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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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References

  1. Louis DN, Ohgaki H, Wiestler OD et al (2007) The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 114:97–109

    Article  PubMed Central  PubMed  Google Scholar 

  2. Stupp R, Mason WP, van den Bent MJ et al (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996

    Article  CAS  PubMed  Google Scholar 

  3. Scott JN, Rewcastle NB, Brasher PM et al (1999) Which glioblastoma multiforme patient will become a long-term survivor? A population-based study. Ann Neurol 46:183–188

    Article  CAS  PubMed  Google Scholar 

  4. Chaichana KL, Pendleton C, Chambless L et al (2013) Multi-institutional validation of a preoperative scoring system which predicts survival for patients with glioblastoma. J Clin Neurosci 20:1422–1426

    Article  PubMed Central  PubMed  Google Scholar 

  5. Adeberg S, Konig L, Bostel T et al (2014) Glioblastoma recurrence patterns after radiation therapy with regard to the subventricular zone. Int J Radiat Oncol Biol Phys 90:886–896

    Article  PubMed  Google Scholar 

  6. Combs SE, Edler L, Rausch R, Welzel T, Wick W, Debus J (2013) Generation and validation of a prognostic score to predict outcome after re-irradiation of recurrent glioma. Acta Oncol 52:147–152

    Article  PubMed  Google Scholar 

  7. Adeberg S, Bostel T, Konig L, Welzel T, Debus J, Combs SE (2014) A comparison of long-term survivors and short-term survivors with glioblastoma, subventricular zone involvement: a predictive factor for survival? Radiat Oncol 9:95

  8. Schulz-Ertner D, Tsujii H (2007) Particle radiation therapy using proton and heavier ion beams. J Clin Oncol 25:953–964

    Article  PubMed  Google Scholar 

  9. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61:69–90

    Article  PubMed  Google Scholar 

  10. Polednak AP (2006) Comorbid diabetes mellitus and risk of death after diagnosis of colorectal cancer: a population-based study. Cancer Detect Prev 30:466–472

    Article  PubMed  Google Scholar 

  11. Weiser MA, Cabanillas ME, Konopleva M et al (2004) Relation between the duration of remission and hyperglycemia during induction chemotherapy for acute lymphocytic leukemia with a hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone/methotrexate-cytarabine regimen. Cancer 100:1179–1185

    Article  CAS  PubMed  Google Scholar 

  12. Yancik R, Wesley MN, Ries LA, Havlik RJ, Edwards BK, Yates JW (2001) Effect of age and comorbidity in postmenopausal breast cancer patients aged 55 years and older. JAMA 285:885–892

    Article  CAS  PubMed  Google Scholar 

  13. Suba Z, Ujpal M (2006) [Correlations of insulin resistance and neoplasms]. Magy Onkol 50:127–135

    PubMed  Google Scholar 

  14. Suba Z, Barabas J, Szabo G, Takacs D, Ujpal M (2005) Increased prevalence of diabetes and obesity in patients with salivary gland tumors. Diabetes Care 28:228

    Article  PubMed  Google Scholar 

  15. Nilsen TI, Vatten LJ (2001) Prospective study of colorectal cancer risk and physical activity, diabetes, blood glucose and BMI: exploring the hyperinsulinaemia hypothesis. Br J Cancer 84:417–422

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Colangelo LA, Gapstur SM, Gann PH, Dyer AR, Liu K (2002) Colorectal cancer mortality and factors related to the insulin resistance syndrome. Cancer Epidemiol Biomarkers Prev 11:385–391

    PubMed  Google Scholar 

  17. Krinsley JS (2004) Effect of an intensive glucose management protocol on the mortality of critically ill adult patients. Mayo Clin Proc 79:992–1000

  18. van den Berghe G, Wouters P, Weekers F et al (2001) Intensive insulin therapy in critically ill patients. N Engl J Med 345:1359–1367

    Article  PubMed  Google Scholar 

  19. Woodworth GF, Chaichana KL, McGirt MJ et al (2007) Predictors of ambulatory function after surgical resection of intramedullary spinal cord tumors. Neurosurgery 61:99–105. (discussion -6)

    Article  PubMed  Google Scholar 

  20. Welch MR, Grommes C (2013) Retrospective analysis of the effects of steroid therapy and antidiabetic medication on survival in diabetic glioblastoma patients. CNS Oncol 2:237–246

    Article  CAS  PubMed  Google Scholar 

  21. Warburg O (1956) On the origin of cancer cells. Science 123:309–314

    Article  CAS  PubMed  Google Scholar 

  22. Warburg O, Wind F, Negelein E (1927) The metabolism of tumors in the body. J Gen Physiol 8:519–530

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Guo D, Cloughesy TF, Radu CG, Mischel PS (2010) AMPK: a metabolic checkpoint that regulates the growth of EGFR activated glioblastomas. Cell Cycle 9:211–212

