Journal of Neuro-Oncology

, Volume 137, Issue 3, pp 503–510 | Cite as

Dexamethasone-induced leukocytosis is associated with poor survival in newly diagnosed glioblastoma

  • Daniel Dubinski
  • Sae-Yeon Won
  • Florian Gessler
  • Johanna Quick-Weller
  • Bedjan Behmanesh
  • Simon Bernatz
  • Marie-Therese Forster
  • Kea Franz
  • Karl-Heinz Plate
  • Volker Seifert
  • Patrick N. Harter
  • Christian Senft
Laboratory Investigation

Abstract

Despite its well-characterized side effects, dexamethasone is widely used in the pre-, peri- and postoperative neurosurgical setting due to its effective relief of tumor-induced symptoms through the reduction of tumor-associated edema. However, some patients show laboratory-defined dexamethasone induced elevation of white blood cell count, and its impact on glioblastoma progression is unknown. We retrospectively analyzed 113 patients with newly diagnosed glioblastoma to describe the incidence, risk factors and clinical features of dexamethasone-induced leukocytosis in primary glioblastoma patients. We further conducted an immunohistochemical analysis of the granulocyte and lymphocyte tumor-infiltration in the available corresponding histological sections. Patient age was identified to be a risk factor for the development of dexamethasone-induced leukocytosis (p < 0.05). The presence of dexamethasone-induced leukocytosis decreased overall survival (HR 2.25 95% CI [1.15–4.38]; p < 0.001) and progression-free survival (HR 2.23 95% CI [1.09–4.59]; p < 0.01). Furthermore, patients with dexamethasone-induced leukocytosis had significantly reduced CD15 + granulocytic- (p < 0.05) and CD3 + lymphocytic tumour infiltration (p < 0.05). We identified a subgroup of glioblastoma patients that are at particularly high risk for poor outcome upon dexamethasone treatment. Therefore, restrictive dosage or other edema reducing substances should be considered in patients with dexamethasone-induced leukocytosis.

Keywords

Glioblastoma Cerebral edema Leukocytosis Survival Tumor-infiltration 

Notes

Acknowledgements

The authors would like to thank Mrs. Heibel for data editing, Mrs Starzetz and Mrs Dunst for excellent technical assistance and Mrs. Dr. Hardung for correcting.

Funding

This study was funded by Daniel Dubinski is a Else Kröner-Fresenius-Foundation scholar (2013_Kolleg.05).

Supplementary material

11060_2018_2761_MOESM1_ESM.png (1.4 mb)
Supplementary material 1 (PNG 1473 KB) Supplementary Figure 1: Immunohistochemistry displaying reduced tumor leukocyte infiltration in patients with DIL. 3A: Representative FFPE section of a GBM patient with preoperative DEX administration and DIL stained for the granulocytic CD15 marker. A decreased amount of CD15+ granulocytic tumor infiltrating cells (black arrows) was observed compared with a patient with preoperative DEX administration but no DIL development 3B. The CD3 + lymphocytic tumor infiltration (red arrows) was reduced in GBM patients with DIL (3C) compared with DIL- primary GBM patients (representative section displayed in 3D). (FFPE: formalin-fixed and paraffin-embedded; GBM: Glioblastoma; DEX: dexamethasone; DIL: Dexamethasone-induced leukocytosis)

