Restrictive Use of Dexamethasone in Glioblastoma

Overview

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

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.

Interventions

• Drug Dexamethasone
  restrictive use of DEX, based on standardized clinical and radiological criteria.

Primary outcome measures

• Failure rate of the restrictive DEX regimen [Time frame: 30 days after surgery]

Secondary outcome measures (11)

• Secondary neurological or systemic complication [Time frame: 30 days after surgery]
• Cumulative dexamethasone dosage [Time frame: 30 days after surgery]
• National Institutes of Health Stroke Scale (NIHSS) over time of the study period [Time frame: 30 days after surgery]
• Glasgow Coma Scale (GCS) over time of the study period and correlation with steroid medication [Time frame: 30 days after surgery]
• Volume of contrast enhancing tumor on preoperative MRI [Time frame: presurgery]
• Volume of contrast enhancing tumor on postoperative MRI [Time frame: 48 hours after surgery]
• Volume of edema on preoperative MRI and correlation with steroid medication [Time frame: presurgery]
• Volume of edema on postoperative MRI [Time frame: 48 hours after surgery]
• Time to start of adjuvant treatment [Time frame: 30 days after surgery]
• Rate of reoperations [Time frame: 30 days after surgery]
• Cause of reoperations [Time frame: 30 days after surgery]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

Switzerland · 4 centers

• Kantonsspital St. Gallen — Sankt Gallen
• Universitätsspital Basel — Basel
• Department of Neurosurgery — Bern
• Universitätsspital Zürich — Zurich

Publications

• GALICICH JH, FRENCH LA, MELBY JC. Use of dexamethasone in treatment of cerebral edema associated with brain tumors. J Lancet. 1961 Feb;81:46-53. No abstract available. PMID 13703072
• KOFMAN S, GARVIN JS, NAGAMANI D, TAYLOR SG 3rd. Treatment of cerebral metastases from breast carcinoma with prednisolone. J Am Med Assoc. 1957 Apr 20;163(16):1473-6. doi: 10.1001/jama.1957.02970510039008. No abstract available. PMID 13415910
• Luedi MM, Singh SK, Mosley JC, Hassan ISA, Hatami M, Gumin J, Andereggen L, Sulman EP, Lang FF, Stueber F, Fuller GN, Colen RR, Zinn PO. Dexamethasone-mediated oncogenicity in vitro and in an animal model of glioblastoma. J Neurosurg. 2018 Dec 1;129(6):1446-1455. doi: 10.3171/2017.7.JNS17668. Epub 2018 Jan 12. PMID 29328002
• Ly KI, Wen PY. Clinical Relevance of Steroid Use in Neuro-Oncology. Curr Neurol Neurosci Rep. 2017 Jan;17(1):5. doi: 10.1007/s11910-017-0713-6. PMID 28138871
• Pitter KL, Tamagno I, Alikhanyan K, Hosni-Ahmed A, Pattwell SS, Donnola S, Dai C, Ozawa T, Chang M, Chan TA, Beal K, Bishop AJ, Barker CA, Jones TS, Hentschel B, Gorlia T, Schlegel U, Stupp R, Weller M, Holland EC, Hambardzumyan D. Corticosteroids compromise survival in glioblastoma. Brain. 2016 May;139(Pt 5):1458-71. doi: 10.1093/brain/aww046. Epub 2016 Mar 28. PMID 27020328
• Roth P, Wick W, Weller M. Steroids in neurooncology: actions, indications, side-effects. Curr Opin Neurol. 2010 Dec;23(6):597-602. doi: 10.1097/WCO.0b013e32833e5a5d. PMID 20962642
• Shields LB, Shelton BJ, Shearer AJ, Chen L, Sun DA, Parsons S, Bourne TD, LaRocca R, Spalding AC. Dexamethasone administration during definitive radiation and temozolomide renders a poor prognosis in a retrospective analysis of newly diagnosed glioblastoma patients. Radiat Oncol. 2015 Oct 31;10:222. doi: 10.1186/s13014-015-0527-0. PMID 26520780
• Ueda S, Mineta T, Nakahara Y, Okamoto H, Shiraishi T, Tabuchi K. Induction of the DNA repair gene O6-methylguanine-DNA methyltransferase by dexamethasone in glioblastomas. J Neurosurg. 2004 Oct;101(4):659-63. doi: 10.3171/jns.2004.101.4.0659. PMID 15481722

Identifiers

NCT: NCT04266977 · RESDEX

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