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Standard of Care

Standard treatment for newly diagnosed glioblastoma consists of maximal safe surgical resection followed by radiotherapy with concurrent and adjuvant temozolomide. The literature below covers the evidence supporting this regimen, the importance of MGMT promoter methylation, temozolomide duration and dosing, and the addition of lomustine for selected patients.

Highlighted Papers

Stupp et al., 2005 — Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma

This landmark phase III trial established radiotherapy with concurrent and adjuvant temozolomide as the standard treatment for newly diagnosed glioblastoma. Median overall survival increased from 12.1 to 14.6 months, while two-year survival increased from 10.4% to 26.5%.

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Hegi et al., 2005 — MGMT Gene Silencing and Benefit from Temozolomide

This analysis showed that patients with MGMT-methylated tumours derive the clearest benefit from temozolomide. It established MGMT promoter methylation as an important biomarker for prognosis and treatment selection.

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Bhandari et al., — Comparative Study of Adjuvant Temozolomide Six Cycles Versus Extended 12 Cycles in Newly Diagnosed Glioblastoma Multiforme. 

This small randomized study compared six versus 12 cycles of adjuvant temozolomide in 40 patients. Twelve cycles were associated with longer median overall survival (23.8 vs 15.4 months), while the progression-free survival difference was not statistically significant; the limited sample size means the findings require confirmation.

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Herrlinger et al., 2019 — "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"

This phase III trial investigated lomustine–temozolomide as an alternative to standard temozolomide for selected patients with MGMT-methylated glioblastoma. Median overall survival was 48.1 versus 31.4 months, but the trial was relatively small and the combination produced greater toxicity.

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Gupta et al., 2023 — "Updated Systematic Review and Meta-analysis of Extended Adjuvant Temozolomide"

This review found an apparent benefit from extended temozolomide when all available studies were combined. However, the observed benefit was largely driven by non-randomised evidence, highlighting the risk of selection and survivor bias.

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Lakomy et al., 2020 — "Real-World Evidence in Glioblastoma: Stupp’s Regimen After a Decade"

This retrospective study examined outcomes after implementation of the Stupp regimen in routine clinical practice. The results support its effectiveness outside the more selective population of a clinical trial.

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Further Literature

  • Alimohammadi, E., Bagheri, S. R., Taheri, S., Dayani, M., Abdi, A. (2020): The impact of extended adjuvant temozolomide in newly diagnosed glioblastoma multiforme: a meta-analysis and systematic review. Oncol Rev. 2020 Feb 18;14(1):461. https://doi.org/10.4081/oncol.2020.461

  • Attarian, F., Taghizadeh-Hesary, F., Fanipakdel, A. et al. (2021): A Systematic Review and Meta-Analysis on the Number of Adjuvant Temozolomide Cycles in Newly Diagnosed Glioblastoma. Front. Oncol. 2021 Nov 23; 11:779491. https://doi.org/10.3389/fonc.2021.779491

  • Balana, C. Optimal duration of adjuvant temozolomide in glioblastoma: An unsolved and unsolvable problem, Neuro-Oncology Practice, Volume 9, Issue 5, October 2022, Pages 349–350, https://doi.org/10.1093/nop/npac054

  • Balana, C., Vaz, M. A, Sepúlveda, et al. (2020): 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 Dec 18;22(12):1851-1861. https://doi.org/10.1093/neuonc/noaa107Top of Form

  • Blumenthal, D. T., Gorlia, T., Gilbert, M. R. et al. (2017): Is more better? The impact of extended adjuvant temozolomide in newly diagnosed glioblastoma: a secondary analysis of EORTC and NRG Oncology/RTOG. Neuro Oncol. 2017 Aug 1;19(8):1119-1126. https://doi.org/10.1093/neuonc/nox025

  • Das, S., Sahgal, A., Perry, J.R. (2020): Commentary: 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. Front. Oncol. 2020, 10:66. https://doi.org/10.3389/fonc.2020.00066

