Skip to main content
Erschienen in: Journal of Neuro-Oncology 3/2017

23.05.2017 | Clinical Study

MGMT promoter methylation status as a prognostic factor for the outcome of gamma knife radiosurgery for recurrent glioblastoma

verfasst von: Byung Sup Kim, Doo-Sik Kong, Ho Jun Seol, Do-Hyun Nam, Jung-Il Lee

Erschienen in: Journal of Neuro-Oncology | Ausgabe 3/2017

Einloggen, um Zugang zu erhalten

Abstract

We conducted this study to determine whether the methylation status of the O6-methylguanine-DNA methyltransferase (MGMT) promoter was a prognostic marker for positive outcomes of gamma knife radiosurgery (GKS) for recurrent glioblastoma (GBM). We retrospectively examined 61 patients, who underwent GKS for local recurrent GBM between 2004 and 2015; in all patients, the methylation status of the MGMT promoter was identified via methylation-specific quantitative real-time polymerase chain reaction. All patients underwent surgical resection and were diagnosed histopathologically with GBM. Prognostic factors associated with progression-free survival (PFS) and overall survival (OS) were identified in univariate and multivariate analyses. Twenty-five (41%) had a methylated MGMT promoter, and 36 (59%) had an unmethylated MGMT promoter. The median age at GKS was 58 years. The median tumor volume at GKS was 7.0 cm3, and the median marginal dose was 16 Gy. The median follow-up period after GKS was 7.5 months. The median PFS time after GKS was 8.9 months (95% CI 4.3–13.5 months) in the methylated and 4.6 months (95% CI 3.7–5.5 months) in the unmethylated group (P = 0.016). The median OS time after GKS was 14.0 months (95% CI 9.3–18.7 months) in the methylated group and 9.0 months (95% CI 6.5–11.5 months) in the unmethylated group (P = 0.026). Methylation of the MGMT promoter correlated with better PFS and OS after GKS for recurrent GBM. Prospective comparative studies are required to determine whether MGMT methylation directly affects the efficiency of GKS.
Literatur
1.
Zurück zum Zitat Stupp R, Mason WP, Van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO, European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups, National Cancer Institute of Canada Clinical Trials Group (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996. doi:10.1056/NEJMoa043330 CrossRefPubMed Stupp R, Mason WP, Van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO, European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups, National Cancer Institute of Canada Clinical Trials Group (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996. doi:10.​1056/​NEJMoa043330 CrossRefPubMed
2.
Zurück zum Zitat Combs SE, Widmer V, Thilmann C, Hof H, Debus J, Schulz-Ertner D (2005) Stereotactic radiosurgery (SRS): treatment option for recurrent glioblastoma multiforme (GBM). Cancer 104:2168–2173. doi:10.1002/cncr.21429 CrossRefPubMed Combs SE, Widmer V, Thilmann C, Hof H, Debus J, Schulz-Ertner D (2005) Stereotactic radiosurgery (SRS): treatment option for recurrent glioblastoma multiforme (GBM). Cancer 104:2168–2173. doi:10.​1002/​cncr.​21429 CrossRefPubMed
3.
6.
Zurück zum Zitat Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L, Bromberg JE, Hau P, Mirimanoff RO, Cairncross JG, Janzer RC, Stupp R (2005) MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352:997–1003. doi:10.1056/NEJMoa043331 CrossRefPubMed Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L, Bromberg JE, Hau P, Mirimanoff RO, Cairncross JG, Janzer RC, Stupp R (2005) MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352:997–1003. doi:10.​1056/​NEJMoa043331 CrossRefPubMed
7.
