Corticosteroids compromise survival in glioblastoma

Kenneth L. Pitter, Ilaria Tamagno, Kristina Alikhanyan, Amira Hosni-Ahmed, Siobhan S. Pattwell, Shannon Donnola, Charles Dai, Tatsuya Ozawa, Maria Chang, Timothy A. Chan, Kathryn Beal, Andrew J. Bishop, Christopher A. Barker, Terreia S. Jones, Bettina Hentschel, Thierry Gorlia, Uwe Schlegel, Roger Stupp, Michael Weller, Eric C. Holland & 1 others Dolores Hambardzumyan

Research output: Contribution to journalArticle

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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.

LanguageEnglish (US)
Pages1458-1471
Number of pages14
JournalBrain
Volume139
Issue number5
DOIs
StatePublished - May 1 2016

Fingerprint

Glioblastoma
Dexamethasone
temozolomide
Adrenal Cortex Hormones
Radiotherapy
Survival
Neoplasms
Atlases
Glioma
Anti-Idiotypic Antibodies
Edema
Cell Death
Cell Proliferation
Genome
Compromise
Brain Edema
Standard of Care
Transcriptome
Brain Neoplasms
Vascular Endothelial Growth Factor A

Keywords

  • astrocytoma
  • CNS tumour: surgical treatment
  • genetics
  • glioma
  • neurooncology

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Pitter, K. L., Tamagno, I., Alikhanyan, K., Hosni-Ahmed, A., Pattwell, S. S., Donnola, S., ... Hambardzumyan, D. (2016). Corticosteroids compromise survival in glioblastoma. Brain, 139(5), 1458-1471. DOI: 10.1093/brain/aww046
Pitter, Kenneth L. ; Tamagno, Ilaria ; Alikhanyan, Kristina ; Hosni-Ahmed, Amira ; Pattwell, Siobhan S. ; Donnola, Shannon ; Dai, Charles ; Ozawa, Tatsuya ; Chang, Maria ; Chan, Timothy A. ; Beal, Kathryn ; Bishop, Andrew J. ; Barker, Christopher A. ; Jones, Terreia S. ; Hentschel, Bettina ; Gorlia, Thierry ; Schlegel, Uwe ; Stupp, Roger ; Weller, Michael ; Holland, Eric C. ; Hambardzumyan, Dolores. / Corticosteroids compromise survival in glioblastoma. In: Brain. 2016 ; Vol. 139, No. 5. pp. 1458-1471
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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 2016, 'Corticosteroids compromise survival in glioblastoma' Brain, vol. 139, no. 5, pp. 1458-1471. DOI: 10.1093/brain/aww046

Corticosteroids compromise survival in glioblastoma. / Pitter, Kenneth L.; Tamagno, Ilaria; Alikhanyan, Kristina; Hosni-Ahmed, Amira; Pattwell, Siobhan S.; Donnola, Shannon; Dai, Charles; Ozawa, Tatsuya; Chang, Maria; Chan, Timothy A.; Beal, Kathryn; Bishop, Andrew J.; Barker, Christopher A.; Jones, Terreia S.; Hentschel, Bettina; Gorlia, Thierry; Schlegel, Uwe; Stupp, Roger; Weller, Michael; Holland, Eric C.; Hambardzumyan, Dolores.

In: Brain, Vol. 139, No. 5, 01.05.2016, p. 1458-1471.

Research output: Contribution to journalArticle

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AU - Chan,Timothy A.

AU - Beal,Kathryn

AU - Bishop,Andrew J.

AU - Barker,Christopher A.

AU - Jones,Terreia S.

AU - Hentschel,Bettina

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KW - CNS tumour: surgical treatment

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Pitter KL, Tamagno I, Alikhanyan K, Hosni-Ahmed A, Pattwell SS, Donnola S et al. Corticosteroids compromise survival in glioblastoma. Brain. 2016 May 1;139(5):1458-1471. Available from, DOI: 10.1093/brain/aww046