  • Gupta, T., Selvarajan, J. M. P., Kannan, S. et al. (2023): Updated systematic review and meta-analysis of extended adjuvant temozolomide in patients with newly diagnosed glioblastoma. Neurooncol Adv. 2023 Jul 13;5(1):vdad086. https://doi.org/10.1093/noajnl/vdad086

  • Ho, K. G., Uhlmann, E. N., Wong, E. T., Uhlmann, E. J. (2020): Leukopenia is a biomarker for effective temozolomide dosing and predicts overall survival of patients with glioblastoma. Mol Clin Oncol. 2020 Dec;13(6):80. https://doi.org/10.3892/mco.2020.2150

  • Jezierzańnski, M., Nafalska, N., Stopyra, M., Furgoł, T., Miciak, M.,,Kabut, J., Gisterek-Grocholska, I. (2024): Temozolomide (TMZ) in the Treatment of Glioblastoma Multiforme - A Literature Review and Clinical Outcomes. Curr. Oncol. 2024, 31, 3994–4002. https://doi.org/10.3390/curroncol31070296

  • Karve, A.S., Desai, J. M., Gadgil, S. N., Dave, N., Wise-Draper, T. M., Gudelsky, G. A., Phoenix, T. N., DasGupta, B., Yogendran, L., Sengupta, S., et al. (2024): A Review of Approaches to Potentiate the Activity of Temozolomide against Glioblastoma to Overcome Resistance. Int. J. Mol. Sci. 2024, 25, 3217. https://doi.org/10.3390/ijms25063217

  • Kordyukova, M. Y., Bulgakov, T. K., Sorokina, M. A., Kudryashova, O. M., Abakumova, T. O., Meshcheryakova, V. I., Grigoriev, I. V., Senko, I. V., Shevchenko, E. K Belousov, V. V.(2026):  Overcoming Chemoresistance in Glioblastoma: Mechanisms, Therapeutic Strategies, and Functional Precision Medicine. International Journal of Molecular Sciences. 2026; 27(5):2207. https://doi.org/10.3390/ijms27052207

  • Lakomy R., Kazda T., Selingerova I., Poprach A., Pospisil P., Belanova R., Fadrus P., Vybihal V., Smrcka M., Jancalek R., Hynkova L., Muckova K., Hendrych M., Sana J., Slaby O. and Slampa P. (2020): Real-World Evidence in Glioblastoma: Stupp’s Regimen After a Decade. Front. Oncol. 10:840. doi: 10.3389/fonc.2020.00840 Frontiers | Real-World Evidence in Glioblastoma: Stupp's Regimen After a Decade

  • Lazaridis, L., Bumes, E et al. (2022): First multicentric real-life experience with the combination of CCNU and temozolomide in newly diagnosed MGMT promoter methylated IDH wildtype glioblastoma. Neurooncol Adv. 2022 Aug 24;4(1):vdac137. https://doi.org/10.1093/noajnl/vdac137

  • Penas-Prado, M., Hess, K. R., Fisch, M. J., et al. (2015): Randomized phase II adjuvant factorial study of dose-dense temozolomide alone and in combination with isotretinoin, celecoxib, and/or thalidomide for glioblastoma. Neuro Oncol. 2015 Feb;17(2):266-273. https://doi.org/10.1093/neuonc/nou155

  • Raghu, A., Killar, S. & Cohen, A.L. (2026): Effects of temozolomide dosing on outcome in glioblastoma. J Neurooncol 176, 89 (2026). https://doi.org/10.1007/s11060-025-05324-2

  • Refae, A. A., Ezzat, A., Salem, D., et al. (2015): Protracted adjuvant temozolomide in glioblastoma multiforme. Journal of Cancer Therapy, Vol.6 No.8, 2015:748–758. http://doi.org/10.4236/jct.2015.68082