Zurück zum Zitat Rivera AL, Pelloski CE, Gilbert MR, Colman H, De La Cruz C, Sulman EP, Bekele BN, Aldape KD (2010) MGMT promoter methylation is predictive of response to radiotherapy and prognostic in the absence of adjuvant alkylating chemotherapy for glioblastoma. Neuro Oncol 12:116–121. doi:10.1093/neuonc/nop020 CrossRefPubMed Rivera AL, Pelloski CE, Gilbert MR, Colman H, De La Cruz C, Sulman EP, Bekele BN, Aldape KD (2010) MGMT promoter methylation is predictive of response to radiotherapy and prognostic in the absence of adjuvant alkylating chemotherapy for glioblastoma. Neuro Oncol 12:116–121. doi:10.​1093/​neuonc/​nop020 CrossRefPubMed
8.
Zurück zum Zitat Metellus P, Coulibaly B, Nanni I, Fina F, Eudes N, Giorgi R, Barrie M, Chinot O, Fuentes S, Dufour H, Ouafik L, Figarella-Branger D (2009) Prognostic impact of O6-methylguanine-DNA methyltransferase silencing in patients with recurrent glioblastoma multiforme who undergo surgery and carmustine wafer implantation: a prospective patient cohort. Cancer 115:4783–4794. doi:10.1002/cncr.24546 CrossRefPubMed Metellus P, Coulibaly B, Nanni I, Fina F, Eudes N, Giorgi R, Barrie M, Chinot O, Fuentes S, Dufour H, Ouafik L, Figarella-Branger D (2009) Prognostic impact of O6-methylguanine-DNA methyltransferase silencing in patients with recurrent glioblastoma multiforme who undergo surgery and carmustine wafer implantation: a prospective patient cohort. Cancer 115:4783–4794. doi:10.​1002/​cncr.​24546 CrossRefPubMed
9.
Zurück zum Zitat Hsieh PC, Chandler JP, Bhangoo S, Panagiotopoulos K, Kalapurakal JA, Marymont MH, Cozzens JW, Levy RM, Salehi S (2005) Adjuvant gamma knife stereotactic radiosurgery at the time of tumor progression potentially improves survival for patients with glioblastoma multiforme. Neurosurgery 57:684–692. doi:10.1227/01.neu.0000175550.96901.a3 CrossRefPubMed Hsieh PC, Chandler JP, Bhangoo S, Panagiotopoulos K, Kalapurakal JA, Marymont MH, Cozzens JW, Levy RM, Salehi S (2005) Adjuvant gamma knife stereotactic radiosurgery at the time of tumor progression potentially improves survival for patients with glioblastoma multiforme. Neurosurgery 57:684–692. doi:10.​1227/​01.​neu.​0000175550.​96901.​a3 CrossRefPubMed
10.
Zurück zum Zitat Souhami L, Seiferheld W, Brachman D, Podgorsak EB, Werner-Wasik M, Lustig R, Schultz CJ, Sause W, Okunieff P, Buckner J, Zamorano L, Mehta MP, Curran WJ Jr (2004) Randomized comparison of stereotactic radiosurgery followed by conventional radiotherapy with carmustine to conventional radiotherapy with carmustine for patients with glioblastoma multiforme: report of radiation therapy oncology group 93-05 protocol. Int J Radiat Oncol Biol Phys 60:853–860. doi:10.1016/j.ijrobp.2004.04.011 CrossRefPubMed Souhami L, Seiferheld W, Brachman D, Podgorsak EB, Werner-Wasik M, Lustig R, Schultz CJ, Sause W, Okunieff P, Buckner J, Zamorano L, Mehta MP, Curran WJ Jr (2004) Randomized comparison of stereotactic radiosurgery followed by conventional radiotherapy with carmustine to conventional radiotherapy with carmustine for patients with glioblastoma multiforme: report of radiation therapy oncology group 93-05 protocol. Int J Radiat Oncol Biol Phys 60:853–860. doi:10.​1016/​j.​ijrobp.​2004.​04.​011 CrossRefPubMed
11.
Zurück zum Zitat Shrieve DC, Alexander E 3rd, Wen PY, Fine HA, Kooy HM, Black PM, Loeffler JS (1995) Comparison of stereotactic radiosurgery and brachytherapy in the treatment of recurrent glioblastoma multiforme. Neurosurgery 36:275–282CrossRefPubMed Shrieve DC, Alexander E 3rd, Wen PY, Fine HA, Kooy HM, Black PM, Loeffler JS (1995) Comparison of stereotactic radiosurgery and brachytherapy in the treatment of recurrent glioblastoma multiforme. Neurosurgery 36:275–282CrossRefPubMed
13.
