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The SAFE-Trial: Awake Craniotomy Versus Surgery Under General Anesthesia for Glioblastoma Patients. (SAFE)

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ClinicalTrials.gov Identifier: NCT03861299
Recruitment Status : Recruiting
First Posted : March 4, 2019
Last Update Posted : October 27, 2020
Sponsor:
Collaborators:
Elisabeth-TweeSteden Ziekenhuis
University Medical Center Groningen
Medical Center Haaglanden
University Hospital, Ghent
Universitair Ziekenhuis Brussel
Information provided by (Responsible Party):
Jasper Gerritsen, Erasmus Medical Center

Brief Summary:
The trial is designed as a multicenter randomized controlled study. 246 patients with presumed Glioblastoma Multiforme in eloquent areas on diagnostic MRI will be selected by the neurosurgeons according the eligibility criteria (see under). After written informed consent is obtained, the patient will be randomized for an awake craniotomy (AC) (+/-123 patients) or craniotomy under general anesthesia (GA) (+/-123 patients), with 1:1 allocation ratio. Under GA the amount of resection of the tumour has to be performed within safe margins as judged by the surgeon during surgery. The second group will be operated with an awake craniotomy procedure where the resection boundaries for motor or language functions will be identified by direct cortical and subcortical stimulation. After surgery, the diagnosis of GBM will have to be histologically confirmed. If GBM is not histologically confirmed, patients will be considered off-study and withdrawn from the study. These patients will be followed-up according to standard practice. Thereafter, patients will receive the standard treatment with concomitant Temozolomide and radiation therapy and standard follow up. Total duration of the study is 5 years. Patient inclusion is expected to take 4 years. Follow-up is 1 year after surgery. Statistical analysis, cost benefit analysis and article writing will take 3 months.

Condition or disease Intervention/treatment Phase
Glioblastoma Glioblastoma Multiforme Glioblastoma Multiforme of Brain Astrocytoma, Grade IV Brain Tumor Brain Cancer Brain Neoplasms Procedure: Awake craniotomy Procedure: Craniotomy under general anesthesia Not Applicable

Detailed Description:

Rationale Glioblastoma Multiforme (GBM) or Astrocytoma's grade IV (WHO) are devastating tumors with one of the worst prognoses in oncology. Extending resection improves survival in patients with GBM. Surgery of GBM nowadays is usually performed under general anesthesia (GA) and resections are not as aggressive as possible, due to the chance of seriously damaging the patient with a rather low life expectancy. A surgical technique optimizing resection of the tumor in eloquent areas but preventing neurological deficits is necessary to improve survival and quality of life in these patients. Awake craniotomy (AC) with the use of cortical and subcortical stimulation is an alternative surgical technique that is standardly implemented in surgery for low grade glioma, but not yet for GBM. AC has shown to increase resection percentage and preserve quality of life in low grade glioma (LGG) and could be of important value in the surgery of GBM.

Objective The study is performed to increase safety and efficacy during surgery in patients with GBM in eloquent areas. This study will compare awake craniotomy with surgery under general anesthesia for patients with GBM near or in eloquent areas. Primary end points are: 1) Proportion of patients with NIH Stroke Scale (NIHSS) deterioration at 6 weeks post- surgery, where deterioration is defined as at least one point increase in total NIHSS score compared to baseline. 2) Proportion of patients without residual contrast-enhancing tumour on postoperative MRI. Secondary end points are: 1) Health related quality of life (HRQoL) at 6 weeks, 3 months and 6 months after operation. 2) Progression-free survival (PFS) at 12 months after operation. 3) Overall survival (OS) at 12 months after operation. 4) Frequency and severity of Serious Adverse Effects in each group: Infections, intracranial bleeding, epilepsy, aphasia, paresis/paralysis in arms or/and legs. Also, a cost benefit analysis will be performed.

Study design The trial is set up as a multicenter randomized controlled study. The study will include 246 patients in 5 neurosurgical centers in the Netherlands. Patients with GBM in eloquent areas on diagnostic MRI will be selected by the neurosurgeons according to the eligibility criteria. After informed consent the patient will be randomized for awake craniotomy (AC) or regular craniotomy under general anesthesia (GA) with 1:1 allocation ratio. After surgery, only patients with histologically proven GBM will continue with the study. Patients in whom no GBM could not be proven histologically, will be considered off-study. Thereafter, patients will receive the standard treatment with concomitant Temozolomide and radiation therapy and standard follow up. Total duration of the study is 5 years. Patient inclusion is 4 years. Follow-up is 1 year.

