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Does dexamethasone worsen mortality in GBM?

Really? Decadron can worsen mortality in GBMs?

This week Karl and I go over the evidence showing that steroids might not be the best thing for GBM patients. Specifically, it looks like dexamethasone might interfere with the effectiveness of chemo and radiation, leading to worse outcomes.

Literature Referenced:

Opinion paper that summarizes the argument against using Decadron in GBM patients:

Wong, E., Swanson, K. (2019). Dexamethasone—Friend or Foe for Patients With Glioblastoma? JAMA Neurology 76(3) https://dx.doi.org/10.1001/jamaneurol.2018.4530

Retrospective post-hoc comparison of Decadron dose in NovoTTF vs. best physician’s choice (BPC) chemo.

Patients were dichotomized to > or < 4mg/day. Improved survival seen in low Decadron dose group. NovoTTF patients: median OS 4.8mo vs. 11.0mo, BPC chemo patients: 6.0mo vs. 8.9mo (effect seemed to be more profound in TTF group).

Wong, E., Lok, E., Gautam, S., Swanson, K. (2015). Dexamethasone exerts profound immunologic interference on treatment efficacy for recurrent glioblastoma British Journal of Cancer 113(2), 232-41. https://dx.doi.org/10.1038/bjc.2015.238

A combination of 3 retrospective human patient cohorts and a mouse model of GBM looking at the correlation of Decadron with survival after RT. Also compared VEGF inhibitor in mouse model.

Found worsening mortality associated with Decadron in all 3 cohorts using a multivariate model. In mouse model, Decadron made radiation therapy ineffective. VEGF inhibitors were able to control edema without worsening outcome.

Pitter, K., Tamagno, I., Alikhanyan, K., Hosni-Ahmed, A., Pattwell, S., Donnola, S., Dai, C., Ozawa, T., Chang, M., Chan, T., Beal, K., Bishop, A., Barker, C., Jones, T., Hentschel, B., Gorlia, T., Schlegel, U., Stupp, R., Weller, M., Holland, E., Hambardzumyan, D. (2016). Corticosteroids compromise survival in glioblastoma Brain 139(5), 1458-1471. https://dx.doi.org/10.1093/brain/aww046

First reference in the literature I could find to this effect.

Tested the effects of adding dex to human glioma cell cultures, treated with vincristine, cytarabine, methotrexate (MTX), and adriamycin. Found that decadron attenuated the effect of all tested chemo agents.

Weller, M., Schmidt, C., Roth, W., Dichgans, J. (1997). Chemotherapy of human malignant glioma: Prevention of efficacy by dexamethasone? Neurology 48(6), 1704-1709. https://dx.doi.org/10.1212/wnl.48.6.1704

Developed findings from Weller (1997) to look at mechanisms. Demonstrated that dDcadron inhibits apoptosis in human astrocytoma cells in culture.

Gorman, A., Hirt, U., Orrenius, S., Ceccatelli, S. (2000). Dexamethasone pre-treatment interferes with apoptotic death in glioma cells Neuroscience 96(2), 417-425. https://dx.doi.org/10.1016/s0306-4522(99)00565-5

Phase II trial testing ipilimumab for brain melanoma mets. Included two cohorts: Cohort A – asymptomatic, Cohort B – symptomatic, taking Decadron. Cohort B survived longer.

Was this due to worse disease, or the Decadron treatment?

Margolin, K., Ernstoff, M., Hamid, O., Lawrence, D., McDermott, D., Puzanov, I., Wolchok, J., Clark, J., Sznol, M., Logan, T., Richards, J., Michener, T., Balogh, A., Heller, K., Hodi, F. (2012). Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial The Lancet Oncology 13(5), 459-465. https://dx.doi.org/10.1016/s1470-2045(12)70090-6

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