Journal of Neuro-Oncology

, Volume 102, Issue 2, pp 311–316 | Cite as

Correlation between O6-methylguanine-DNA methyltransferase and survival in elderly patients with glioblastoma treated with radiotherapy plus concomitant and adjuvant temozolomide

  • Giuseppe Minniti
  • M. Salvati
  • A. Arcella
  • F. Buttarelli
  • A. D’Elia
  • G. Lanzetta
  • V. Esposito
  • S. Scarpino
  • R. Maurizi Enrici
  • F. Giangaspero
Clinical Study – Patient Study

Abstract

Epigenetic silencing of the O6-methylguanine-DNA-methyltransferase (MGMT) gene by promoter methylation is correlated with improved progression-free survival (PFS) and overall survival (OS) in adult patients with newly diagnosed glioblastoma multiforme (GBM) who receive alkylating agents. The aim of this study is to determine the correlation between MGMT and survival in elderly patients with GBM treated with radiotherapy (RT) and temozolomide (TMZ). Eighty-three patients aged 70 years or older with histologically confirmed GBM treated with RT plus TMZ between February 2005 and September 2009 were investigated in this study. The methylation status of the MGMT promoter was determined by polymerase chain reaction analysis. Median PFS and OS were 7.5 and 12.8 months, respectively. The MGMT promoter was methylated in 42 patients (50.6%) and unmethylated in 41 patients (49.4%). Median OS was 15.3 months in methylated patients and 10.2 months in unmethylated patients (P = 0.0001). Median PFS was 10.5 months in methylated tumors and 5.5 months in unmethylated tumors (P = 0.0001). On multivariate analysis MGMT methylation status emerged as the strongest independent prognostic factor for OS and PFS (P = 0.004 and P = 0.005, respectively). The results of the present study suggest that MGMT methylation status might be an important prognostic factor associated with better OS and PFS in elderly patients with GBM treated with RT and TMZ.