Study population Patients aged 18-90 years old, with Glioblastoma Multiforme near or in eloquent areas and eligible for awake craniotomy.

Intervention Awake craniotomy compared to craniotomy under general anaesthesia

Main study parameters/endpoints

  1. Proportion of patients with NIHSS deterioration at 6 weeks post-surgery
  2. Proportion of patients without residual contrast-enhancing tumour on postoperative MRI

Nature and extent of the burden and risks associated with participation, benefit and group relatedness Patients have 50% chance to be randomized for an awake procedure. The risk-benefit-ratio of this procedure in patients with GBM is subject of this trial and the investigators expect less neurological morbidity than surgery under generalised anaesthesia. Three quality of life questionnaires and 1 neurological examination will take place preoperatively, 6 weeks after, 3 months after and 6 months after the surgery. The burden of this trial for the patient is therefore confined.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 246 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Each participating center will randomise eligible and willing patients through the webbased clinical database and randomisation application ALEA. The Clinical Trial Centre (CTC) of the Erasmus MC will build the randomisation application by use of a dynamic allocation algorithm (minimization), in which patients are allocated to keep the imbalance between treatment groups to a minimum at every stage of recruitment within the covariates age (≤55 years vs >55years), Karnofsky performance scale (80-90 vs >90), and left or right hemisphere. Treatment allocation and allocated subject number will be shown immediately on screen and will in addition automatically be emailed to local investigators and other study personnel
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: The SAFE-Trial: Safe Surgery for Glioblastoma Multiforme: Awake Craniotomy Versus Surgery Under General Anesthesia. A Multicenter Prospective Randomised Controlled Study
Actual Study Start Date : April 1, 2019
Estimated Primary Completion Date : April 1, 2023
Estimated Study Completion Date : April 1, 2024

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Awake craniotomy
Cortical stimulation is performed with a bipolar electrical stimulator. The Boston naming test and repetition of words is done in cooperation with a neuropsychologist/linguist, who will inform the neurosurgeon of any kind of speech arrest or dysarthria. When localizing the motor and sensory cortex, the patient is asked to report any unintended movement or sensation in extremities or face. Functional cortical areas are marked with a number. When the tumour margins or white matter is encountered or when on regular neuronavigation the eloquent white matter tracts are thought to be in close proximity, subcortical stimulation (biphasic currents of 8-16 mA, pulse frequency 60 Hz, single pulse phase duration of 100 microsec., 2-second train) is performed to localize functional tracts.
Procedure: Awake craniotomy
Awake craniotomy
Other Names:
  • Intraoperative stimulation monitoring with (sub)cortical electrostimulation
  • Intraoperative brain mapping with (sub)cortical electrostimulation

Active Comparator: Craniotomy under general anesthesia
Trephination and tumour resection are performed without any additional neuro-psychological monitoring or brain mapping, guided by STEALTH-neuronavigation.
Procedure: Craniotomy under general anesthesia
Craniotomy under general anesthesia




Primary Outcome Measures :
  1. Postoperative neurological morbidity [ Time Frame: Between operation and 6 weeks postoperatively ]
    Proportion of patients with NIHSS (National Institute of Health Stroke Scale) deterioration at 6 weeks post-surgery, where deterioration is defined as at least one point increase in total NIHSS score compared to baseline

  2. Proportion of gross-total resections [ Time Frame: Assessed on 48 hours postoperative scan ]
    Proportion of patients without residual contrast-enhancing tumour on postoperative MRI, where residual tumour is defined as contrast-enhancement with a volume more than 0.175 cm3.


Secondary Outcome Measures :
  1. Health-related quality of life assessed by EQ-5D questionnaire [ Time Frame: Between baseline and 6 weeks/3 months/6 months postoperatively ]
    Health related quality of life (HRQoL) at 6 weeks, 3 and 6 months after operation, where HRQol is measured with the EQ-5D questionnaire

  2. Health-related quality of life assessed by EORTC-QLQ-BN20 questionnaire [ Time Frame: Between baseline and 6 weeks/3 months/6 months postoperatively ]
    Health related quality of life (HRQoL) at 6 weeks, 3 and 6 months after operation, where HRQol is measured with the EORTC QLQ-BN20 questionnaire

  3. Health-related quality of life assessed by EORTC-QLQ-C30 questionnaire [ Time Frame: Between baseline and 6 weeks/3 months/6 months postoperatively ]
    Health related quality of life (HRQoL) at 6 weeks, 3 and 6 months after operation, where HRQol is measured with the EORTC-QLQ-C30 questionnaire

