title: Corticosteroids compromise survival in glioblastoma.
abstract: Glioblastoma is the most common and most aggressive primary brain tumour. Standard of care consists of surgical resection followed by radiotherapy and concomitant and maintenance temozolomide (temozolomide/radiotherapy→temozolomide). Corticosteroids are commonly used perioperatively to control cerebral oedema and are frequently continued throughout subsequent treatment, notably radiotherapy, for amelioration of side effects. The effects of corticosteroids such as dexamethasone on cell growth in glioma models and on patient survival have remained controversial. We performed a retrospective analysis of glioblastoma patient cohorts to determine the prognostic role of steroid administration. A disease-relevant mouse model of glioblastoma was used to characterize the effects of dexamethasone on tumour cell proliferation and death, and to identify gene signatures associated with these effects. A murine anti-VEGFA antibody was used in parallel as an alternative for oedema control. We applied the dexamethasone-induced gene signature to The Cancer Genome Atlas glioblastoma dataset to explore the association of dexamethasone exposure with outcome. Mouse experiments were used to validate the effects of dexamethasone on survival in vivo Retrospective clinical analyses identified corticosteroid use during radiotherapy as an independent indicator of shorter survival in three independent patient cohorts. A dexamethasone-associated gene expression signature correlated with shorter survival in The Cancer Genome Atlas patient dataset. In glioma-bearing mice, dexamethasone pretreatment decreased tumour cell proliferation without affecting tumour cell viability, but reduced survival when combined with radiotherapy. Conversely, anti-VEGFA antibody decreased proliferation and increased tumour cell death, but did not affect survival when combined with radiotherapy. Clinical and mouse experimental data suggest that corticosteroids may decrease the effectiveness of treatment and shorten survival in glioblastoma. Dexamethasone-induced anti-proliferative effects may confer protection from radiotherapy- and chemotherapy-induced genotoxic stress. This study highlights the importance of identifying alternative agents such as vascular endothelial growth factor antagonists for managing oedema in glioblastoma patients. Beyond the established adverse effect profile of protracted corticosteroid use, this analysis substantiates the request for prudent and restricted use of corticosteroids in glioblastoma.
authors.affiliation: 1 Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA dhambar@emory.edu eholland@fhcrc.org michael.weller@usz.ch.
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Pitter
authors.affiliation: 2 Department of Neurosciences at the Cleveland Clinic Lerner Research Institute, Cleveland, Ohio, 44195, USA dhambar@emory.edu eholland@fhcrc.org michael.weller@usz.ch.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Tamagno
authors.affiliation: 3 Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA, USA dhambar@emory.edu eholland@fhcrc.org michael.weller@usz.ch.
authors.forename: Kristina
authors.initials: K
authors.lastname: Alikhanyan
authors.affiliation: 4 University of Tennessee Health Science Center, Department of Clinical Pharmacy, Memphis, TN, 39103, USA dhambar@emory.edu eholland@fhcrc.org michael.weller@usz.ch.
authors.forename: Amira
authors.initials: A
authors.lastname: Hosni-Ahmed
authors.affiliation: 5 Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA (FH) dhambar@emory.edu eholland@fhcrc.org michael.weller@usz.ch.
authors.forename: Siobhan S
authors.initials: SS
authors.lastname: Pattwell
authors.affiliation: 2 Department of Neurosciences at the Cleveland Clinic Lerner Research Institute, Cleveland, Ohio, 44195, USA dhambar@emory.edu eholland@fhcrc.org michael.weller@usz.ch.
authors.forename: Shannon
authors.initials: S
authors.lastname: Donnola
authors.affiliation: 2 Department of Neurosciences at the Cleveland Clinic Lerner Research Institute, Cleveland, Ohio, 44195, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Dai
authors.affiliation: 5 Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA (FH).
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Ozawa
authors.affiliation: 6 Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Chang
authors.affiliation: 6 Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA 7 Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Chan
authors.affiliation: 6 Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA 7 Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Beal
authors.affiliation: 6 Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Bishop
authors.affiliation: 6 Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Barker
authors.affiliation: 4 University of Tennessee Health Science Center, Department of Clinical Pharmacy, Memphis, TN, 39103, USA.
authors.forename: Terreia S
authors.initials: TS
authors.lastname: Jones
authors.affiliation: 8 Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.
authors.forename: Bettina
authors.initials: B
authors.lastname: Hentschel
authors.affiliation: 9 European Organisation for Research and Treatment of Cancer, Brussels, Belgium.
authors.forename: Thierry
authors.initials: T
authors.lastname: Gorlia
authors.affiliation: 10 Department of Neurology, University Hospital Knappschaftskrankenhaus Bochum-Langendreer, Bochum, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Schlegel
authors.affiliation: 11 Department of Oncology, University Hospital and University of Zurich, CH-8091 Zurich, Switzerland.
authors.forename: Roger
authors.initials: R
authors.lastname: Stupp
authors.affiliation: 12 Department of Neurology, University Hospital and University of Zurich, CH-8091 Zurich, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Weller
authors.affiliation: 5 Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA (FH) 13 Alvord Brain Tumor Center and Department of Neurosurgery, University of Washington, Seattle, WA 98109, USA 14 Solid Tumor and Translational Research, University of Washington, Seattle, WA 98109, USA dhambar@emory.edu eholland@fhcrc.org michael.weller@usz.ch.
authors.forename: Eric C
authors.initials: EC
authors.lastname: Holland
authors.affiliation: 2 Department of Neurosciences at the Cleveland Clinic Lerner Research Institute, Cleveland, Ohio, 44195, USA 3 Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA, USA dhambar@emory.edu eholland@fhcrc.org michael.weller@usz.ch.
authors.forename: Dolores
authors.initials: D
authors.lastname: Hambardzumyan
mesh_terms: D000305:Adrenal Cortex Hormones / Q000009:adverse effects* / Q000494:pharmacology*; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001932:Brain Neoplasms / Q000188:drug therapy / Q000401:mortality* / Q000532:radiotherapy; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003131:Combined Modality Therapy / Q000009:adverse effects; D003907:Dexamethasone / Q000009:adverse effects / Q000494:pharmacology; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D005909:Glioblastoma / Q000188:drug therapy / Q000401:mortality* / Q000532:radiotherapy; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011878:Radiotherapy; D012189:Retrospective Studies; D016019:Survival Analysis; D042461:Vascular Endothelial Growth Factor A / Q000276:immunology
chemical_list: D000305:Adrenal Cortex Hormones; D000906:Antibodies; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D003907:Dexamethasone
keywords: CNS tumour: surgical treatment; astrocytoma; genetics; glioma; neurooncology