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Strong adverse prognostic impact of hyperglycemic episodes during adjuvant chemoradiotherapy of glioblastoma multiforme

Ausgeprägt negativer prognostischer Einfluss von hyperglykämischen Episoden während der adjuvanten Radiochemotherapie des Glioblastoma multiforme

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Abstract

Background

In comparison to normal brain tissue, glioblastomas exhibit significantly increased glucose uptake. Brain edema is a common complication during adjuvant chemoradiotherapy, leading to a requirement for glucocorticoid treatment. Glucocorticoid treatment frequently causes considerable deregulation of blood glucose levels. Therefore, episodes of hyperglycemia may contribute to radio- and/or chemoresistance.

Patients and methods

This study comprises a retrospective analysis of the influence of hyperglycemic episodes (HEs) during adjuvant therapy on the overall survival of 106 glioblastoma multiforme patients.

Results

The occurrence of one or more deregulated blood glucose value(s) > 10 mM is associated with a reduction in median overall survival from 16.7 to 8.8 months. A significantly poorer overall survival of patients with hyperglycemia could also be detected in subgroup analyses of patients with complete tumor resection and complete treatment according to the EORTC 22891/26891 trial protocol, as well as in a multivariate Cox proportional hazards analysis. A history of diabetes mellitus had no influence on prognosis.

Discussion

Our data suggest that the observed negative impact of elevated blood glucose levels on overall survival may not solely be explained by the patients’ poorer general condition; the elevated blood glucose concentration itself may play a pathogenetic role. This could be due to increased activity of antioxidant systems, elevated expression of DNA damage response proteins and protection of hypoxic tumor cells against apoptosis combined with hypoxia-mediated radioresistance.

Conclusion

A possible prognostic impact of elevated blood glucose levels during the period of adjuvant (chemo-) radiotherapy of glioblastoma should be evaluated in a prospective clinical trial.

Zusammenfassung

Hintergrund

Glioblastome zeigen im Vergleich mit normalem Gehirngewebe eine deutlich vermehrte Glukoseaufnahme. Im Rahmen der adjuvanten Radio(chemo)therapie von Glioblastomen treten vielfach Hirnödeme auf, die eine Glukokortikoidgabe erforderlich machen. Hierdurch kommt es häufig zu nicht unerheblichen Blutzuckerentgleisungen. Es stellt sich die Frage, ob Hyperglykämieepisoden während der adjuvanten Therapie zu einer Radio- und/oder Chemoresi­stenz beitragen können.

Patienten und Methoden

Die Studie analysiert retrospektiv den Einfluss von Hyperglykämieepisoden während der adjuvanten Therapie auf das Gesamtüberleben von 106 Pati­enten mit Glioblastoma multiforme.

Ergebnisse

Das Auftreten von einer oder mehreren Entgleisungen des Blutzuckers mit Werten > 10 mM war mit einer Verminderung des medianen Gesamtüberlebens von 16,7 Monaten auf 8,8 Monate verbunden. Ein signifikant schlechteres Gesamtüberleben von Patienten mit Blutzuckerentgleisungen ließ sich auch in Subgruppenanalysen von vollständig resezierten und vollständig nach EORTC-22891/26891-Protokoll therapierten Patienten sowie in einer multivari­aten Cox-Analyse (Cox proportional hazards) nachweisen. Ein manifester Diabetes mellitus als Vorerkrankung hatte keinen Einfluss auf die Prognose.

Diskussion

Unsere Daten weisen darauf hin, dass der beobachtete negative Einfluss erhöhter Blutglukosekonzentrationen auf das Gesamtüberleben möglicherweise nicht allein mit einem schlechteren Allgemeinzustand der Patienten zu erklären ist und der Hyperglykämie selbst somit eine pathogenetische Bedeutung zukäme. Dies könnte in einer erhöhten Aktivität antioxidativer Systeme, gesteigerter Expression von Proteinen der DNA-Schadensantwort und in einem Schutz hypoxischer Tumorzellen vor Apoptose bei gleichzeitig erhöhter hypoxiebedingter Radioresistenz begründet sein.

Schlussfolgerung

Ein möglicher pro­gnostischer Einfluss von Blutzuckerentgleisungen während der Phase der adjuvanten Radio(chemo)therapie sollte in einer pro­spektiven klinischen Studie untersucht werden.

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Acknowledgements

The authors thank Erika Budo-Guetaifi for careful evaluation of patient data and Dr. Debra Kelleher for her valuable editorial help during preparation of this manuscript.

Conflict of interest

A. Mayer, P. Vaupel, H.-G. Struss, A. Giese, M. Stockinger and H. Schmidberger state that there are no conflicts of interest. The accompanying manuscript does not include studies on humans or animals.

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Correspondence to Arnulf Mayer M.D..

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Mayer, A., Vaupel, P., Struss, HG. et al. Strong adverse prognostic impact of hyperglycemic episodes during adjuvant chemoradiotherapy of glioblastoma multiforme. Strahlenther Onkol 190, 933–938 (2014). https://doi.org/10.1007/s00066-014-0696-z

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  • DOI: https://doi.org/10.1007/s00066-014-0696-z

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