Clinical variables serve as prognostic factors in a model for survival from glioblastoma multiforme: an observational study of a cohort of consecutive non-selected patients from a single institution

Signe Regner Michaelsen, Ib Jarle Christensen, Kirsten Grunnet, Marie-Thérése Stockhausen, Helle Broholm, Michael Kosteljanetz, Hans Skovgaard Poulsen, Signe Regner Michaelsen, Ib Jarle Christensen, Kirsten Grunnet, Marie-Thérése Stockhausen, Helle Broholm, Michael Kosteljanetz, Hans Skovgaard Poulsen

Abstract

Background: Although implementation of temozolomide (TMZ) as a part of primary therapy for glioblastoma multiforme (GBM) has resulted in improved patient survival, the disease is still incurable. Previous studies have correlated various parameters to survival, although no single parameter has yet been identified. More studies and new approaches to identify the best and worst performing patients are therefore in great demand.

Methods: This study examined 225 consecutive, non-selected GBM patients with performance status (PS) 0-2 receiving postoperative radiotherapy with concomitant and adjuvant TMZ as primary therapy. At relapse, patients with PS 0-2 were mostly treated by reoperation and/or combination with bevacizumab/irinotecan (BEV/IRI), while a few received TMZ therapy if the recurrence-free period was >6 months.

Results: Median overall survival and time to progression were 14.3 and 8.0 months, respectively. Second-line therapy indicated that reoperation and/or BEV/IRI increased patient survival compared with untreated patients and that BEV/IRI was more effective than reoperation alone. Patient age, ECOG PS, and use of corticosteroid therapy were significantly correlated with patient survival and disease progression on univariate analysis, whereas p53, epidermal growth factor receptor, and O⁶-methylguanine-DNA methyltransferase expression (all detected by immunohistochemistry), tumor size or multifocality, and extent of primary operation were not. A model based on age, ECOG PS, and corticosteroids use was able to predict survival probability for an individual patient.

Conclusion: The survival of RT/TMZ-treated GBM patients can be predicted based on patient age, ECOG PS, and corticosteroid therapy status.

Figures

Figure 1
Figure 1
Examples of IHC stainings. p53, EGFR, and MGMT expression by IHC scored semiquantitatively on the scale: <10%, 10–25%, 25–50%, and >50% cells stained positive. Representative photomicrographs (200× magnification) are given for GBM tissue with <10% (I, III, V) and >50% (II, IV, VI) positive cells. Cells staining positive for MGMT in V represent macrophages and endothelial cells of vessels, while it is tumor cells that stains positive for p53 in I.
Figure 2
Figure 2
Kaplan-Meier plots showing TTP and OS for the patient population. The curves are based on data from all 225 examined patients. Numbers for patients at risk at selected times are shown in addition to the total number of events (deaths for OS and progression for TTP).

