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Neoplasms, Neuroepithelial

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Neuroectodermal Tumors, Primitive

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Anesthetics

Cohort undergoing craniotomy utilizing general anesthesia protocol

Cohort undergoing craniotomy utilizing awake anesthesia protocol

Awake is defined as the patient being awake with electrical brain stimulation mapping during the critical portions of the procedure.

Awake Anesthesia Protocol

Non-awake is general anesthesia as per convention with intubation.

Non-awake Anesthesia Protocol

Kaisorn L Chaichana

This study protocol examines a comparison between local and general anesthesia (Awake vs. Asleep Craniotomy) in the removal of brain tumors that are in areas of the brain that do not directly control bodily functions (non-eloquent gliomas).

This is a single-center, prospective randomized open or non-blinded end-point (PROBE) clinical trial. Patients will be selected by the neurosurgeon according to the inclusion and exclusion criteria. Patients who consent to randomization will have confirmed non-eloquent status confirmed by independent surgeon and will be randomized into 1 of 2 treatment groups utilizing a dynamic minimization approach. The experimental group with randomization of patients who will undergo awake craniotomy for both high and low grade gliomas in non-eloquent areas or a control group of patients who will have asleep craniotomy for both high and low grade gliomas in non-eloquent regions.

Awake vs. Asleep Craniotomy for Non-eloquent Gliomas

Randomized Control Trial for Awake vs. Asleep Craniotomy for Non-eloquent Gliomas

(KPS) ranking runs from 100 to 0, where 100 is "perfect" health and 0 is death

The FACT-Brain (FACT-Br) provides an additional set of disease-specific questions pertaining to brain neoplasms

0 to 10 (0: No pain, 10: Worst pain) - Numeric Scale

Analysis to include standardized cost, physician service cost, cost of hospitalization and 30 days post-hospitalization cost

Extent of resection (EOR) defined as the residual volume, in cm3, of tumor measured by MRI

Postoperative Anxiety scale measured using a 0 to 10 visual analog scale (0: no anxiety, 10: worst anxiety)

defined as time entering OR and leaving OR

Mayo Clinic

Senior Associate Consultant

Nervous System Diseases

Brain Neoplasms

Central Nervous System Neoplasms

Nervous System Neoplasms

Brain Diseases

Central Nervous System Diseases

Virtual reality headset

Philippe MENEI, MDPHD

Feasibility and tolerance study of virtual reality headset for brain mapping during brain awake surgery.

Brain Awake Surgery Using Virtual Reality Headset

Chirurgie Eveillee du Cerveau Sous Realite Virtuelle Integree Aux Outils Bloc Operatoire : Etude de Tolerance

University Hospital, Angers

Symptoms and General Pathology

Language Disorders

The investigators use a monopolar stimulator to determine and retain the tumor margin within 5mm in the sensitive area which is posterior superior longitudinal fasciculus or posterior arcuate fasciculus.

The investigators use bipolar stimulator according to the current standard surgery plan. After the positive points are identified, those points would be retained to avoiding language function impairment after the tumor resection.

Randomly select 30 participants to implement new surgical plan, which is using a monopolar stimulator to determine positive function sites and save tumors within 5 mm of the posterior superior longitudinal fasciculus/arcuate fasciculus

Awake craniotomy

Shimeng Weng, MD

Shengyu Fang, MD

Jiang Tao

This study is designed to compare the language function after traditional or a new surgical plan during awake craniotomy for glioma resection.

This study concentrates on patient who has type II language area glioma occupation. The investigators designed new surgical plan which is using monopolar stimulator to determine and retain the tumor margin within 5 mm from the posterior superior longitudinal fasciculus or posterior arcuate fasciculus. For the tradiitional surgical plan, the investigators use bipolar stimulator according to the current standard surgery plan. After they positive points are identified by stimulator, the positive points are retained to preserve the motor function while all the negative points of the tumor are resected. This study is to determine whether the new surgical plan is more suitable for type II language area glioma occupation.

Strategic Intervention on Preserving Language Function During Awake Craniotomy

Strategic Intervention on Preserving Language Function During Awake Craniotomy for Glioma Resection

The investigators don't plan to share individual participant data with other researchers

The ratio of language function recovery in patients with new surgical plan would higher than those receive traditional surgical plan. The main tool is to use Western Aphasia Battery (WAB) language evaluation form to record each patient's language ability in 4-7days after surgery and every other 3 months. The executive function and attention would also be evaluated by cognitive assessment (MoCA) and Mini-Mental State Exam (MMSE). Each patient's scores and reponse time would be used to compare the differences between two surgical plans.