Zurück zum Zitat Fogh SE, Andrews DW, Glass J, Curran W, Glass C, Champ C, Evans JJ, Hyslop T, Pequignot E, Downes B, Comber E, Maltenfort M, Dicker AP, Werner-Wasik M (2010) Hypofractionated stereotactic radiation therapy: an effective therapy for recurrent high-grade gliomas. J Clin Oncol 28:3048–3053. doi:10.1200/JCO.2009.25.6941 CrossRefPubMedPubMedCentral Fogh SE, Andrews DW, Glass J, Curran W, Glass C, Champ C, Evans JJ, Hyslop T, Pequignot E, Downes B, Comber E, Maltenfort M, Dicker AP, Werner-Wasik M (2010) Hypofractionated stereotactic radiation therapy: an effective therapy for recurrent high-grade gliomas. J Clin Oncol 28:3048–3053. doi:10.​1200/​JCO.​2009.​25.​6941 CrossRefPubMedPubMedCentral
14.
Zurück zum Zitat Maranzano E, Anselmo P, Casale M, Trippa F, Carletti S, Principi M, Loreti F, Italiani M, Caserta C, Giorgi C (2011) Treatment of recurrent glioblastoma with stereotactic radiotherapy: long-term results of a mono-institutional trial. Tumori 97:56–61PubMed Maranzano E, Anselmo P, Casale M, Trippa F, Carletti S, Principi M, Loreti F, Italiani M, Caserta C, Giorgi C (2011) Treatment of recurrent glioblastoma with stereotactic radiotherapy: long-term results of a mono-institutional trial. Tumori 97:56–61PubMed
15.
Zurück zum Zitat Greenspoon JN, Sharieff W, Hirte H, Overholt A, Devillers R, Gunnarsson T, Whitton A (2014) Fractionated stereotactic radiosurgery with concurrent temozolomide chemotherapy for locally recurrent glioblastoma multiforme: a prospective cohort study. Onco Targets Ther 7:485–490. doi:10.2147/OTT.S60358 CrossRefPubMedPubMedCentral Greenspoon JN, Sharieff W, Hirte H, Overholt A, Devillers R, Gunnarsson T, Whitton A (2014) Fractionated stereotactic radiosurgery with concurrent temozolomide chemotherapy for locally recurrent glioblastoma multiforme: a prospective cohort study. Onco Targets Ther 7:485–490. doi:10.​2147/​OTT.​S60358 CrossRefPubMedPubMedCentral
16.
Zurück zum Zitat Lederman G, Arbit E, Odaimi M, Wertheim S, Lombardi E (1997) Recurrent glioblastoma multiforme: potential benefits using fractionated stereotactic radiotherapy and concurrent taxol. Stereotact Funct Neurosurg 69:162–174CrossRefPubMed Lederman G, Arbit E, Odaimi M, Wertheim S, Lombardi E (1997) Recurrent glioblastoma multiforme: potential benefits using fractionated stereotactic radiotherapy and concurrent taxol. Stereotact Funct Neurosurg 69:162–174CrossRefPubMed
17.
Zurück zum Zitat Hudes RS, Corn BW, Werner-Wasik M, Andrews D, Rosenstock J, Thoron L, Downes B, Curran WJ Jr (1999) A phase I dose escalation study of hypofractionated stereotactic radiotherapy as salvage therapy for persistent or recurrent malignant glioma. Int J Radiat Oncol Biol Phys 43:293–298CrossRefPubMed Hudes RS, Corn BW, Werner-Wasik M, Andrews D, Rosenstock J, Thoron L, Downes B, Curran WJ Jr (1999) A phase I dose escalation study of hypofractionated stereotactic radiotherapy as salvage therapy for persistent or recurrent malignant glioma. Int J Radiat Oncol Biol Phys 43:293–298CrossRefPubMed
18.
Zurück zum Zitat Cuneo KC, Vredenburgh JJ, Sampson JH, Reardon DA, Desjardins A, Peters KB, Friedman HS, Willett CG, Kirkpatrick JP (2012) Safety and efficacy of stereotactic radiosurgery and adjuvant bevacizumab in patients with recurrent malignant gliomas. Int J Radiat Oncol Biol Phys 82:2018–2024. doi:10.1016/j.ijrobp.2010.12.074 CrossRefPubMed Cuneo KC, Vredenburgh JJ, Sampson JH, Reardon DA, Desjardins A, Peters KB, Friedman HS, Willett CG, Kirkpatrick JP (2012) Safety and efficacy of stereotactic radiosurgery and adjuvant bevacizumab in patients with recurrent malignant gliomas. Int J Radiat Oncol Biol Phys 82:2018–2024. doi:10.​1016/​j.​ijrobp.​2010.​12.​074 CrossRefPubMed
19.
