Restrictive Use of Dexamethasone in Glioblastoma

Study Overview
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Brief Summary
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The administration of steroids, most commonly dexamethasone (DEX), has established as standard of care during treatment of glioblastoma (GBM) and is widely used during the entire course of the disease including pre- and postoperative management, chemo- and radiotherapy. The primary purpose is to reduce tumor-associated vasogenic edema and to prevent or treat increased intracranial pressure. However, steroids are also linked to a multitude of adverse side effects that may affect survival of GBM patients such as major immunosuppression. The use of steroids during radiotherapy is associated with reduced overall- and progression-free survival and has been identified as an independent poor prognostic factor. Despite these findings, the suspicion of GBM often triggers the administration of DEX in routine clinical practice, regardless of neurological symptoms, tumor size, or extension of cerebral edema. The purpose of this study is to assess whether selected GBM patients can be treated safely with a restrictive DEX regimen from referral to the neurosurgical center until discharge. The primary objective is to determine the failure rate of a restrictive DEX regimen defined as edema or mass effect leading to any of the following: GCS deterioration ≥ 2 points, NIHSS increase ≥ 3 points, increase of midline Shift ≥ 2mm, or any surgical rescue procedure for increasing mass effect.

Detailed Description
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Background Glioblastoma (GBM) is the most common and devastating malignant brain tumor in adults. Patients with glioblastoma face a poor prognosis. Despite maximal treatment, most patients suffer tumor progression after 6-7 months and die within 1-2 years. Standard treatment for newly diagnosed glioblastoma contains maximal safe surgery and adjuvant radiochemotherapy with temozolomide. Additional administration of steroids has established as standard of care during treatment of GBM. It is widely used during the entire course of the disease including pre- and postoperative management, chemotherapy and radiotherapy. Dexamethasone (DEX) is the most frequently used steroid. The main purpose is to reduce the tumor associated vasogenic cerebral edema, to prevent or treat increased intracranial pressure. In addition, DEX helps to cope with adverse effects of GBM-treatment like nausea, vomiting and fatigue. However, steroids are also linked to a multitude of adverse side effects that may affect the survival of GBM patients such as major immunosuppression, and metabolic changes like hyperglycemia. The use of steroids during radiotherapy is associated with reduced overall- and progression-free survival and has been identified as an independent poor prognostic factor. DEX was also related to a poor prognosis in recurrent GBM. Despite these findings, in routine clinical practice, the suspicion of glioblastoma often triggers the administration of DEX, regardless of neurologic symptoms or the extension of cerebral edema. Many patients are treated with larger doses of DEX per day before being referred to a neurosurgical center and are kept on steroids during the entire treatment. On the other hand, the clinical experience shows that GBM-patients with no, or only mild neurologic symptoms, normal intracranial pressure and relatively small cerebral edema can be managed without administration of DEX. The rationale for this study is to objectify the criteria and safety of a restrictive DEX regimen (based on standardized clinical and radiological criteria). A restrictive DEX regimen may help to reduce over-use, limit the number of patients exposed to the adverse effects of DEX, and potentially improve survival in GBM-patients. The purpose of this study is to assess whether selected GBM patients can be treated safely with a restrictive DEX regimen from referral to the neurosurgical center until discharge. Objective The primary objective is to determine the failure rate of a restrictive DEX regimen defined as edema or mass effect leading to any of the following: GCS deterioration ≥ 2 points, NIHSS increase ≥ 3 points, increase of midline Shift ≥ 2mm, or any surgical rescue procedure for increasing mass effect. Methods All patients referred to the neurosurgical center with suspicion of glioblastoma are screened for inclusion- and exclusion criteria. If eligible and consenting of the patient to the study protocol, no steroids will be administered until discharge (except optional intraoperative single shot dexamethasone of max. 4mg if necessary). If steroids have been administered for a maximum of one day before referral, they will be stopped immediately. Patients are followed clinically. If one of the above-described failure criteria occurs, the primary endpoint is reached and DEX will be administered.

Official Title
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Restrictive Use of Dexamethasone in Glioblastoma

Conditions
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Glioblastoma, Dexamethasone, Steroids

Intervention / Treatment
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* Drug: Dexamethasone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Newly diagnosed supratentorial contrast enhancing lesion suspicious of glioblastoma without major mass effect, amenable to surgical resection Age 18 - 90 years Midline Shift ≤ 3mm GCS ≥ 14 NIHSS ≤ 3 Provided written informed consent Exclusion Criteria: Infratentorial lesions, brainstem lesions, multifocal lesions Therapy with steroids for >1 day before inclusion Need for treatment with steroids due to any other disease Contraindications to the administration of Dexamethasone Pregnancy or breastfeeding

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: restrictive use of DEX, based on standardized clinical and radiological criteria.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Dexamethasone<br>The restrictive DEX regimen is applied from referral to the neurosurgical center until discharge. All administered steroids will be stopped immediately after study inclusion. If one or more of the previously defined failure criteria occurs, patients will be treated with DEX. | Drug: Dexamethasone<br>* restrictive use of DEX, based on standardized clinical and radiological criteria.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Failure rate of the restrictive DEX regimen | Failure rate of the restrictive DEX regimen, defined as cerebral edema or mass effect causing any of the following: GCS deterioration ≥ 2 points or NIHSS increase ≥ 3 points or Increase of midline Shift ≥ 2mm or any new herniation sign on imaging or Any surgical rescue procedure for increasing mass effect (hemicraniectomy, removal of bone flap, abortion of the procedure or emergency tumor debulking | 30 days after surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Secondary neurological or systemic complication | Secondary neurological or systemic complication resulting in a 30-day morbidity or mortality | 30 days after surgery | 
| Cumulative dexamethasone dosage | Cumulative dexamethasone dosage during study period | 30 days after surgery | 
| National Institutes of Health Stroke Scale (NIHSS) over time of the study period | NIHSS over time of the study period and correlation with steroid medication (Score 0-42, 0 = no deficits and 1-42 deficits) | 30 days after surgery | 
| Glasgow Coma Scale (GCS) over time of the study period and correlation with steroid medication | GCS over time of the study period and correlation with steroid medication GCS over time of the study period and correlation with steroid medication (Score 15-3, 15 = patient is fully oriented, 3 = patient is intubated) | 30 days after surgery | 
| Volume of contrast enhancing tumor on preoperative MRI | Volume of contrast enhancing tumor on preoperative MRI | presurgery | 
| Volume of contrast enhancing tumor on postoperative MRI | Volume of contrast enhancing tumor on postoperative MRI | 48 hours after surgery | 
| Volume of edema on preoperative MRI and correlation with steroid medication | Volume of edema on preoperative MRI and correlation with steroid medication | presurgery | 
| Volume of edema on postoperative MRI | Volume of edema on postoperative MRI and correlation with steroid medication | 48 hours after surgery | 
| Time to start of adjuvant treatment | Time to start of adjuvant treatment | 30 days after surgery | 
| Rate of reoperations | Rate of reoperations | 30 days after surgery | 
| Cause of reoperations | Cause of reoperations | 30 days after surgery |