References

    1. Ohgaki H, Kleihues P. Epidemiology and etiology of gliomas. Acta Neuropathol. 2005;109:93–108. doi: 10.1007/s00401-005-0991-y.
    1. 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. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352:987–996. doi: 10.1056/NEJMoa043330.
    1. Ryken TC, Frankel B, Julien T, Olson JJ. Surgical management of newly diagnosed glioblastoma in adults: role of cytoreductive surgery. J Neurooncol. 2008;89:271–286. doi: 10.1007/s11060-008-9614-5.
    1. Sanai N, Berger MS. Recent surgical management of gliomas. Adv Exp Med Biol. 2012;746:12–25. doi: 10.1007/978-1-4614-3146-6_2.
    1. Quick A, Patel D, Hadziahmetovic M, Chakravarti A, Mehta M. Current therapeutic paradigms in glioblastoma. Rev Recent Clin Trials. 2010;5:14–27. doi: 10.2174/157488710790820544.
    1. Fukushima T, Takeshima H, Kataoka H. Anti-glioma therapy with temozolomide and status of the DNA-repair gene MGMT. Anticancer Res. 2009;29:4845–4854.
    1. Yung WK, Albright RE, Olson J, Fredericks R, Fink K, Prados MD, Brada M, Spence A, Hohl RJ, Shapiro W, Glantz M, Greenberg H, Selker RG, Vick NA, Rampling R, Friedman H, Phillips P, Bruner J, Yue N, Osoba D, Zaknoen S, Levin VA. A phase II study of temozolomide vs. procarbazine in patients with glioblastoma multiforme at first relapse. Br J Cancer. 2000;83:588–593. doi: 10.1054/bjoc.2000.1316.
    1. Wedge SR, Porteous JK, Glaser MG, Marcus K, Newlands ES. In vitro evaluation of temozolomide combined with X-irradiation. Anticancer Drugs. 1997;8:92–97. doi: 10.1097/00001813-199701000-00013.
    1. Chakravarti A, Erkkinen MG, Nestler U, Stupp R, Mehta M, Aldape K, Gilbert MR, Black PM, Loeffler JS. Temozolomide-mediated radiation enhancement in glioblastoma: a report on underlying mechanisms. Clin Cancer Res. 2006;12:4738–4746. doi: 10.1158/1078-0432.CCR-06-0596.
    1. Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, Ludwin SK, Allgeier A, Fisher B, Belanger K, Hau P, Brandes AA, Gijtenbeek J, Marosi C, Vecht CJ, Mokhtari K, Wesseling P, Villa S, Eisenhauer E, Gorlia T, Weller M, Lacombe D, Cairncross JG, Mirimanoff RO. 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. 2009;10:459–466. doi: 10.1016/S1470-2045(09)70025-7.
    1. Hegi ME, Diserens AC, Gorlia T, Hamou MF, De TN, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L, Bromberg JE, Hau P, Mirimanoff RO, Cairncross JG, Janzer RC, Stupp R. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005;352:997–1003. doi: 10.1056/NEJMoa043331.
    1. Iliadis G, Kotoula V, Chatzisotiriou A, Televantou D, Eleftheraki AG, Lambaki S, Misailidou D, Selviaridis P, Fountzilas G. Volumetric and MGMT parameters in glioblastoma patients: Survival analysis. BMC Cancer. 2012;12:3. doi: 10.1186/1471-2407-12-3.
    1. Felsberg J, Rapp M, Loeser S, Fimmers R, Stummer W, Goeppert M, Steiger HJ, Friedensdorf B, Reifenberger G, Sabel MC. Prognostic significance of molecular markers and extent of resection in primary glioblastoma patients. Clin Cancer Res. 2009;15:6683–6693. doi: 10.1158/1078-0432.CCR-08-2801.
    1. Gorlia T, van den Bent MJ, Hegi ME, Mirimanoff RO, Weller M, Cairncross JG, Eisenhauer E, Belanger K, Brandes AA, Allgeier A, Lacombe D, Stupp R. Nomograms for predicting survival of patients with newly diagnosed glioblastoma: prognostic factor analysis of EORTC and NCIC trial 26981-22981/CE.3. Lancet Oncol. 2008;9:29–38. doi: 10.1016/S1470-2045(07)70384-4.
    1. Combs SE, Wagner J, Bischof M, Welzel T, Wagner F, Debus J, Schulz-Ertner D. Postoperative treatment of primary glioblastoma multiforme with radiation and concomitant temozolomide in elderly patients. Int J Radiat Oncol Biol Phys. 2008;70:987–992. doi: 10.1016/j.ijrobp.2007.07.2368.