Zurück zum Zitat Minniti G, Scaringi C, De Sanctis V, Lanzetta G, Falco T, Di Stefano D, Esposito V, Enrici RM (2013) Hypofractionated stereotactic radiotherapy and continuous low-dose temozolomide in patients with recurrent or progressive malignant gliomas. J Neurooncol 111:187–194. doi:10.1007/s11060-012-0999-9 CrossRefPubMed Minniti G, Scaringi C, De Sanctis V, Lanzetta G, Falco T, Di Stefano D, Esposito V, Enrici RM (2013) Hypofractionated stereotactic radiotherapy and continuous low-dose temozolomide in patients with recurrent or progressive malignant gliomas. J Neurooncol 111:187–194. doi:10.​1007/​s11060-012-0999-9 CrossRefPubMed
20.
Zurück zum Zitat Lederman G, Wronski M, Arbit E, Odaimi M, Wertheim S, Lombardi E, Wrzolek M (2000) Treatment of recurrent glioblastoma multiforme using fractionated stereotactic radiosurgery and concurrent paclitaxel. Am J Clin Oncol 23:155–159CrossRefPubMed Lederman G, Wronski M, Arbit E, Odaimi M, Wertheim S, Lombardi E, Wrzolek M (2000) Treatment of recurrent glioblastoma multiforme using fractionated stereotactic radiosurgery and concurrent paclitaxel. Am J Clin Oncol 23:155–159CrossRefPubMed
21.
Zurück zum Zitat Imber BS, Kanungo I, Braunstein S, Barani IJ, Fogh SE, Nakamura JL, Berger MS, Chang EF, Molinaro AM, Cabrera JR, McDermott MW, Sneed PK, Aghi MK (2016) Indications and efficacy of Gamma Knife stereotactic radiosurgery for recurrent glioblastoma: 2 decades of institutional experience. Neurosurgery. doi:10.1227/neu.0000000000001344 PubMed Imber BS, Kanungo I, Braunstein S, Barani IJ, Fogh SE, Nakamura JL, Berger MS, Chang EF, Molinaro AM, Cabrera JR, McDermott MW, Sneed PK, Aghi MK (2016) Indications and efficacy of Gamma Knife stereotactic radiosurgery for recurrent glioblastoma: 2 decades of institutional experience. Neurosurgery. doi:10.​1227/​neu.​0000000000001344​ PubMed
22.
23.
Zurück zum Zitat Park KJ, Kano H, Iyer A, Liu X, Niranjan A, Flickinger JC, Lieberman FS, Lunsford LD, Kondziolka D (2012) Salvage gamma knife stereotactic radiosurgery followed by bevacizumab for recurrent glioblastoma multiforme: a case-control study. J Neurooncol 107:323–333. doi:10.1007/s11060-011-0744-9 CrossRefPubMed Park KJ, Kano H, Iyer A, Liu X, Niranjan A, Flickinger JC, Lieberman FS, Lunsford LD, Kondziolka D (2012) Salvage gamma knife stereotactic radiosurgery followed by bevacizumab for recurrent glioblastoma multiforme: a case-control study. J Neurooncol 107:323–333. doi:10.​1007/​s11060-011-0744-9 CrossRefPubMed
24.
Zurück zum Zitat Koga T, Maruyama K, Tanaka M, Ino Y, Saito N, Nakagawa K, Shibahara J, Todo T (2012) Extended field stereotactic radiosurgery for recurrent glioblastoma. Cancer 118:4193–4200. doi:10.1002/cncr.27372 CrossRefPubMed Koga T, Maruyama K, Tanaka M, Ino Y, Saito N, Nakagawa K, Shibahara J, Todo T (2012) Extended field stereotactic radiosurgery for recurrent glioblastoma. Cancer 118:4193–4200. doi:10.​1002/​cncr.​27372 CrossRefPubMed
25.
Zurück zum Zitat Elliott RE, Parker EC, Rush SC, Kalhorn SP, Moshel YA, Narayana A, Donahue B, Golfinos JG (2011) Efficacy of gamma knife radiosurgery for small-volume recurrent malignant gliomas after initial radical resection. World Neurosurg 76:128–140. doi:10.1016/j.wneu.2010.12.053 CrossRefPubMed Elliott RE, Parker EC, Rush SC, Kalhorn SP, Moshel YA, Narayana A, Donahue B, Golfinos JG (2011) Efficacy of gamma knife radiosurgery for small-volume recurrent malignant gliomas after initial radical resection. World Neurosurg 76:128–140. doi:10.​1016/​j.​wneu.​2010.​12.​053 CrossRefPubMed
26.
28.
Zurück zum Zitat Kohshi K, Yamamoto H, Nakahara A, Katoh T, Takagi M (2007) Fractionated stereotactic radiotherapy using gamma unit after hyperbaric oxygenation on recurrent high-grade gliomas. J Neurooncol 82:297–303. doi:10.1007/s11060-006-9283-1 CrossRefPubMed Kohshi K, Yamamoto H, Nakahara A, Katoh T, Takagi M (2007) Fractionated stereotactic radiotherapy using gamma unit after hyperbaric oxygenation on recurrent high-grade gliomas. J Neurooncol 82:297–303. doi:10.​1007/​s11060-006-9283-1 CrossRefPubMed
