Letter: When Less is More: Dexamethasone Dosing for Brain Tumors (2019)

To the Editor: We are writing to highlight the discrepancy in dosing schedules for corticosteroids used to treat peritumoral edema between the neurosurgical community and the neuro-oncology community and suggest that it may be time to re-evaluate the dosing of dexamethasone for brain tumors. Corticosteroids have been ubiquitously used to treat brain tumor patients with cerebral edema since the 1950s. In particular, dexamethasone, due to its low mineralocorticoid potency and high glucocorticoid activity, is arguably the most commonly used symptomatic agent out of the limited armamentarium available to physicians caring for brain tumor patients. This widespread practice traces its origin in part to the landmark paper by Dr Joseph Galicich and colleagues from the University of Minnesota in 1961.1 In this study, 14 patients with brain tumor-related cerebral edema were treated with an initial bolus of 10 to 40 mg of dexamethasone, followed by a regimen of 4 mg intramuscularly every 6 h. A total of 13 out of the 14 patients experienced a significant improvement in their neurological symptoms, and dexamethasone was hence deemed a “safe and highly effective” agent in the treatment of tumor-related cerebral edema. Since that time, it has been standard practice for dexamethasone to be administered to patients every 6 h, including, frequently, in the middle of the night. While the benefit of dexamethasone can be dramatic both clinically and radiographically, particularly in patients with brain metastases and lymphoma, balancing the side effects remains a real challenge, and overuse of dexamethasone is common. Steroid-related toxicities present a significant concern over time and include iatrogenic Cushing's syndrome, behavioral issues, myopathy, opportunistic infections, and osteoporosis. In addition, early steroid use in primary brain tumor patients has been associated with increased morbidity and mortality.2 As newer therapies attempt to augment the immune response in the treatment of brain tumors, the use of steroids for symptomatic relief has become counterproductive in many cases. Every attempt should be made to start at the lowest effective dose and taper as rapidly and as safely as possible. Dosage and tapering of dexamethasone in brain tumor-related cerebral edema are physician, specialty, institution, and patient dependent. Over time, there has been a growing discrepancy between the dose and schedule of dexamethasone used by the neurosurgical and the neuro-oncology communities. Most neurosurgeons initiate dexamethasone at 4 mg every 6 h, following a bolus, and maintain an every 6 h schedule for lower doses. In contrast, most neuro-oncologists administer dexamethasone twice daily or even once daily. These schedules are significantly easier for patients and have not been associated with diminished efficacy. Dexamethasone has a biological half-life of 36 to 54 h (despite a plasma half-life of about 4 hs) and can provide a symptomatic benefit for a prolonged duration.3 A study published in 1990, which utilized autoradiography to monitor capillary permeability to study peritumoral edema in a C6 rat glioma model, revealed that a single dose of dexamethasone maintained a reduction in capillary permeability over a 12-h course.4 Another study corroborated a substantial reduction in vascular permeability and water content of tumor and peritumoral brain tissue in RG2 rat glioma following twice daily dexamethasone dosing.5 Although rigorous patient studies on twice per day dexamethasone dosing are lacking, a small pilot study of 14 patients with intracranial metastases on a twice daily tapering regimen starting at 8 mg twice a day showed similar rates of clinical response and no neurological decline when compared to historical cohorts.6 Administering corticosteroids every 6 h frequently can result in poor sleep due to medication-related effects or medication administration itself, contributing to increased daytime fatigue. In a population where preserving the quality of life is paramount, and in the absence of evidence to justify more frequent dosing, we hope the neurosurgical community will join the neuro-oncology community and consider changing its practice to once or twice a day dosing of dexamethasone for brain tumor patients. Disclosures Dr Colman is on the Advisory Board for and is a consultant for Abbvie, Foundation Medicine, Innocrin, Tactical Therapeutics, Deciphera, Newlink Genetics, Best Doctors, Merck, and Karyopharm Therapeutics, and receives research funding (Site PI/Institutional Contract): Newlink Genetics, Plexxikon, Kadmon, Orbus, Merck, DNATrix, Abbvie, Beigene, and Forma. Dr Lo is on the Advisory Board for Gilead Sciences and is a consultant for Viiv Healthcare. Dr Mellinghoff receives research funding from General Electric, Amgen, and Lilly, has advisory roles with Agios, Puma Biotechnology, and Debiopharm Group, and has received honoraria from Roche for a presentation. Dr Mehta is a consultant for Varian, Abbvie, Celgene, Astra-Zeneca, Tocagen, and Blue Earth Diagnostics, and is on the Board of Directors for Oncoceutics. Dr Lassman has received honoraria/travel/research support (prior 12 mo, all outside the submitted work) from Karyopharm, NW Bio, Agios, AbbVie, Sapience, Oncoceutics, Novocure, Tocagen, Genentech/Roche, Amgen, Millenium, Celldex, Novartis, Pfizer, Aeterna Zentaris, Pfizer, Kadmon, VBI Vaccines, Beigene, and Bioclinica. Dr Ahluwalia has received grants/research support from Astrazeneca, Abbvie, BMS, Bayer, Incyte, Pharmacyclics, Novocure, and Merck, has received honoraria or consultation fees from Elsevier, Wiley, Astrazeneca, Abvvie, VBI Vaccines, Flatiron, Varian Medical Systems, and Prime Education, and is a stock shareholder in Doctible and Mimiva.