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.

Contrasting impact of corticosteroids on anti-PD-1 immunotherapy efficacy for tumor histologies located within or outside the central nervous system

“…56,57 Although different immune-stimulatory agents were investigated, the discrepancies between these results may be due to the timing of dexamethasone treatment relative to tumor implantation. Whereas treatment was postponed until tumor establishment, other studies gave dexamethasone either before or immediately following tumor implantation.…”

Effects of tumor grade and dexamethasone on myeloid cells in patients with glioma

“…14 Although glucocorticoid signaling increases expression of CD163 on myeloid cells, 22,29 the effects on accumulation of CD163+ cells in tumor tissue are less well understood. Recent work suggests that variation in the expression of macrophage immune modulatory proteins is more critical to disease progression than macrophage accumulation within the tumor.…”

“…Wehave shown that the impact of dexamethasone on myeloid cell phenotype is reversible suggesting any compromise on immunotherapeutic interventions may be avoided by limiting steroid treatment to the peri-operative window. Additionally, alternative approaches to treating cerebral edema, such as the use of VEGF antagonists, are being explored and may improve survival in glioblastoma patients when co-administered with other therapies 14 …”

“…Although the relationship between Dex treatment and circulating myeloid cell frequency or phenotype has been reported, 14 this variable is often overlooked in the development of novel therapeutic targets. Furthermore, though the impact of Dex treatment on immune suppression 15,16 and survival 14 in GBM patients has been studied, it is yet unclear if these effects are systemic or restricted to the tumor microenvironment in patients with low and high grade astrocytomas.…”

Fasting, Fats, and Physics: Combining Ketogenic and Radiation Therapy against Cancer

“…This could have prevented some further reductions in side effects or blunted the effect sizes. More alarming are findings that corticosteroid use prior to RT was associated with significantly shorter overall and progression-free survival in 3 large cohorts of glioblastoma patients [137]. This was linked to a corticosteroid-induced redistribution of tumor cells from the relatively radiosensitive G2/M phase to the relatively radioresistant G1 phase, with maintenance of cell viability.…”