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Jalving M, Gietema JA, Lefrandt JD et al (2010) Metformin: taking away the candy for cancer? Eur J Cancer 46:2369–2380

    Article  CAS  PubMed  Google Scholar 

  25. Jelluma N, Yang X, Stokoe D, Evan GI, Dansen TB, Haas-Kogan DA (2006) Glucose withdrawal induces oxidative stress followed by apoptosis in glioblastoma cells but not in normal human astrocytes. Mol Cancer Res 4:319–330

    Article  CAS  PubMed  Google Scholar 

  26. Sandulache VC, Hamblin JS, Skinner HD, Kubik MW, Myers JN, Zevallos JP (2014) Association between metformin use and improved survival in patients with laryngeal squamous cell carcinoma. Head Neck 36:1039–1043

    Article  PubMed  Google Scholar 

  27. Skinner HD, Crane CH, Garrett CR et al (2013) Metformin use and improved response to therapy in rectal cancer. Cancer Med 2:99–107

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Skinner HD, McCurdy MR, Echeverria AE et al (2013) Metformin use and improved response to therapy in esophageal adenocarcinoma. Acta Oncol 52:1002–1009

    Article  CAS  PubMed  Google Scholar 

  29. Storozhuk Y, Hopmans SN, Sanli T et al (2013) Metformin inhibits growth and enhances radiation response of non-small cell lung cancer (NSCLC) through ATM and AMPK. Br J Cancer 108:2021–2032

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Ling S, Feng T, Ke Q et al (2014) Metformin inhibits proliferation and enhances chemosensitivity of intrahepatic cholangiocarcinoma cell lines. Oncol Rep 31:2611–2618

    CAS  PubMed  Google Scholar 

  31. Li H, Chen X, Yu Y et al (2014) Metformin inhibits the growth of nasopharyngeal carcinoma cells and sensitizes the cells to radiation via inhibition of the DNA damage repair pathway. Oncol Rep 32:2596–2604

    CAS  PubMed  Google Scholar 

  32. Mohammed A, Janakiram NB, Brewer M et al (2013) Antidiabetic drug metformin prevents progression of pancreatic cancer by targeting in part cancer stem cells and mTOR signaling. Transl Oncol 6:649–659

    Article  PubMed Central  PubMed  Google Scholar 

  33. Kalender A, Selvaraj A, Kim SY et al (2010) Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner. Cell Metab 11:390–401

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Rozengurt E (2014) Mechanistic target of rapamycin (mTOR): a point of convergence in the action of insulin/IGF-1 and G protein-coupled receptor agonists in pancreatic cancer cells. Front Physiol 5:357

    Article  PubMed Central  PubMed  Google Scholar 

  35. Isakovic A, Harhaji L, Stevanovic D et al (2007) Dual antiglioma action of metformin: cell cycle arrest and mitochondria-dependent apoptosis. Cell Mol Life Sci 64:1290–1302

    Article  CAS  PubMed  Google Scholar 

  36. Scheithauer BW, Fuller GN, VandenBerg SR (2008) The 2007 WHO classification of tumors of the nervous system: controversies in surgical neuropathology. Brain Pathol 18:307–316

    Article  PubMed  Google Scholar 

  37. Nathan DM, Buse JB, Davidson MB et al (2009) Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 32:193–203

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. Wen PY, Macdonald DR, Reardon DA et al (2010) Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. J Clin Oncol 28:1963–1972

    Article  PubMed  Google Scholar 

  39. Shrieve DC, Alexander E 3rd, Black PM et al (1999) Treatment of patients with primary glioblastoma multiforme with standard postoperative radiotherapy and radiosurgical boost: prognostic factors and long-term outcome. J Neurosurg 90:72–77

    Article  CAS  PubMed  Google Scholar 

  40. Mirimanoff RO, Gorlia T, Mason W et al (2006) Radiotherapy and temozolomide for newly diagnosed glioblastoma: recursive partitioning analysis of the EORTC 26981/22981-NCIC CE3 phase III randomized trial. J Clin Oncol 24:2563–2569

    Article  CAS  PubMed  Google Scholar 

  41. Mayer A, Vaupel P, Struss HG, Giese A, Stockinger M, Schmidberger H (2014) Strong adverse prognostic impact of hyperglycemic episodes during adjuvant chemoradiotherapy of glioblastoma multiforme. Strahlenther Onkol 19:933–938

    Article  Google Scholar 

  42. McGirt MJ, Chaichana KL, Gathinji M et al (2008) Persistent outpatient hyperglycemia is independently associated with decreased survival after primary resection of malignant brain astrocytomas. Neurosurgery 63:286–291. (discussion 91)