30.
Zurück zum Zitat Dunn J, Baborie A, Alam F, Joyce K, Moxham M, Sibson R, Crooks D, Husband D, Shenoy A, Brodbelt A, Wong H, Liloglou T, Haylock B, Walker C (2009) Extent of MGMT promoter methylation correlates with outcome in glioblastomas given temozolomide and radiotherapy. Br J Cancer 101:124–131. doi:10.1038/sj.bjc.6605127 CrossRefPubMedPubMedCentral Dunn J, Baborie A, Alam F, Joyce K, Moxham M, Sibson R, Crooks D, Husband D, Shenoy A, Brodbelt A, Wong H, Liloglou T, Haylock B, Walker C (2009) Extent of MGMT promoter methylation correlates with outcome in glioblastomas given temozolomide and radiotherapy. Br J Cancer 101:124–131. doi:10.​1038/​sj.​bjc.​6605127 CrossRefPubMedPubMedCentral
31.
Zurück zum Zitat Felsberg J, Thon N, Eigenbrod S, Hentschel B, Sabel MC, Westphal M, Schackert G, Kreth FW, Pietsch T, Löffler M, Weller M, Reifenberger G, Tonn JC, German Glioma Network (2011) Promoter methylation and expression of MGMT and the DNA mismatch repair genes MLH1, MSH2, MSH6 and PMS2 in paired primary and recurrent glioblastomas. Int J Cancer 129:659–670. doi:10.1002/ijc.26083 CrossRefPubMed Felsberg J, Thon N, Eigenbrod S, Hentschel B, Sabel MC, Westphal M, Schackert G, Kreth FW, Pietsch T, Löffler M, Weller M, Reifenberger G, Tonn JC, German Glioma Network (2011) Promoter methylation and expression of MGMT and the DNA mismatch repair genes MLH1, MSH2, MSH6 and PMS2 in paired primary and recurrent glioblastomas. Int J Cancer 129:659–670. doi:10.​1002/​ijc.​26083 CrossRefPubMed
32.
Zurück zum Zitat Crinière E, Kaloshi G, Laigle-Donadey F, Lejeune J, Auger N, Benouaich-Amiel A, Everhard S, Mokhtari K, Polivka M, Delattre JY, Hoang-Xuan K, Thillet J, Sanson M (2007) MGMT prognostic impact on glioblastoma is dependent on therapeutic modalities. J Neurooncol 83:173–179. doi:10.1007/s11060-006-9320-0 CrossRefPubMed Crinière E, Kaloshi G, Laigle-Donadey F, Lejeune J, Auger N, Benouaich-Amiel A, Everhard S, Mokhtari K, Polivka M, Delattre JY, Hoang-Xuan K, Thillet J, Sanson M (2007) MGMT prognostic impact on glioblastoma is dependent on therapeutic modalities. J Neurooncol 83:173–179. doi:10.​1007/​s11060-006-9320-0 CrossRefPubMed
33.
Zurück zum Zitat Parker NR, Hudson AL, Khong P, Parkinson JF, Dwight T, Ikin RJ, Zhu Y, Cheng ZJ, Vafaee F, Chen J, Wheeler HR, Howell VM (2016) Intratumoral heterogeneity identified at the epigenetic, genetic and transcriptional level in glioblastoma. Sci Rep 6:22477. doi:10.1038/srep22477 CrossRefPubMedPubMedCentral Parker NR, Hudson AL, Khong P, Parkinson JF, Dwight T, Ikin RJ, Zhu Y, Cheng ZJ, Vafaee F, Chen J, Wheeler HR, Howell VM (2016) Intratumoral heterogeneity identified at the epigenetic, genetic and transcriptional level in glioblastoma. Sci Rep 6:22477. doi:10.​1038/​srep22477 CrossRefPubMedPubMedCentral
Metadaten
Titel
MGMT promoter methylation status as a prognostic factor for the outcome of gamma knife radiosurgery for recurrent glioblastoma
verfasst von
Byung Sup Kim
Doo-Sik Kong
Ho Jun Seol
Do-Hyun Nam
Jung-Il Lee
Publikationsdatum
23.05.2017
Verlag
Springer US
Erschienen in
Journal of Neuro-Oncology / Ausgabe 3/2017
Print ISSN: 0167-594X
Elektronische ISSN: 1573-7373
DOI
https://doi.org/10.1007/s11060-017-2478-9

Weitere Artikel der Ausgabe 3/2017

Journal of Neuro-Oncology 3/2017 Zur Ausgabe

Leitlinien kompakt für die Neurologie

Mit medbee Pocketcards sicher entscheiden.

Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag

Update Neurologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.