    1. Jeon HJ, Kong DS, Park KB, Lee JI, Park K, Kim JH, Kim ST, Lim dH, Kim WS, Nam DH. Clinical outcome of concomitant chemoradiotherapy followed by adjuvant temozolomide therapy for glioblastaomas: single-center experience. Clin Neurol Neurosurg. 2009;111:679–682. doi: 10.1016/j.clineuro.2009.06.013.
    1. Verbeek B, Southgate TD, Gilham DE, Margison GP. O6-Methylguanine-DNA methyltransferase inactivation and chemotherapy. Br Med Bull. 2008;85:17–33. doi: 10.1093/bmb/ldm036.
    1. Malkoun N, Chargari C, Forest F, Fotso MJ, Cartier L, Auberdiac P, Thorin J, Pacaut C, Peoc’h M, Nuti C, Schmitt T, Magne N. Prolonged temozolomide for treatment of glioblastoma: preliminary clinical results and prognostic value of p53 overexpression. J Neurooncol. 2012;106:127–133. doi: 10.1007/s11060-011-0643-0.
    1. Hobbs J, Nikiforova MN, Fardo DW, Bortoluzzi S, Cieply K, Hamilton RL, Horbinski C. Paradoxical relationship between the degree of EGFR amplification and outcome in glioblastomas. Am J Surg Pathol. 2012;36:1186–1193. doi: 10.1097/PAS.0b013e3182518e12.
    1. Hochberg FH, Pruitt A. Assumptions in the radiotherapy of glioblastoma. Neurology. 1980;30:907–911. doi: 10.1212/WNL.30.9.907.
    1. Park JK, Hodges T, Arko L, Shen M, Dello ID, McNabb A, Olsen BN, Kreisl TN, Iwamoto FM, Sul J, Auh S, Park GE, Fine HA, Black PM. Scale to predict survival after surgery for recurrent glioblastoma multiforme. J Clin Oncol. 2010;28:3838–3843. doi: 10.1200/JCO.2010.30.0582.
    1. Reardon DA, Turner S, Peters KB, Desjardins A, Gururangan S, Sampson JH, McLendon RE, Herndon JE, Jones LW, Kirkpatrick JP, Friedman AH, Vredenburgh JJ, Bigner DD, Friedman HS. A review of VEGF/VEGFR-targeted therapeutics for recurrent glioblastoma. J Natl Compr Canc Netw. 2011;9:414–427.
    1. Brem S, Cotran R, Folkman J. Tumor angiogenesis: a quantitative method for histologic grading. J Natl Cancer Inst. 1972;48:347–356.
    1. Salmaggi A, Eoli M, Frigerio S, Silvani A, Gelati M, Corsini E, Broggi G, Boiardi A. Intracavitary VEGF, bFGF, IL-8, IL-12 levels in primary and recurrent malignant glioma. J Neurooncol. 2003;62:297–303. doi: 10.1023/A:1023367223575.
    1. Chamberlain MC. Bevacizumab for the treatment of recurrent glioblastoma. Clin Med Insights Oncol. 2011;5:117–129.
    1. Curran WJ Jr, Scott CB, Horton J, Nelson JS, Weinstein AS, Fischbach AJ, Chang CH, Rotman M, Asbell SO, Krisch RE. Recursive partitioning analysis of prognostic factors in three Radiation Therapy Oncology Group malignant glioma trials. J Natl Cancer Inst. 1993;85:704–710. doi: 10.1093/jnci/85.9.704.
    1. Mirimanoff RO, Gorlia T, Mason W, van den Bent MJ, Kortmann RD, Fisher B, Reni M, Brandes AA, Curschmann J, Villa S, Cairncross G, Allgeier A, Lacombe D, Stupp R. Radiotherapy and temozolomide for newly diagnosed glioblastoma: recursive partitioning analysis of the EORTC 26981/22981-NCIC CE3 phase III randomized trial. J Clin Oncol. 2006;24:2563–2569. doi: 10.1200/JCO.2005.04.5963.
    1. Li J, Wang M, Won M, Shaw EG, Coughlin C, Curran WJ Jr, Mehta MP. Validation and simplification of the Radiation Therapy Oncology Group recursive partitioning analysis classification for glioblastoma. Int J Radiat Oncol Biol Phys. 2011;81:623–630. doi: 10.1016/j.ijrobp.2010.06.012.
    1. Gorlia T, Stupp R, Brandes AA, Rampling RR, Fumoleau P, Dittrich C, Campone MM, Twelves CC, Raymond E, Hegi ME, Lacombe D, van den Bent MJ. New prognostic factors and calculators for outcome prediction in patients with recurrent glioblastoma: a pooled analysis of EORTC Brain Tumour Group phase I and II clinical trials. Eur J Cancer. 2012;48:1176–1184. doi: 10.1016/j.ejca.2012.02.004.