The new surgical plan preserves the language function to improve the quality of life, in order to influence the patient's length of life after surgery. Hence, the overall survival days of patients in two surgical plans would be compared by recording patients' date of death from any cause.

Beijing Neurosurgical Institute

The investigators use monopolar stimulators to determine and retain the tumor margin within 5mm from the posterior limb of the inner capsule in type III motor area glioma patients.

The investigators use bipolar stimulator according to the current standard surgery plan. After the positive points are identified by stimulator, the positive points are retained in order to preserve the motor function while all the non-positive points of the tumor are resected.

The awake neurosurgical procedure performed on the brain is to provide a real-time neurological functions monitoring in order to preserve the functions of brain to the greatest extent.

Tao Jiang, MD and PhD

Yuhao Guo, MD

This study aims to compare the motor functions after traditional or a new surgical plan during awake glioma resection surgery.

This study concentrates on patients with type III motor area glioma. In the awake surgery, The investigators compare the new surgical plan, which the investigators use a monopolar stimulator to determine and retain the tumor margin within 5mm from the posterior limb of the inner capsule. For the traditional surgical plan, the investigators use bipolar stimulator according to the current standard surgery plan. After the positive points are identified by stimulator, the positive points are retained in order to preserve the motor function while all the non-positive points of the tumor are resected. This study is designed to determine whether the new surgical plan is more suitable for type III motor area glioma patients.

Strategic Intervention on Preserving Motor Function During Awake Craniotomy

Strategic Intervention on Preserving Motor Function With Application of Monopolar Stimulator During Awake Glioma Resection Surgery

The investigators do not plan to share individual participant data with other researchers

Motor function of the participants in new surgical plan group is better preserved and recover faster than the participants in traditional surgical group.The difference between the motor functions of two groups are analyzed using t-test or chi-square test according to the type of data.

Beijing Tiantan Hospital

Brain Tumor, Adult

Maximum Grip Strength will be measured using a hand-held dynamometer (K-FORCE Grip dynamometer®. Kinvent Biomequanique S.A.S, Montpellier, France) during the preoperative, intraoperative (Awake craniotomy) and postoperative period.

Hand-held dynamometer

Kaisorn L Chaichana, M.D.

Lina C Marenco-Hillembrand, M.D.

Kaisorn Chaichana, MD

The primary purpose of this study is to assess the feasibility, safety and reliability of the use of handheld dynamometry in evaluating intraoperative motor function for patients undergoing awake craniotomy for the resection of brain lesions located within or adjacent to the motor cortex.

Handheld Dynamometer During Awake Craniotomy Pilot

Use of Handheld Dynamometer as a Novel Tool to Assess Motor Function During Awake Craniotomy for Brain Lesions Located Within or Adjacent to the Motor Cortex: A Single-Center Pilot Study

Maximum grip strength (KgF) will be measured using hand-held dynamometry every 2 minutes from the time the patient awakes until the end of surgery. Intraoperative maximum grip strength baseline is defined as the mean of 3 consecutive measures with \<10% variability.

To validate the use of hand-held dynamometry as an adequate tool to monitor intraoperative motor function during awake craniotomies (AC), maximum grip strength (KgF) will be measured every 2 minutes from the time the patient awakes to the end of surgery. The intra-individual variability will be defined as the percent difference between sets with 10% or greater defined as substantial variability.

To validate the use of hand-held dynamometry as an adequate tool to monitor intraoperative motor function during AC, each patient will be baselined (mean of 6 consecutive measurements) during the preoperative neuropsychology evaluation. Variability from preoperative baseline will be calculated as a percentile \[ (Preoperative Baseline/ Intraoperative Baseline)/ Preoperative Baseline) \* 100\]

Defined as the duration of the procedure from the initiation of skin incision to the completion of skin closure according to anesthesia records. Measured in minutes.

Concordance between hand-held dynamometer and manual motor testing will be evaluated using Spearmans' correlation coefficient.

Postoperative Maximum Grip strength (KgF) will be measured using hand-held dynamometer at day 1 and at 1 month follow-up.

Principal Investigator

Behaviors and Mental Disorders

Postoperative Complications

Glioblastoma

Astrocytoma

Disease Progression

Quality of Life

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.

Trephination and tumour resection are performed without any additional neuro-psychological monitoring or brain mapping, guided by STEALTH-neuronavigation.