  • Sepulveda, J. M. et al. (2025): Azeliragon, a RAGE inhibitor, in combination with temozolomide and radiotherapy in patients with newly diagnosed glioblastoma: Preliminary results of phase Ib/II CAN-201 NDG trial.. J Clin Oncol 43, 2069-2069(2025). https://doi.org/10.1200/JCO.2025.43.16_suppl.2069

  • Stupp R., M.D., Mason W.P., M.D., Van den Bent M.J., M.D. et al. (2005): Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma. N Engl J Med 2005;352:987-96. https://www.nejm.org/doi/full/10.1056/NEJMoa043330

  • Stupp R., MD; Taillibert S., MD; Kanner A., MD et al. (2017): Effect of Tumor-Treating Fields Plus Maintenance Temozolomide vs Maintenance Temozolomide Alone on Survival in Patients With Glioblastoma: A Randomized Clinical Trial. JAMA.2017;318(23):2306-2316. doi:10.1001/jama.2017.18718. https://jamanetwork.com/journals/jama/fullarticle/2666504

  • Stupp, R., Taillibert, S., Kanner, A. A., et al. (2015): Maintenance Therapy With Tumor-Treating Fields Plus Temozolomide vs Temozolomide Alone for Glioblastoma: A Randomized Clinical Trial. JAMA. 2015;314(23):2535–2543. https://doi.org/10.1001/jama.2015.16669

  • Struve, N., Binder, Z. A., Stead, L. F. et al. (2020): EGFRvIII upregulates DNA mismatch repair resulting in increased temozolomide sensitivity of MGMT promoter methylated glioblastoma. Oncogene 39, 3041–3055 (2020). https://doi.org/10.1038/s41388-020-1208-5

  • Roh Tae Hoon, Moon Ju Hyung, Kim Se Hoon, Park Hun Ho, Kim Eui Hyun, Hong Chang‑Ki, Kang Seok‑Gu, Chang Jong Hee (2020): Association between survival and levetiracetam use in glioblastoma patients treated with temozolomide chemoradiotherapy. Nature Research. Scientific RepoRtS (2020) 10:10783. https://doi.org/10.1038/s41598-020-67697-w

  • Taal, W. (2015): Chemotherapy in Glioma. PhD Thesis, Erasmus University Rotterdam 2015. https://repub.eur.nl/pub/78961/Proefschrift_WalterTaal_bib.pdf

  • Taal, W., Bromberg, J. E., van den Bent, M. J. (2015): Chemotherapy in glioma. CNS Oncol. 2015;4(3):179-92. https://doi.org/10.2217/cns.15.2

  • Weller, J., Schäfer, N., Schaub, C. et al. (2023): Patterns, predictors and prognostic relevance of high-grade hematotoxicity after temozolomide or temozolomide-lomustine in the CeTeG/NOA-09 trial. J Neurooncol 161, 147–153 (2023). https://doi.org/10.1007/s11060-022-04203-4

  • Weller, J., Tzaridis, T,, Mack, F. et al. (2019): Health-related quality of life and neurocognitive functioning with lomustine-temozolomide versus temozolomide in patients with newly diagnosed, MGMT-methylated glioblastoma (CeTeG/NOA-09): a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol. 2019;20(10):1444-1453. https://doi.org/10.1016/S1470-2045(19)30502-9

  • Xu, H., Yu, S., Wang, C., et al. (2024): Extended cycles of adjuvant temozolomide improves survival outcomes in glioblastoma: a retrospective analysis. Journal of Cancer Metastasis and Treatment, 2024 10: 24. https://doi.org/10.20517/2394-4722.2024.51

  • Zeyen T, Treiber A, Schneider M, Potthoff AL, Schaub C, Roever L, Layer JP, Gkika E, Vatter H, Paech D, Radbruch A, Schaefer N, Herrlinger U, Weller J. (2025): Second-line temozolomide in first recurrent MGMT-methylated glioblastoma after lomustine/temozolomide: Efficacy and safety. Neurooncol Adv. 2025 Apr 28;7(1):vdaf084. https://doi.org/10.1093/noajnl/vdaf084

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