    1. Emami B, Lyman J, Brown A, Coia L, Goitein M, Munzenrider JE, Shank B, Solin LJ, Wesson M. Tolerance of normal tissue to therapeutic irradiation. Int J Radiat Oncol Biol Phys. 1991;21:109–122.
    1. Poulsen HS, Grunnet K, Sorensen M, Olsen P, Hasselbalch B, Nelausen K, Kosteljanetz M, Lassen U. Bevacizumab plus irinotecan in the treatment patients with progressive recurrent malignant brain tumours. Acta Oncol. 2009;48:52–58. doi: 10.1080/02841860802537924.
    1. Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649–655. doi: 10.1097/00000421-198212000-00014.
    1. NCI common terminology criteria for adverse events v.3.0 (CTCAE) [ ] Accessed January 9 2013.
    1. Macdonald DR, Cascino TL, Schold SC Jr, Cairncross JG. Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol. 1990;8:1277–1280.
    1. Harrell FE Jr, Lee KL, Mark DB. Multivariable prognostic models: issues in developing models, evaluating assumptions and adequacy, and measuring and reducing errors. Stat Med. 1996;15:361–387. doi: 10.1002/(SICI)1097-0258(19960229)15:4<361::AID-SIM168>;2-4.
    1. Pencina MJ, D’Agostino RB. Overall C as a measure of discrimination in survival analysis: model specific population value and confidence interval estimation. Stat Med. 2004;23:2109–2123. doi: 10.1002/sim.1802.
    1. Liu L, Forman S, Barton B. SAS Institute Inc. 2009. Proceedings of the SAS®Global Forum 2009 Conference. Cary, NC: SAS Institute Inc.; Fitting Cox model using PROC PHREG and beyond in SAS; pp. 1–10. (Paper 236-2009).
    1. Barbagallo GM, Jenkinson MD, Brodbelt AR. ‘Recurrent’ glioblastoma multiforme, when should we reoperate? Br J Neurosurg. 2008;22:452–455. doi: 10.1080/02688690802182256.
    1. Li S, Zhang W, Chen B, Jiang T, Wang Z. Prognostic and predictive value of p53 in low MGMT expressing glioblastoma treated with surgery, radiation and adjuvant temozolomide chemotherapy. Neurol Res. 2010;32:690–694. doi: 10.1179/016164109X12478302362536.
    1. Ang C, Guiot MC, Ramanakumar AV, Roberge D, Kavan P. Clinical significance of molecular biomarkers in glioblastoma. Can J Neurol Sci. 2010;37:625–630.
    1. Chakravarti A, Chakladar A, Delaney MA, Latham DE, Loeffler JS. The epidermal growth factor receptor pathway mediates resistance to sequential administration of radiation and chemotherapy in primary human glioblastoma cells in a RAS-dependent manner. Cancer Res. 2002;62:4307–4315.
    1. Nagane M, Narita Y, Mishima K, Levitzki A, Burgess AW, Cavenee WK, Huang HJ. Human glioblastoma xenografts overexpressing a tumor-specific mutant epidermal growth factor receptor sensitized to cisplatin by the AG1478 tyrosine kinase inhibitor. J Neurosurg. 2001;95:472–479. doi: 10.3171/jns.2001.95.3.0472.
    1. Blough MD, Beauchamp DC, Westgate MR, Kelly JJ, Cairncross JG. Effect of aberrant p53 function on temozolomide sensitivity of glioma cell lines and brain tumor initiating cells from glioblastoma. J Neurooncol. 2011;102:1–7. doi: 10.1007/s11060-010-0283-9.
    1. Dinca EB, Lu KV, Sarkaria JN, Pieper RO, Prados MD, Haas-Kogan DA, Vandenberg SR, Berger MS, James CD. p53 Small-molecule inhibitor enhances temozolomide cytotoxic activity against intracranial glioblastoma xenografts. Cancer Res. 2008;68:10034–10039. doi: 10.1158/0008-5472.CAN-08-1687.
