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Metformin influences progression in diabetic glioblastoma patients

Metforminbeeinflusst die Progression bei diabetischen Glioblastompatienten

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Abstract

Purpose

Changes in metabolism, including high glucose serum levels, seem to influence the initiation of malignancy as well as recurrence. Therefore, limiting the energy supply in tumor cells with the antidiabetic drug metformin might be a useful approach to inhibit glioma cell progression. However, little is known about the effects of endocrine disorders (e.g., diabetes mellitus, corticosteroid therapy, and metformin therapy) on progression and survival in primary glioblastoma patients.

Patients and methods

Between 2006 and 2013, 276 patients with primary glioblastoma underwent radiation therapy at Heidelberg University Hospital and German Cancer Research Center. Clinical records as well as pretherapeutic and follow-up magnetic resonance (MR) images were assessed. Forty patients (14.5 %) were identified with a pretherapeutic history of diabetes, and 20 (50 %) of them were treated with metformin. Survival and correlations were calculated using t-test and log-rank, univariate and multivariate Cox proportional hazards ratio analyses.

Results

Persistent mild and excessive hyperglycemia were correlated with decreased survival. Corticosteroid therapy was associated with decreased progression-free and overall survival in the multivariate analysis. No negative influence of diabetes on progression and survival could be detected. Interestingly, diabetic patients with metformin therapy demonstrated prolonged progression-free intervals.

Conclusion

Corticosteroid therapy and hyperglycemia were strongly associated with impaired survival rates and serves as negative prognostic factors. Diabetes did not influence survival. Interestingly, our findings showed an association of metformin therapy and prolonged progression-free survival in glioblastoma patients with diabetes and therefore serve as a foundation for further preclinical and clinical investigations.

Zusammenfassung

Ziel

Veränderungen im körperlichen Metabolismus, darunter hohe Serumglukosespiegel, beeinflussen die Entstehung, das Wachstum und die rezidivierenden Eigenschaften maligner Tumore. Die Limitierung der Energieversorgung maligner Zellen mit dem Antidiabetikum Metformin könnte einen vielversprechenden Ansatz darstellen, das Glioblastomwachstum zu hemmen. Jedoch ist bis heute wenig über den Einfluss von endokrinen Dysfunktionen wie Diabetes mellitus, Kortikosteroidtherapie und dem Antidiabetikum Metformin auf die Progression und das Überleben bei Glioblastompatienten bekannt.

Patienten und Methoden

Zwischen 2006 und 2013 erhielten 276 Glioblastompatienten am Universitätsklinikum Heidelberg und am Deutschen Krebsforschungszentrum Heidelberg (DKFZ) eine Radiotherapie. Sowohl die klinischen Dokumente als auch die prä- und posttherapeutischen Magnetresonanztomogramme (MRT) wurden für diese Studie ausgewertet. Es konnten 40 Patienten (14,5 %) mit einer prätherapeutischen Diabetesdiagnose identifiziert werden, von den 20 (50 %) eine antidiabetische Therapie mit Metformin erhielten. Die Überlebensraten und Korrelationen mit klinischen Faktoren wurden mit Hilfe des t-Test, Log-rank-Test und der univariaten und multivariaten Cox-Regression berechnet.

Ergebnisse

Unsere Daten zeigen, dass milde und exzessive persistierende Hyperglykämien und eine Kortikosteroidtherapie in der multivariaten Analyse mit einem verminderten Überleben assoziiert waren. Diabetes selbst hatte keinen Einfluss auf die Progression oder das Überleben. Interessanterweise wiesen Diabetespatienten die eine Metformin-Therapie erhielten, ein signifikant verlängertes progressionfreies Intervall auf.

Schlussfolgerung

Zusammenfassend zeigen unsere Daten einen negativen prognostischen Einfluss der Hyperglykämie und Kortikosteroidtherapie auf das Überleben der Glioblastompatienten. Diabetes zeigte keinen Effekt auf das Überleben. Des Weiteren war eine Metformin-Therapie bei Diabetikern mit einem verlängerten progressionsfreien Intervall vergesellschaftet. Diese Ergebnisse sind von therapeutischem Interesse und dienen als Grundlage für weitere notwendige präklinische und klinische Untersuchungen.

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Correspondence to Sebastian Adeberg M.D..

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Conflicts of interest

S. Adeberg, D. Bernhardt, S.B. Harrabi, T. Bostel, A. Mohr, C. Koelsche, C. Diehl, S. Rieken, and J. Debus state that there are no conflicts of interest.

All studies on humans described in the present manuscript were carried out with the approval of the responsible ethics committee and in accordance with national law and the Helsinki Declaration of 1975 (in its current, revised form). Informed consent was obtained from all patients included in studies.

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Presented in part at the 3rd ESTRO Forum, 24–28 April 2015, Barcelona, Spain

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Adeberg, S., Bernhardt, D., Harrabi, S. et al. Metformin influences progression in diabetic glioblastoma patients. Strahlenther Onkol 191, 928–935 (2015). https://doi.org/10.1007/s00066-015-0884-5

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