Craniotomy under general anesthesia

Jasper Gerritsen, MD PhD

Giorgio Hallaert, MD PhD

Geert Jan Rutten, MD PhD

Arnaud Vincent, MD PhD

Jasper Gerritsen, MD

Marike Broekman, MD PhD

Michiel Wagemakers, MD PhD

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.

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.

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

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

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

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

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.

Health related quality of life (HRQoL) at 6 weeks, 3 and 6 months after operation, where HRQol is measured with the EQ-5D 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

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

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

Overall survival (OS) at 12 months defined as time from diagnosis to death from any cause

Frequency and severity of (Serious) Adverse Effects in each group: Infections, intracerebral hemorrhage, epilepsy, aphasia, paresis/paralysis in arms or/and legs

Elisabeth-TweeSteden Ziekenhuis

University Medical Center Groningen

Medical Center Haaglanden

University Hospital, Ghent

Jasper Gerritsen

Study Coordinator

Analgesics

Dexmedetomidine

Propofol

Remifentanil

Hypnotics and Sedatives

Analgesics, Non-Narcotic

Adrenergic Agents

Adrenergic alpha-Agonists

Adrenergic Agonists

Neurotransmitter Agents

Anesthetics, Intravenous

Anesthetics, General

Analgesics, Opioid

Narcotics

Group I. (propofol/remifentanil): Infusions begin at remifentanil (0.01-0.1 mcg/kg/min) and propofol (25-250 mcg/kg/min) for 15 min, and then titrated to effect.

Group II. (dexmedetomidine): The infusion begins at 0.3-0.4 mcg/kg/hr for 15 min, and then titrated down to 0.1-0.2 mcg/kg/hr.

The infusion begins at dexmedetomidine 0.3-0.4 mcg/kg/hr for 15 min, and then titrated down to 0.1-0.2 mcg/kg/hr.

The infusion begins at propofol 25-250 mcg/kg/min for 15 min, and then titrated to effect.

The infusion begins at remifentanil 0.01-0.1 mcg/kg/min for 15 min, and then titrated to effect.

Pirjo Manninen, MD, FRCPC

Nicolai Goettel, MD

Awake craniotomy for resection of brain tumor located in close proximity to areas of eloquent brain function, such as speech, motor and sensory, is an accepted procedure used to minimize neurological injury during resection. During awake craniotomy, anesthesia is usually provided using a combination of local anesthesia (regional scalp block and/or local infiltration) and intravenous (IV) agents to provide sedation, anxiolysis and analgesia. Propofol sedation, commonly in combination with a shorter acting opioid such as fentanyl, or remifentanil, is an effective and popular technique during awake craniotomy, achieving a high degree of patient satisfaction and acceptance. Most of the anesthetic agents are associated with some respiratory depression.

The anesthetic agent called dexmedetomidine is a potent, highly selective α2-adrenoceptor agonist. The effects of dexmedetomidine are anxiolysis, analgesia, sedation and sympatholysis, and it is not associated with respiratory depressive effect. Bekker et al. first reported the successful use of dexmedetomidine in awake craniotomy in 2001.

The purpose of this blinded, prospective, randomized study is to compare the efficacy of dexmedetomidine versus propofol-remifentanil based sedation in patients undergoing awake craniotomy for resection of tumors. The study hypothesis is that the efficacy of performing intra-operative brain mapping is identical between dexmedetomidine and the propofol-remifentanil based sedation. The primary end-points are to assess the ability to perform intraoperative mapping during awake craniotomy. Secondary end-points will assess the incidence of complications (respiratory depression, failure to provide adequate analgesia), as well as patient and surgeon satisfaction to the corresponding anesthetic technique.

Awake craniotomy for resection of brain tumor located in close proximity to areas of eloquent brain function, such as speech, motor and sensory, is an accepted procedure used to minimize neurological injury during resection. The level of sedation and analgesia during the different stages of surgery varies, but importantly, the patient needs to be awake and alert during brain mapping. During awake craniotomy, anesthesia is usually provided using a combination of local anesthesia (regional scalp block and/or local infiltration) and intravenous (IV) agents to provide sedation, anxiolysis and analgesia. There is considerable variation in the anesthetic management of the awake craniotomy in different institutions. Propofol sedation, commonly in combination with a shorter acting opioid such as fentanyl, or remifentanil, is an effective and popular technique during awake craniotomy, achieving a high degree of patient satisfaction and acceptance. However, the awake craniotomy remains one of the most challenging techniques of anesthesia care in terms of balancing an adequate depth of sedation and analgesia to combat the rapid changes of surgical stimulation yet having an alert patient for brain mapping. Furthermore, most of the anesthetic agents are associated with some respiratory depression.