  4. Progression-free survival [ Time Frame: Between surgery and 12 months postoperatively ]
    Progression-free survival (PFS) at 12 months defined as time from diagnosis to disease progression (occurrence of a new tumour lesion with a volume greater than 0.175 cm3, or an increase in residual tumour volume of more than 25%) or death, whichever comes first

  5. Overall survival [ Time Frame: Between surgery and 12 months postoperatively ]
    Overall survival (OS) at 12 months defined as time from diagnosis to death from any cause

  6. Postoperative (serious) adverse events [ Time Frame: Between surgery and 6 weeks postoperatively ]
    Frequency and severity of (Serious) Adverse Effects in each group: Infections, intracerebral hemorrhage, epilepsy, aphasia, paresis/paralysis in arms or/and legs



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 90 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age ≥18 years and ≤ 90 years
  2. Tumor diagnosed as Glioblastoma Multiforme on MRI with distinct ring-like pattern of contrast enhancement with thick irregular walls and a core area reduced signal suggestive of tumour necrosis as assessed by the surgeon
  3. Tumors situated in or near eloquent areas; motor cortex, sensory cortex, subcortical pyramidal tract or speech areas as indicated on MRI (Sawaya Grading II and II)
  4. The tumor is suitable for resection (according to neurosurgeon)
  5. Karnofsky performance scale 80 or more
  6. Written Informed consent

Exclusion Criteria:

  1. Tumors of the cerebellum, brain stem or midline
  2. Multifocal contrast enhancing lesions
  3. Substantial non-contrast enhancing tumor areas suggesting low grade gliomas with malignant transformation
  4. Medical reasons precluding MRI (eg, pacemaker)
  5. Inability to give consent because of or language barrier
  6. Psychiatric history
  7. Previous brain tumour surgery
  8. Previous low-grade glioma.
  9. Second primary malignancy within the past 5 years with the exception of adequately treated in situ carcinoma of any organ or basal cell carcinoma of the skin.
  10. Severe aphasia or dysphasia

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03861299


Contacts
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Contact: Jasper Gerritsen, MD +31629119553 j.gerritsen@erasmusmc.nl

Locations
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Belgium
University Hospital Brussels Recruiting
Brussels, Belgium, 1090
Contact: Johnny Duerinck, MD PhD    0032486185121    johnny.duerinck@uzbrussel.be   
University Hospital Ghent Recruiting
Ghent, Belgium, 9000
Contact: Giorgio Hallaert, MD PhD    003293326876    g.hallaert@uzgent.be   
Netherlands
Elisabeth-Tweesteden Ziekenhuis Recruiting
Tilburg, Noord-Brabant, Netherlands, 5022 GC
Contact: Geert Jan Rutten, MD PhD    +310132210000    g.rutten@etz.nl   
Erasmus MC Recruiting
Rotterdam, Zuid-Holland, Netherlands, 3015 CE
Contact: Arnaud Vincent, MD PhD    +31639428949    a.vincent@erasmusmc.nl   
Contact: Jasper Gerritsen, MD    +31629119553    j.gerritsen@erasmusmc.nl   
Medical Center Haaglanden Recruiting
The Hague, Zuid-Holland, Netherlands, 2261 CP
Contact: Marike Broekman, MD PhD    +31639758253    m.broekman@haaglandenmc.nl   
University Medical Center Groningen Recruiting
Groningen, Netherlands, 9700 RB
Contact: Michiel Wagemakers, MD PhD    +310503616161    m.wagemakers@umcg.nl   
Sponsors and Collaborators
Jasper Gerritsen
Elisabeth-TweeSteden Ziekenhuis
University Medical Center Groningen
Medical Center Haaglanden
University Hospital, Ghent
Universitair Ziekenhuis Brussel
Investigators
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Principal Investigator: Arnaud Vincent, MD PhD Erasmus Medical Center
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Jasper Gerritsen, Study Coordinator, Erasmus Medical Center
ClinicalTrials.gov Identifier: NCT03861299    
Other Study ID Numbers: NL66673.078.18
MEC-2018-1564 ( Other Identifier: Medical Ethical Committee Erasmus MC )
First Posted: March 4, 2019    Key Record Dates
Last Update Posted: October 27, 2020
Last Verified: October 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Jasper Gerritsen, Erasmus Medical Center:
Glioblastoma
Neurological morbidity
Postoperative complications
Extent of resection
Gross-total resection
Health-related quality of life
Progression-free survival
Overall survival
Additional relevant MeSH terms:
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Glioblastoma
Brain Neoplasms
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Central Nervous System Neoplasms
Nervous System Neoplasms
Neoplasms by Site
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Anesthetics
Central Nervous System Depressants
Physiological Effects of Drugs