    1. Brown PD, Krishnan S, Sarkaria JN, Wu W, Jaeckle KA, Uhm JH, Geoffroy FJ, Arusell R, Kitange G, Jenkins RB, Kugler JW, Morton RF, Rowland KM Jr, Mischel P, Yong WH, Scheithauer BW, Schiff D, Giannini C, Buckner JC. Phase I/II trial of erlotinib and temozolomide with radiation therapy in the treatment of newly diagnosed glioblastoma multiforme: North Central Cancer Treatment Group Study N0177. J Clin Oncol. 2008;26:5603–5609. doi: 10.1200/JCO.2008.18.0612.
    1. Quillien V, Lavenu A, Karayan-Tapon L, Carpentier C, Labussiere M, Lesimple T, Chinot O, Wager M, Honnorat J, Saikali S, Fina F, Sanson M, Figarella-Branger D. Comparative assessment of 5 methods (methylation-specific polymerase chain reaction, MethyLight, pyrosequencing, methylation-sensitive high-resolution melting, and immunohistochemistry) to analyze O6-methylguanine-DNA-methyltranferase in a series of 100 glioblastoma patients. Cancer. 2012;118:4201–4211. doi: 10.1002/cncr.27392.
    1. Brell M, Ibanez J, Tortosa A. O6-Methylguanine-DNA methyltransferase protein expression by immunohistochemistry in brain and non-brain systemic tumours: systematic review and meta-analysis of correlation with methylation-specific polymerase chain reaction. BMC Cancer. 2011;11:35. doi: 10.1186/1471-2407-11-35.
    1. Phillips HS, Kharbanda S, Chen R, Forrest WF, Soriano RH, Wu TD, Misra A, Nigro JM, Colman H, Soroceanu L, Williams PM, Modrusan Z, Feuerstein BG, Aldape K. Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer Cell. 2006;9:157–173. doi: 10.1016/j.ccr.2006.02.019.
    1. Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, Miller CR, Ding L, Golub T, Mesirov JP, Alexe G, Lawrence M, O’Kelly M, Tamayo P, Weir BA, Gabriel S, Winckler W, Gupta S, Jakkula L, Feiler HS, Hodgson JG, James CD, Sarkaria JN, Brennan C, Kahn A, Spellman PT, Wilson RK, Speed TP, Gray JW. et al.Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell. 2010;17:98–110. doi: 10.1016/j.ccr.2009.12.020.
    1. Colman H, Zhang L, Sulman EP, McDonald JM, Shooshtari NL, Rivera A, Popoff S, Nutt CL, Louis DN, Cairncross JG, Gilbert MR, Phillips HS, Mehta MP, Chakravarti A, Pelloski CE, Bhat K, Feuerstein BG, Jenkins RB, Aldape K. A multigene predictor of outcome in glioblastoma. Neuro Oncol. 2010;12:49–57. doi: 10.1093/neuonc/nop007.
    1. van den Bent MJ, Gravendeel LA, Gorlia T, Kros JM, Lapre L, Wesseling P, Teepen JL, Idbaih A, Sanson M, Smitt PA, French PJ. A hypermethylated phenotype is a better predictor of survival than MGMT methylation in anaplastic oligodendroglial brain tumors: a report from EORTC study 26951. Clin Cancer Res. 2011;17:7148–7155. doi: 10.1158/1078-0432.CCR-11-1274.
    1. Brandes AA, Bartolotti M. Neuro-oncology: treatment decisions in elderly patients with glioblastoma. Nat Rev Neurol. 2012;8:664–665. doi: 10.1038/nrneurol.2012.220.
    1. Keime-Guibert F, Chinot O, Taillandier L, Cartalat-Carel S, Frenay M, Kantor G, Guillamo JS, Jadaud E, Colin P, Bondiau PY, Menei P, Loiseau H, Bernier V, Honnorat J, Barrie M, Mokhtari K, Mazeron JJ, Bissery A, Delattre JY. Radiotherapy for glioblastoma in the elderly. N Engl J Med. 2007;356:1527–1535. doi: 10.1056/NEJMoa065901.
    1. Malmstrom A, Gronberg BH, Marosi C, Stupp R, Frappaz D, Schultz H, Abacioglu U, Tavelin B, Lhermitte B, Hegi ME, Rosell J, Henriksson R. Temozolomide versus standard 6-week radiotherapy versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma: the Nordic randomised, phase 3 trial. Lancet Oncol. 2012;13:916–926. doi: 10.1016/S1470-2045(12)70265-6.
    1. Minniti G, De SV, Muni R, Filippone F, Bozzao A, Valeriani M, Osti MF, De PU, Lanzetta G, Tombolini V, Maurizi ER. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma in elderly patients. J Neurooncol. 2008;88:97–103. doi: 10.1007/s11060-008-9538-0.

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