    Article  PubMed  Google Scholar 

  43. Derr RL, Ye X, Islas MU, Desideri S, Saudek CD, Grossman SA (2009) Association between hyperglycemia and survival in patients with newly diagnosed glioblastoma. J Clin Oncol 27:1082–1086

    Article  PubMed Central  PubMed  Google Scholar 

  44. Adeberg S, Bernhardt D, Foerster R, Bostel T, Koerber SA, Mohr A, Koelsche C, Rieken S, Debus J (2015) The influence of hyperglycemia during radiotherapy on survival in patients with primary glioblastoma. Acta Oncol 20:1-7

  45. Oudard S, Arvelo F, Miccoli L et al (1996) High glycolysis in gliomas despite low hexokinase transcription and activity correlated to chromosome 10 loss. Br J Cancer 74:839–845

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  46. Kwon T, Jeong IG, You D et al (2014) Obesity and prognosis in muscle-invasive bladder cancer: the continuing controversy. Int J Urol 21:1106–1112

    Article  PubMed  Google Scholar 

  47. Siegel EM, Ulrich CM, Poole EM, Holmes RS, Jacobsen PB, Shibata D (2010) The effects of obesity and obesity-related conditions on colorectal cancer prognosis. Cancer Control 17:52–57

    PubMed  Google Scholar 

  48. Daniell HW (2010) Smoking, obesity, and statin therapy in the prognosis of prostate cancer. J Clin Oncol 28:e643. (author reply e5–6)

    Article  PubMed  Google Scholar 

  49. Sinicrope FA, Dannenberg AJ (2011) Obesity and breast cancer prognosis: weight of the evidence. J Clin Oncol 29:4–7

    Article  PubMed  Google Scholar 

  50. Del Barco S, Vazquez-Martin A, Cufi S et al (2011) Metformin: multi-faceted protection against cancer. Oncotarget 2:896–917

    Article  PubMed Central  PubMed  Google Scholar 

  51. Giannarelli R, Aragona M, Coppelli A, Del Prato S (2003) Reducing insulin resistance with metformin: the evidence today. Diabetes Metab 29:6S28–6S35

    Article  Google Scholar 

  52. Sato A, Sunayama J, Okada M, et al (2012) Glioma-initiating cell elimination by metformin activation of FOXO3 via AMPK. Stem cells Transl Med 1:811–824

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  53. Soritau O, Tomuleasa C, Aldea M et al (2011) Metformin plus temozolomide-based chemotherapy as adjuvant treatment for WHO grade III and IV malignant gliomas. J BUON 16:282–289

    CAS  PubMed  Google Scholar 

  54. Ferla R, Haspinger E, Surmacz E (2012) Metformin inhibits leptin-induced growth and migration of glioblastoma cells. Oncol Lett 4:1077–1081

    PubMed Central  CAS  PubMed  Google Scholar 

  55. Dietrich J, Rao K, Pastorino S, Kesari S (2011) Corticosteroids in brain cancer patients: benefits and pitfalls. Expert Rev Clin Pharmacol 4:233–242

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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Author information

Authors and Affiliations

  1. Department of Radiation Oncology, University Hospital of Heidelberg, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany

    Sebastian Adeberg M.D., Denise Bernhardt M.D., Semi Ben Harrabi M.D., Tilman Bostel M.D., Angela Mohr M.D., Stefan Rieken M.D. & Juergen Debus M.D., Ph.D.

  2. Clinical Cooperation Unit Radiation Oncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany

    Sebastian Adeberg M.D., Semi Ben Harrabi M.D., Tilman Bostel M.D., Angela Mohr M.D. & Juergen Debus M.D., Ph.D.

  3. Heidelberg Ion-Beam Therapy Center (HIT), Im Neuenheimer Feld 450, 69120, Heidelberg, Germany

    Stefan Rieken M.D. & Juergen Debus M.D., Ph.D.

  4. Department of Neuropathology, University Hospital of Heidelberg, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany

    Christian Koelsche M.D.

  5. Technische Universität München, Department of Radiation Oncology, Ismaninger Straße 22, 81675, München, Germany

    Christian Diehl M.D.

  6. Department of Neurosurgery, University Hospital of Heidelberg, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany

    Christian Diehl M.D.

  7. Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany

    Christian Koelsche M.D.

Authors
  1. Sebastian Adeberg M.D.
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  2. Denise Bernhardt M.D.
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  3. Semi Ben Harrabi M.D.
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  4. Tilman Bostel M.D.
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  5. Angela Mohr M.D.
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  6. Christian Koelsche M.D.
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  7. Christian Diehl M.D.
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  8. Stefan Rieken M.D.
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  9. Juergen Debus M.D., Ph.D.
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Corresponding author

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.

Additional information

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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