preserve neurological function, other (please specify)

Operative data

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12. Date of operation Dd/mm/yyyy13. Please tick, Surgical

adjunct used (select all that apply)

5-ALA, Neuronavigation, Intraoperative MRI, Intraoperative US, Direct Electrical Stimulation/neurophysiology, awake craniotomy, endoscopic assisted craniotomy, Other i.e. merging IoUS with neuronavigation (Please specify)

14. In awake craniotomy group, please tick other specialists involved (select all that apply)

Neuropsychologists, Speech and Language Therapists, Psychiatrists, physiotherapists other (Please specify)

15. In 5-ALA group, was there a visible red/pink fluorescence during surgery?

Yes, No

16. If yes (for n.15), was the visible fluorescence completed resected during the operation?

Yes, No

17. In IoMRI group, tick settings used (select all that apply)

1.5T,3T, T1, T2, Flair, T1c, DWI, other

18. In IoMRI group, is a 1-room or 2-room solution used?

1 room2 room

19. In IoMRI group, was there further resection of the tumour after the MRI was performed?

Yes, no

20. Duration of operation (Hrs)

1-2,2-3,3-4,4-5,5-6,6-7,7-8,8-9,9-10 >10

Post-operative data21. GBM histologically

confirmed? Yes, No, other (please specify)

22. Molecular characterisation

IDH mutant, IDH wildtype , IDH NOS (unknown), other (Please specify eg MGMT)

23. MRI done within 72 hours?

Yes, No

24. If no, why not? Patient unwell, patient died, MRI department issues, other25. **Was Gross total

Resection achieved as seen in the 72-hour contrast enhance T1-weighted MRI?

Yes, No

26. If no, why not? To preserve neurological function,Other (Please specify)

27. Adverse Events Yes, No

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28. If yes to adverse effects then tick from options

Infection, Stroke, Seizure, CSF leak, Haematoma, other [Please describe]

29. Post-operative deficit Yes, No

30. If yes to post-operative deficit, then tick from the options (please tick all that apply)

Motor, sensory, language, vision, cognition, other (Please describe)

31. WHO performance status – on discharge?

0, 1, 2, 3, 4 or 5

32. Date of discharge Dd/mm/yyyy33. Place of discharge Patient’s usual home, to friends/relatives, care facility (eg

nursing home, hospice), community hospital, local acute hospital, died, (other)

* Areas that are responsible for sensory, motor (premotor, supplementary motor, primary motor) and language (Broca’s & Wernicke’s) functions of the brain found during intraoperative cortical stimulation or functional imaging during surgery

** In our audit, GTR is defined as NO residual enhancing disease (RED) of contrast enhanced tumour as seen on T1-weighted, contrast-enhanced MRI within 72hours post operatively as judged/seen by the neuroradiologist and the neurosurgeon i.e. complete resection. The neuroradiologist and the neurosurgeon will have to reach an agreement.

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Appendix B – Neurosurgical centres and Local Data Collection GroupsNeurosurgical Centre Medical School NANSIG CollaboratorsAberdeen Royal Infirmary University of Aberdeen Addenbrookes University of Cambridge Beaumont Hospital Royal College of Surgeons in

IrelandCharing Cross Hospital Imperial College London Cork University Hospital University College CorkDerriford Hospital Plymouth University Essex Neurological Centre Bart’s and The LondonHull Royal Infirmary University of Hull James Cook University Hospital

University of Durham

John Radcliffe Hospital University of Oxford King’s College Hospital King’s College LondonLeeds General Infirmary University of Leeds Ninewells Hospital University of Dundee QMC University Hospital University of Nottingham Royal Hallamshire Hospital University of Sheffield Royal London Hospital Bart’s and The LondonRoyal Preston Hospital University of Central Lancashire Royal Stoke, North Midlands Keele University Royal Victoria Hospital Queen’s University BelfastRoyal Victoria Infirmary Newcastle University Salford Royal Hospital University of Manchester Southampton General Hospital

University of Southampton

Southern General Hospital University of Glasgow Southmead Hospital University of Bristol St Bartholemew’s and Royal London Hospital

Bart’s and The London

St George’s Hospital St George’s University of London

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The National Hospital for Neurology and Neurosurgery

University College London

The Princess Royal Hospital University of Brighton The Queen Elizabeth Hospital University of BirminghamThe Walton Centre Liverpool University/University

of Central Lancashire University Hospital of Wales Cardiff University Walsgrave Hospital University of Warwick Western General Hospital University of Edinburgh

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