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Improving Overall survival with adjuvant Lomustine-temozolomide in patients with newly diagnosed glioblastoma with methylated MGMT promoter

03 Jul 2019
Central nervous system malignancies
Mohamed Alorabi
Mohamed Alorabi

Glioblastoma multiforme (GBM) is one of the most malignant types of CNS tumors with limited treatment options [1]. The current of standard of treatment for patients with a good performance status is multimodal with surgery, radiation and chemotherapy. However, despite this intensive treatment, patients have a poor prognosis with a progression-free survival (PFS) of 7-8 months, a median survival of 14-16 months and 5-year overall survival (OS) of 9.8% [2, 3]. The addition of tumor-treating fields to temozolomide was associated with moderate improvements in survival [4]. The DNA repair protein O6-Methylguanine-DNA methyltransferase (MGMT) is suggested to be associated with resistance to alkylating agents as Temozolomide [5]. The predictive factor O-6-methylguanine-DNA methyltransferase (MGMT) is now used in treatment decisions because the median OS in patients with MGMT-methylated tumor is 22-26 months compared to 12-15 months in non-MGMT-methylated tumors [6].

Nitrosoureas represent one of the most active classes of agents in the treatment of high-grade gliomas and glioblastoma, and they can penetrate the brain through an intact blood-brain barrier. In clinical practice, the most commonly used compounds are lomustine (either alone or in combination with procarbazine and vincristine), carmustine, and fotemustine [7]. The combination of nitrosoureas with temozolomide can produce different types of DNA damage with potential additive or even synergistic effects [8].

The single-arm phase 2 UKT-03 trial included 31 patients and evaluated the value of combining lomustine with temozolomide in patients with newly diagnosed glioblastoma. the findings from this trial suggested an improved overall survival with a median of 23 months, compared to 15-17 months in historical controls. However, improved overall survival was mostly seen in patients with glioblastoma with methylated MGMT promoter. The median overall survival of these patients was 34·5 months, compared to 23·4 months in patients with non-methylated MGMT promotor.

These data represented a base to start CeTeG/NOA-09 trial. This open-label, randomized, phase 3 trial enrolled 141 patients between June 17, 2011, and April 8, 2014 from 17 German university hospitals who were aged 18-70 years, with newly diagnosed glioblastoma with methylated MGMT promoter, and a Karnofsky Performance Score of 70% and higher. Patients were randomly assigned (1:1) to standard temozolomide chemoradiotherapy (75 mg/m² per day concomitant to radiotherapy [59-60 Gy] followed by six courses of temozolomide 150-200 mg/m² per day on the first 5 days of the 4-week course) or to up to six courses of lomustine (100 mg/m² on day 1) plus temozolomide (100-200 mg/m² per day on days 2-6 of the 6-week course) in addition to radiotherapy (59-60 Gy). Because of the different schedules, patients and physicians were not masked to treatment groups. Median overall survival was improved from 31·4 months (95% CI 27·7-47·1) with temozolomide to 48·1 month with lomustine-temozolomide (hazard ratio [HR] 0·60, 95% CI 0·35-1·03; p=0·0492 for log-rank analysis). A significant overall survival difference between groups was also found in a secondary analysis of the intention-to-treat population (n=141, HR 0·60, 95% CI 0·35-1·03; p=0·0432 for log-rank analysis). Adverse events of grade 3 or higher were observed in 32 (51%) of 63 patients in the temozolomide group and 39 (59%) of 66 patients in the lomustine-temozolomide group. There were no treatment-related deaths.

Authors suggested that lomustine-temozolomide chemotherapy might improve survival compared with temozolomide standard therapy in patients with newly diagnosed glioblastoma with methylated MGMT promoter.

However, the findings should be interpreted with caution, owing to the small size of the trial.

References

  1. Davis ME. Glioblastoma: Overview of Disease and Treatment. Clinical journal of oncology nursing. 2016;20(5 Suppl):S2-S8.
  2. Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, 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. 2009;10(5):459-66.
  3. Michaelsen SR, Christensen IJ, Grunnet K, Stockhausen M-T, Broholm H, Kosteljanetz M, et al. 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. 2013;13(1):402.
  4. Stupp R, Taillibert S, Kanner AA, Kesari S, Steinberg DM, Toms SA, et al. Maintenance therapy with tumor-treating fields plus temozolomide vs temozolomide alone for glioblastoma: a randomized clinical trial. 2015;314(23):2535-43.
  5. Thon N, Kreth S, Kreth F-W. Personalized treatment strategies in glioblastoma: MGMT promoter methylation status. OncoTargets and therapy. 2013;6:1363-72.
  6. Hegi ME, Diserens A-C, Gorlia T, Hamou M-F, De Tribolet N, Weller M, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. 2005;352(10):997-1003.
  7. Brandes AA, Bartolotti M, Tosoni A, Franceschi E. Nitrosoureas in the Management of Malignant Gliomas. Current neurology and neuroscience reports. 2016;16(2):13.
  8. Kohn KWJCr. Interstrand cross-linking of DNA by 1, 3-bis (2-chloroethyl)-1-nitrosourea and other 1-(2-haloethyl)-1-nitrosoureas. 1977;37(5):1450-4.

Discussion question

  1. At your institute, do you have special protocols For newly diagnosed glioblastoma patients with methylated MGMT promoter as extended adjuvant temozolomide?
  2. Based on the results of CeTeG/NOA-09, will you adopt the adjuvant Lomustine-temozolomide for this group of patients?
Last update: 03 Jul 2019

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