A newer anesthetic agent called dexmedetomidine (Precedex (TM), Hospira Healthcare Corporation, Saint Laurent, Québec, Canada) is a potent, highly selective α2-adrenoceptor agonist with an α2:α1 selectivity ratio of 1600:1. It has been available in the Canada since 2009 as a short-term sedative agent, and is available in the UHN. The use of dexmedetomidine has been in mechanically ventilated patients in ICU and for intra-operative sedation. The well-documented beneficial effects of dexmedetomidine are anxiolysis, analgesia, sedation and sympatholysis, and it is not associated with respiratory depressive effect.

Dexmedetomidine has been successfully used to provide sedation in dental procedures, awake fibreoptic intubation, bariatric surgery and morbidly obese patients, as well as obstructive sleep apnea patients. The pharmacokinetic properties of dexmedetomidine is very predictable and titratable, with a rapid distribution half-life (t1/2α) being approximately 5-6min and an elimination half-life (t1/2β) of approximately 2h. Bekker et al. first reported the successful use of dexmedetomidine in awake craniotomy in 2001. Subsequent case series published by Souter et al. demonstrated that dexmedetomidine can be used either as a sole agent or in combination with other agents such as fentanyl during seizure foci resection with accurate intraoperative brain mapping.

The hypnotic effect of dexmedetomidine is mediated by the hyperpolarization of noradrenergic neurons in the locus ceruleus, which proposed that dexmedetomidine converges on a natural sleep pathway to exert its sedative effect. Venn and co-workers, as part of a large European multicentre trial investigating dexmedetomidine for postoperative sedation in the ICU, reported that: "Patients are calmly and easily roused from sleep to allow excellent communication and cooperation while intubated and ventilated, and then similarly quickly return to sleep". This unique sedation state is very useful for awake craniotomy, which requires deep level of sedation during painful operative procedures, as well as easily rousable state during mapping of eloquent function.

The purpose of this blinded, prospective, randomized study is to compare the efficacy of dexmedetomidine versus propofol-remifentanil based sedation in patients undergoing awake craniotomy for resection of tumors. The study hypothesis is that the efficacy of performing intra-operative brain mapping is identical between dexmedetomidine and the propofol-remifentanil based sedation. The primary end-points are to assess the ability to perform intraoperative mapping during awake craniotomy. Secondary end-points will assess the incidence of complications (respiratory depression, failure to provide adequate analgesia), as well as patient and surgeon satisfaction to the corresponding anesthetic technique.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Awake vs. Asleep Craniotomy for Non-eloquent Gliomas	NCT03621748	Intracranial Gl...	Awake Anesthesi... Non-awake Anest...	18 Years -	Mayo Clinic
Brain Awake Surgery Using Virtual Reality Headset	NCT03010943	Brain Tumor Virtual Reality	Virtual reality...	18 Years -	University Hospital, Angers
Strategic Intervention on Preserving Language Function During Awake Craniotomy	NCT05143775	Glioma	Awake craniotom...	18 Years - 70 Years	Beijing Neurosurgical Institute
Strategic Intervention on Preserving Motor Function During Awake Craniotomy	NCT05143788	Glioma	Awake craniotom...	18 Years - 65 Years	Beijing Neurosurgical Institute
Brain Awake Surgery Using Virtual Reality Headset	NCT03010943	Brain Tumor Virtual Reality	Virtual reality...	18 Years -	University Hospital, Angers
Handheld Dynamometer During Awake Craniotomy Pilot	NCT04742231	Brain Lesion Brain Tumor Adu... Brain Tumor	Hand-held dynam...	18 Years -	Mayo Clinic
The SAFE-Trial: Awake Craniotomy Versus Surgery Under General Anesthesia for Glioblastoma Patients.	NCT03861299	Glioblastoma Glioblastoma Mu... Glioblastoma Mu... Astrocytoma, Gr... Brain Tumor Brain Cancer Brain Neoplasms	Awake craniotom... Craniotomy unde...	18 Years - 90 Years	Erasmus Medical Center
Comparison of Dexmedetomidine and Propofol-Remifentanil Conscious Sedation for Awake Craniotomy for Tumor Surgery	NCT01545297	Brain Tumor	Dexmedetomidine Propofol Remifentanil	18 Years -	University Health Network, Toronto

Spots Global Cancer Trial Database for awake craniotomy