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

Glioblastoma Clinical Trial

— SAFE  

Official title:

The SAFE-Trial: Safe Surgery for Glioblastoma Multiforme: Awake Craniotomy Versus Surgery Under General Anesthesia. A Multicenter Prospective Randomised Controlled Study

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03861299
• Other study ID #: NL66673.078.18
• Secondary ID: MEC-2018-1564
• Status: Recruiting
• Phase: N/A
• Start date: April 1, 2019
• Est. completion date: September 1, 2027

Study information

• Verified date: November 2023
• Source: Erasmus Medical Center
• Contact: Jasper Gerritsen, MD PhD
• Phone: +31629119553
• Email: j.gerritsen[@]erasmusmc.nl
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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 If GBM is not histologically confirmed, patients will be considered off-study and withdrawn from the study.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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 246
• Est. completion date: September 1, 2027
• Est. primary completion date: September 1, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 90 Years

Eligibility

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

Related Conditions & MeSH terms

• Astrocytoma
• Astrocytoma, Grade IV
• Brain Cancer
• Brain Neoplasms
• Brain Tumor
• Glioblastoma
• Glioblastoma Multiforme
• Glioblastoma Multiforme of Brain

Intervention

Procedure:
• Awake craniotomy
Awake craniotomy
• Craniotomy under general anesthesia
Craniotomy under general anesthesia

Locations

Country	Name	City	State
Belgium	University Hospital Ghent	Ghent
Netherlands	University Medical Center Groningen	Groningen
Netherlands	Erasmus MC	Rotterdam	Zuid-Holland
Netherlands	Medical Center Haaglanden	The Hague	Zuid-Holland
Netherlands	Elisabeth-Tweesteden Ziekenhuis	Tilburg	Noord-Brabant

Sponsors (5)

Lead Sponsor	Collaborator
Jasper Gerritsen	Elisabeth-TweeSteden Ziekenhuis, Medical Center Haaglanden, University Hospital, Ghent, University Medical Center Groningen

Countries where clinical trial is conducted

Belgium,  Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Postoperative neurological morbidity	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	Between operation and 6 weeks postoperatively
Primary	Proportion of gross-total resections	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.	Assessed on 48 hours postoperative scan
Secondary	Health-related quality of life assessed by EQ-5D questionnaire	Health related quality of life (HRQoL) at 6 weeks, 3 and 6 months after operation, where HRQol is measured with the EQ-5D questionnaire	Between baseline and 6 weeks/3 months/6 months postoperatively
Secondary	Health-related quality of life assessed by EORTC-QLQ-BN20 questionnaire	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	Between baseline and 6 weeks/3 months/6 months postoperatively
Secondary	Health-related quality of life assessed by EORTC-QLQ-C30 questionnaire	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	Between baseline and 6 weeks/3 months/6 months postoperatively
Secondary	Progression-free survival	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	Between surgery and 12 months postoperatively
Secondary	Overall survival	Overall survival (OS) at 12 months defined as time from diagnosis to death from any cause	Between surgery and 12 months postoperatively
Secondary	Postoperative (serious) adverse events	Frequency and severity of (Serious) Adverse Effects in each group: Infections, intracerebral hemorrhage, epilepsy, aphasia, paresis/paralysis in arms or/and legs	Between surgery and 6 weeks postoperatively