References

  1. 1.
    Stupp R, Hegi ME, Mason WP et al (2009) Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 10:459–466.  https://doi.org/10.1016/S1470-2045(09)70025-7 CrossRefPubMedGoogle Scholar
  2. 2.
    Papadopoulos MC, Saadoun S, Binder DK et al (2004) Molecular mechanisms of brain tumor edema. Neuroscience 129:1011–1020.  https://doi.org/10.1016/j.neuroscience.2004.05.044 CrossRefPubMedGoogle Scholar
  3. 3.
    Galicich JH, French LA (1961) Use of dexamethasone in the treatment of cerebral edema resulting from brain tumors and brain surgery. Am Pract Dig Treat 12:169–174PubMedGoogle Scholar
  4. 4.
    Galicich JH, French LA, Melby JC (1961) Use of dexamethasone in treatment of cerebral edema associated with brain tumors. J Lancet 81:46–53PubMedGoogle Scholar
  5. 5.
    Vecht CJ, Hovestadt A, Verbiest HB et al (1994) Dose-effect relationship of dexamethasone on Karnofsky performance in metastatic brain tumors: a randomized study of doses of 4, 8, and 16 mg per day. Neurology 44:675–680CrossRefPubMedGoogle Scholar
  6. 6.
    Marantidou A, Levy C, Duquesne A et al (2010) Steroid requirements during radiotherapy for malignant gliomas. J Neurooncol 100:89–94.  https://doi.org/10.1007/s11060-010-0142-8 CrossRefPubMedGoogle Scholar
  7. 7.
    Gutin PH (1975) Corticosteroid therapy in patients with cerebral tumors: benefits, mechanisms, problems, practicalities. Semin Oncol 2:49–56PubMedGoogle Scholar
  8. 8.
    Heimdal K, Hirschberg H, Slettebø H et al (1992) High incidence of serious side effects of high-dose dexamethasone treatment in patients with epidural spinal cord compression. J Neurooncol 12:141–144CrossRefPubMedGoogle Scholar
  9. 9.
    Shoenfeld Y, Gurewich Y, Gallant LA, Pinkhas J (1981) Prednisone-induced leukocytosis. Influence of dosage, method and duration of administration on the degree of leukocytosis. Am J Med 71:773–778.  https://doi.org/10.1016/0002-9343(81)90363-6 CrossRefPubMedGoogle Scholar
  10. 10.
    Abramson N, Melton B (2000) Leukocytosis: basics of clinical assessment. Am Fam Physician 62:2053–2060PubMedGoogle Scholar
  11. 11.
    Nakagawa M, Terashima T, D’yachkova Y et al (1998) Glucocorticoid-induced granulocytosis: contribution of marrow release and demargination of intravascular granulocytes. Circulation 98:2307–2313CrossRefPubMedGoogle Scholar
  12. 12.
    Liles WC, Dale DC, Klebanoff SJ (1995) Glucocorticoids inhibit apoptosis of human neutrophils. Blood 86:3181–3188PubMedGoogle Scholar
  13. 13.
    Burton JL, Kehrli ME, Kapil S, Horst RL (1995) Regulation of l-selectin and CD18 on bovine neutrophils by glucocorticoids: effects of cortisol and dexamethasone. J Leukoc Biol 57:317–325CrossRefPubMedGoogle Scholar
  14. 14.
    Dubinski D, Wölfer J, Hasselblatt M et al (2015) CD4 + T effector memory cell dysfunction is associated with the accumulation of granulocytic myeloid-derived suppressor cells in glioblastoma patients. Neuro Oncol.  https://doi.org/10.1093/neuonc/nov280 PubMedPubMedCentralGoogle Scholar
  15. 15.
    Gabrusiewicz K, Rodriguez B, Wei J et al Glioblastoma-infiltrated innate immune cells resemble M0 macrophage phenotype. JCI Insight.  https://doi.org/10.1172/jci.insight.85841
  16. 16.
    Fossati G, Ricevuti G, Edwards SW et al (1999) Neutrophil infiltration into human gliomas. Acta Neuropathol 98:349–354CrossRefPubMedGoogle Scholar
  17. 17.
    Pitter KL, Tamagno I, Alikhanyan K et al (2016) Corticosteroids compromise survival in glioblastoma. Brain 139:1458–1471.  https://doi.org/10.1093/brain/aww046 CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Shields LBE, Shelton BJ, Shearer AJ et al (2015) Dexamethasone administration during definitive radiation and temozolomide renders a poor prognosis in a retrospective analysis of newly diagnosed glioblastoma patients. Radiat Oncol 10:4–11.  https://doi.org/10.1186/s13014-015-0527-0 CrossRefGoogle Scholar
  19. 19.
    Lescher S, Schniewindt S, Jurcoane A et al (2014) Time window for postoperative reactive enhancement after resection of brain tumors: less than 72 hours. Neurosurg Focus 37:E3.  https://doi.org/10.3171/2014.9.FOCUS14479 CrossRefPubMedGoogle Scholar
  20. 20.
    Wong ET, Lok E, Gautam S, Swanson KD (2015) Dexamethasone exerts profound immunologic interference on treatment efficacy for recurrent glioblastoma. Br J Cancer 113:232–241.  https://doi.org/10.1038/bjc.2015.238 CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Roggendorf W, Strupp S, Paulus W (1996) Distribution and characterization of microglia/macrophages in human brain tumors. Acta Neuropathol 92:288–293CrossRefPubMedGoogle Scholar
  22. 22.
    Morimura T, Neuchrist C, Kitz K et al (1990) Monocyte subpopulations in human gliomas: expression of Fc and complement receptors and correlation with tumor proliferation. Acta Neuropathol 80:287–294.  https://doi.org/10.1007/BF00294647 CrossRefPubMedGoogle Scholar
  23. 23.
    Okada M, Saio M, Kito Y et al (2009) Tumor-associated macrophage/microglia infiltration in human gliomas is correlated with MCP-3, but not MCP-1. Int J Oncol 34:1621–1627PubMedGoogle Scholar
  24. 24.
    Vredenburgh JJ, Cloughesy T, Samant M et al (2010) Corticosteroid use in patients with glioblastoma at first or second relapse treated with bevacizumab in the BRAIN study. Oncologist 15:1329–1334.  https://doi.org/10.1634/theoncologist.2010-0105 CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Diaz RJ, Ali S, Qadir MG et al (2017) The role of bevacizumab in the treatment of glioblastoma. J Neurooncol 133:455–467.  https://doi.org/10.1007/s11060-017-2477-x CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Daniel Dubinski
    • 1
    • 2
  • Sae-Yeon Won
    • 1
  • Florian Gessler
    • 1
  • Johanna Quick-Weller
    • 1
  • Bedjan Behmanesh
    • 1
  • Simon Bernatz
    • 2
  • Marie-Therese Forster
    • 1
  • Kea Franz
    • 1
  • Karl-Heinz Plate
    • 2
    • 3
  • Volker Seifert
    • 1
  • Patrick N. Harter
    • 2
    • 3
  • Christian Senft
    • 1
  1. 1.Department of Neurosurgery, University HospitalGoethe UniversityFrankfurt am MainGermany
  2. 2.Institute of Neurology (Edinger Institute)Goethe UniversityFrankfurt am MainGermany
  3. 3.German Cancer Research Center DKFZ HeidelbergGermany and German Cancer Consortium DKTK Partner SiteFrankfurt/mainzGermany

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