Restrictive Use of Dexamethasone in Glioblastoma (RESDEX)

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.

Study Overview

• Status: Recruiting
• Conditions: Glioblastoma; Dexamethasone; Steroids
• Intervention / Treatment: Drug: Dexamethasone

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.

• Study Type: Interventional
• Enrollment (Anticipated): 50
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Johannes Goldberg, MD; Phone Number: +41316322409; Email: johannes.goldberg@insel.ch
• Study Contact Backup: Name: Nicole Söll, CDM; Phone Number: +41316323164; Email: nicole.soell@insel.ch

Study Locations

• Switzerland
  • Basel, Switzerland, 4031
    • Not yet recruiting
    • Universitatsspital Basel
    • Contact: Gregor Hutter, MD; Email: Gregor.Hutter@usb.ch
  • Bern, Switzerland, 3010
    • Recruiting
    • Department of Neurosurgery
    • Contact: Johannes Goldberg, MD; Phone Number: +41316322409; Email: johannes.goldberg@insel.ch
    • Contact: Nicole Söll, CDM; Phone Number: +41316323164; Email: nicole.soell@insel.ch
    • Sub-Investigator: Johannes Goldberg
  • Zürich, Switzerland, 8091
    • Not yet recruiting
    • Universitätsspital Zürich
    • Contact: Vincens Kälin, MD; Email: Vincens.Kaelin@usz.ch
    • Contact: Carki Serra, MD; Email: Carlo.Serra@usz.ch
  • St.Gallen
    • Saint Gallen, St.Gallen, Switzerland, 9007
      • Not yet recruiting
      • Kantonsspital St. Gallen
      • Contact: Marian Neidert, MD; Email: marian.neidert@kssg.ch

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 90 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment Dexamethasone; 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; restrictive use of DEX, based on standardized clinical and radiological criteria.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University Hospital Inselspital, Berne
• Investigators: Principal Investigator: Andreas Raabe, MD, Inselspital Bern, Department of Neurosurgery

Publications and helpful links

General 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• Wong ET, Lok E, Gautam S, Swanson KD. Dexamethasone exerts profound immunologic interference on treatment efficacy for recurrent glioblastoma. Br J Cancer. 2015 Dec 1;113(11):1642. doi: 10.1038/bjc.2015.404. No abstract available.
• Weinstein JD, Toy FJ, Jaffe ME, Goldberg HI. The effect of dexamethasone on brain edema in patients with metastatic brain tumors. Neurology. 1973 Feb;23(2):121-9. doi: 10.1212/wnl.23.2.121. No abstract available.
• Derr RL, Ye X, Islas MU, Desideri S, Saudek CD, Grossman SA. Association between hyperglycemia and survival in patients with newly diagnosed glioblastoma. J Clin Oncol. 2009 Mar 1;27(7):1082-6. doi: 10.1200/JCO.2008.19.1098. Epub 2009 Jan 12.

Study record dates

Study Major Dates

• Study Start (Actual): May 8, 2020
• Primary Completion (Anticipated): April 1, 2025
• Study Completion (Anticipated): April 1, 2026

Study Registration Dates

• First Submitted: February 3, 2020
• First Submitted That Met QC Criteria: February 10, 2020
• First Posted (Actual): February 12, 2020

Study Record Updates

• Last Update Posted (Actual): March 24, 2023
• Last Update Submitted That Met QC Criteria: March 22, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma; Physiological Effects of Drugs; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Antineoplastic Agents; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Dexamethasone
• Other Study ID Numbers: RESDEX

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No