Outcome of Combined Temozolomide/CCNU versus Temozolomide (Standard or Extended) For Patients with Methylated MGMT Glioblastoma

• Fatma Gharib

  Department of Clinical Oncology, Faculty of Medicine, Tanta University, Egypt

• Nehal K.H. Kamel

  Department of Pathology, Faculty of Medicine, Tanta University, Egypt

• Ahmed El hamouly

  Neurosurgery Department, Al Azhar University, Egypt

• Asma M. Elkady

  Department of Clinical Oncology, Faculty of Medicine, Tanta University, Egypt

Glioblastoma treatment is a real challenge despite better understanding of molecular characterization of gliomas. More effective treatment protocols are urgently required. The current study compared the efficacy of combined Temozolomide/CCNU versus temozolomide (standard or extended) for patients with methylated O6-methylguanine-DNA-methyltransferase (MGMT) Glioblastoma.

Method: The current trial is a prospective, randomized, open-label study including ninety participants initially diagnosed with glioblastoma isocitrate dehydrogenase (IDH) wildtype, methylated MGMT promoter. The Participants were randomly allocated (1:1:1) to concomitant and adjuvant temozolomide/CCNU combined therapy, standard temozolomide or temozolomide extended therapy. The main end point was overall survival. Other endpoints were progression-free survival and toxicity.

Results: In the current study, the median overall survival was significantly higher in temozolomide/CCNU group (43 months) and extended temozolomide group (40 months) compared to standard temozolomide group (30 months). The median progression free survival was longer with temozolomide/CCNU and extended temozolomide compared to standard temozolomide without significant correlation (95% CI 0.815-1.496; p=0.055).

Conclusion: Multivariate analysis revealed that Eastern Cooperative Oncology Group (ECOG) scale ≤1 continued as a significant prognostic variant with overall survival in different treatment groups Conclusion: The effectiveness and safety of combined CCNU/ temozolomide and extended adjuvant temozolomide should be considered for treatment of recently diagnosed IDH-wildtype glioblastoma with MGMT methylated.

[1] Central Nervous System Tumours, 5th ed, WHO Classification of Tumours Editorial Board (Ed), International Agency for Research on Cancer 2021.

[2] Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005; 352(10): 987-996.

[3] Stupp R, Hegi ME, Mason WP, et al. 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(5): 459-466.

[4] Hegi ME, Diserens AC, Gorlia T, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 2005; 352(10): 997-1003.

[5] Velázquez Vega JE, Brat DJ, Ryken TC, Olson JJ. The role of neuropathology in the management of newly diagnosed glioblastoma: a systematic review and evidence-based clinical practice guideline. J Neurooncol 2020; 150(2): 143-164.

[6] Omuro A, Brandes AA, Carpentier AF, et al. Radiotherapy combined with nivolumab or temozolomide for newly diagnosed glioblastoma with unmethylated MGMT promoter: An international randomized phase III trial. Neuro Oncol 2023; 25(1): 123-134.

[7] Herrlinger U, Tzaridis T, Mack F, et al. Lomustine-temozolomide combination therapy versus standard temozolomide therapy in patients with newly diagnosed glioblastoma with methylated MGMT promoter (CeTeG/NOA-09): a randomised, open-label, phase 3 trial. Lancet 2019; 393(10172): 678-688.

[8] Gupta T, Chatterjee A, Patil V. Extended adjuvant temozolomide in newly diagnosed glioblastoma: is more less? Comment on “A phase II randomized, multicenter, open-label trial of continuing adjuvant temozolomide beyond 6 cycles in patients with glioblastoma (GEINO 14-01)”. Neuro Oncol 2020; 22(12): 1887-1888.

[9] Guo X, Shi Y, Liu D, et al. Clinical updates on gliomas and implications of the 5th edition of the WHO classification of central nervous system tumors. Front Oncol 2023; 14(13): 1131642.

[10] Goyal R, Mathur SK, Gupta S, et al. Immunohistochemical expression of glial fibrillary acidic protein and CAM5.2 in glial tumors and their role in differentiating glial tumors from metastatic tumors of central nervous system. J Neurosci Rural Pract 2015; 6(4): 499-503.

[11] Camelo -Piragua S, Jansen M, Ganguly A, et al. Mutant IDH1-specific immunohistochemistry distinguishes diffuse astrocytoma from astrocytosis. Acta Neuropathol 2010; 119(4): 509–511.

[12] Rodriguez FJ, Thibodeau SN, Jenkins RB, et al. MGMT immunohistochemical expression and promoter methylation in human glioblastoma. Appl Immunohistochem Mol Morphol 2008; 16(1): 59-65.

[13] Cabrera AR, Kirkpatrick JP, Fiveash JB, et al. Radiation therapy for glioblastoma: Executive summary of an American Society for Radiation Oncology Evidence-Based Clinical Practice Guideline. Pract Radiat Oncol 2016; 6(4): 217-225.

[14] Kruser TJ, Bosch WR, Badiyan SN, et al. NRG brain tumor specialists consensus guidelines for glioblastoma contouring. J Neurooncol 2019; 143(1): 157-166.

[15] Stupp R, Hegi ME, Gorlia T, et al. Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma with methylated MGMT promoter (CENTRIC EORTC 26071-22072 study): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol 2014; 15(10): 1100-1108.

[16] Weller M, Lim M, Idbaih A, et al. A randomized phase 3 study of nivolumab or placebo combined with radiotherapy plus temozolomide in patients with newly diagnosed glioblastoma with methyl ated MGMT promoter: CheckMate 548 [abstract]. Neuro Oncol 2021; 23(Suppl 6): vi55-6.

[17] Quan R, Zhang H, Li Z, et al. Survival analysis of patients with glioblastoma treated by long-term administration of temozolomide. Medicine 2020; 99(2): e18591.

[18] Attarian F, Taghizadeh-Hesary F, Fanipakdel A, et al. A systematic review and meta-analysis on the number of adjuvant temozolomide cycles in newly diagnosed glioblastoma. Front Oncol 2021; 11: 779491.

[19] Alimohammadi E, Bagheri SR, Taheri S, et al. The impact of extended adjuvant temozolomide in newly diagnosed glioblastoma multiforme: a meta-analysis and systematic review. Oncol Rev 2020; 14(1): 461.

[20] Wang J, Huang Y, Zhao F, et al. Standard or extended STUPP? Optimal duration of temozolomide for patients with high-grade gliomas: a retrospective analysis. J Neurooncol 2022; 160(2): 433-443.

[21] Gramatzki D, Kickingereder P, Hentschel B, et al. Limited role for extended maintenance temozolomide for newly diagnosed glioblastoma. Neurology 2017; 88(15): 1422-1430.

[22] Lazaridis L, Bumes E, Cäcilia Spille D, et al. First multicentric real-life experience with the combination of CCNU and temozolomide in newly diagnosed MGMT promoter methylated IDH wildtype glioblastoma. Neurooncol Adv 2022; 4(1): vdac137.

• PDF

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.