Keywords

Glioblastoma Elderly Radiotherapy Temozolomide  MGMT 

References

  1. 1.
    Stupp R, Mason W, Van der Bent M et al (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996PubMedCrossRefGoogle Scholar
  2. 2.
    Esteller M, Garcia-Foncillas J et al (2000) Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. N Engl J Med 343:1350–1354PubMedCrossRefGoogle Scholar
  3. 3.
    Herman JG, Baylin SB (2003) Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med 349:2042–2054PubMedCrossRefGoogle Scholar
  4. 4.
    Jaeckle KA, Eyre HJ, Townsend JJ et al (1998) Correlation of tumor O6 methylguanine-DNA methyltransferase levels with survival of malignant astrocytoma patients treated with bis-chloroethylnitrosourea: a Southwest Oncology Group Study. J Clin Oncol 16:3310–3315PubMedGoogle Scholar
  5. 5.
    Hegi ME, Diserens AC, Gorlia T et al (2005) MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352:997–1003PubMedCrossRefGoogle Scholar
  6. 6.
    Fleury A, Menegoz F, Grosclaude P et al (1997) Descriptive epidemiology of cerebral gliomas in France. Cancer 79:1195–2202PubMedCrossRefGoogle Scholar
  7. 7.
    Davis FG, Freels S, Grutsch J, Barlas S, Brem S (1998) Survival rates in patients with primary malignant brain tumors stratified by patient age and tumor histological type: an analysis based on Surveillance, Epidemiology, and End Results (SEER) data, 1973–1991. J Neurosurg 88:1–10PubMedCrossRefGoogle Scholar
  8. 8.
    Chakrabarti I, Cockburn M, Cozen W et al (2005) A population-based description of glioblastoma multiforme in Los Angeles County, 1974–1999. Cancer 104:2798–2806PubMedCrossRefGoogle Scholar
  9. 9.
    Bauman GS, Fisher BJ, Halperin EC et al (1994) A prospective study of short course RT in poor prognosis glioblastoma multiforme. Int J Radiat Oncol Biol Phys 29:835–839PubMedCrossRefGoogle Scholar
  10. 10.
    Thomas R, James N, Guerrero D et al (1994) Hypofractionated radiotherapy as palliative treatment in poor prognosis patients with high grade glioma. Radiother Oncol 33:113–116PubMedCrossRefGoogle Scholar
  11. 11.
    Ford JM, Stenning SP, Bootle DJ et al (1997) A short fractionation radiotherapy treatment for poor prognosis patients with high grade glioma. Clin Oncol (R Coll Radiol) 9:20–24Google Scholar
  12. 12.
    Hoegler DB, Davey P (1997) A prospective study of short course radiotherapy in elderly patients with malignant glioma. J Neurooncol 33:201–214PubMedCrossRefGoogle Scholar
  13. 13.
    McAleese JJ, Stenning SP, Ashley S et al (2003) Hypofractionated radiotherapy for poor prognosis malignant glioma: matched pair survival analysis with MRC controls. Radiother Oncol 67:177–182PubMedCrossRefGoogle Scholar
  14. 14.
    Roa W, Brasher PMA, Bauman G et al (2004) Abbreviated course of radiation therapy in older patients with glioblastoma multiforme: a prospective randomized clinical trial. J Clin Oncol 22:1593–1598CrossRefGoogle Scholar
  15. 15.
    Keime-Guiber F, Chinot O, Taillandier L et al (2007) Radiotherapy for glioblastoma in the elderly. N Engl J Med 356:1527–1535CrossRefGoogle Scholar
  16. 16.
    Glantz M, Chamberlain M, Liu Q et al (2003) Temozolomide as an alternative to irradiation for elderly patients with newly diagnosed malignant gliomas. Cancer 97:2262–2266PubMedCrossRefGoogle Scholar
  17. 17.
    Chinot OL, Barrie M, Frauger E et al (2004) Phase II study of temozolomide without radiotherapy in newly diagnosed glioblastoma multiforme in an elderly populations. Cancer 100:2208–2214PubMedCrossRefGoogle Scholar
  18. 18.
    Chamberlain MC, Chalmers L (2007) A pilot study of primary temozolomide chemotherapy and deferred radiotherapy in elderly patients with glioblastoma. J Neurooncol 82:207–209PubMedCrossRefGoogle Scholar
  19. 19.
    Brandes AA, Vastola F, Basso U (2003) A prospective study in glioblastoma multiforme. Cancer 3:657–662CrossRefGoogle Scholar
  20. 20.
    Combs SE, Wagner J, Bischof M et al (2008) Postoperative treatment of primary glioblastoma multiforme with radiation and concomitant temozolomide in elderly patients. Int J Radiat Oncol Biol Phys 15(70):987–992Google Scholar
  21. 21.
    Minniti G, De Sanctis V, Muni R et al (2008) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma in elderly patients. J Neurooncol 88:97–103PubMedCrossRefGoogle Scholar
  22. 22.
    Minniti G, De Sanctis V, Muni R et al (2009) Hypofractionated radiotherapy followed by adjuvant chemotherapy with temozolomide in elderly patients with glioblastoma. J Neurooncol 91:95–100PubMedCrossRefGoogle Scholar
  23. 23.
    Sijben AE, McIntyre JB, Roldán GB (2008) Toxicity from chemoradiotherapy in older patients with glioblastoma multiforme. J Neurooncol 89(1):97–103PubMedCrossRefGoogle Scholar
  24. 24.
    Brandes AA, Franceschi E, Tosoni A et al (2009) Temozolomide concomitant and adjuvant to radiotherapy in elderly patients with glioblastoma: correlation with MGMT promoter methylation status. Cancer 115:3512–3518PubMedCrossRefGoogle Scholar
  25. 25.
    Gerstner ER, Yip S, Wang DL, Louis DN, Iafrate AJ, Batchelor TT (2009) Mgmt methylation is a prognostic biomarker in elderly patients with newly diagnosed glioblastoma. Neurology 73(18):1509–1510PubMedCrossRefGoogle Scholar
  26. 26.
    MacDonald DR, Cascino TL, Schold SC Jr et al (1990) Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol 8:1277–1280PubMedGoogle Scholar
  27. 27.
    Chamberlain MC, Glantz MJ, Chalmers L, Van Horn A, Sloan AE (2007) Early necrosis following concurrent Temodar and radiotherapy in patients with glioblastoma. J Neurooncol 82:81–83PubMedCrossRefGoogle Scholar
  28. 28.
    Esteller M, Hamilton SR, Burger PC, Baylin SB, Herman JG (1999) Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is a common event in primary human neoplasia. Cancer Res 59:793–797PubMedGoogle Scholar
  29. 29.
    Stupp R, Hegi ME, Mason WP, European Organisation for Research and Treatment of Cancer Brain Tumour and Radiation Oncology Groups, National Cancer Institute of Canada Clinical Trials Group 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 10:459–466Google Scholar
  30. 30.
    Piccirilli M, Bistazzoni S, Gagliardi FM et al (2006) Treatment of glioblastoma multiforme in elderly patients. Clinico-therapeutic remarks in 22 patients older than 80 years. Tumori 92:98–103PubMedGoogle Scholar
  31. 31.
    Friedman HS, McLendon RE, Kerby T et al (1998) DNA mismatch repair and O6-alkylguanine-DNA alkyltransferase analysis and response to Temodal in newly diagnosed malignant glioma. J Clin Oncol 16:3851–3857PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2010

Authors and Affiliations

  • Giuseppe Minniti
    • 1
    • 2
  • M. Salvati
    • 2
  • A. Arcella
    • 2
  • F. Buttarelli
    • 3
  • A. D’Elia
    • 4
  • G. Lanzetta
    • 2
  • V. Esposito
    • 2
  • S. Scarpino
    • 5
  • R. Maurizi Enrici
    • 1
  • F. Giangaspero
    • 2
    • 3
  1. 1.Department of Radiation OncologySant’ Andrea Hospital, University “La Sapienza”RomeItaly
  2. 2.Department of Neurological SciencesNeuromed InstitutePozzilli (IS)Italy
  3. 3.Department of PathologyUmberto I Hospital, University “La Sapienza”RomeItaly
  4. 4.Department of NeurosurgeryUmberto I Hospital, University “La Sapienza”RomeItaly
  5. 5.Department of PathologySant’ Andrea Hospital, University “La Sapienza”RomeItaly

Personalised recommendations