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

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.

• Health-related quality of life assessed by EQ-5D questionnaire [Срок оценки: Between baseline and 6 weeks/3 months/6 months postoperatively]
• Health-related quality of life assessed by EORTC-QLQ-BN20 questionnaire [Срок оценки: Between baseline and 6 weeks/3 months/6 months postoperatively]
• Health-related quality of life assessed by EORTC-QLQ-C30 questionnaire [Срок оценки: Between baseline and 6 weeks/3 months/6 months postoperatively]
• Progression-free survival [Срок оценки: Between surgery and 12 months postoperatively]
• Overall survival [Срок оценки: Between surgery and 12 months postoperatively]
• Postoperative (serious) adverse events [Срок оценки: Between surgery and 6 weeks postoperatively]