First multicentric real-life experience with the combination of CCNU and temozolomide in newly diagnosed MGMT promoter methylated IDH wildtype glioblastoma

Abstract

Background: The randomized phase 3 CeTeG/NOA-09 trial assessed whether CCNU plus temozolomide was superior to temozolomide alone in newly diagnosed MGMT promoter methylated glioblastoma patients. Survival was significantly improved from 31.4 months (temozolomide) to 48.1 months (CCNU plus temozolomide). In view of this encouraging data, we assessed safety and efficacy of this regimen under real-life conditions.

Methods: We retrospectively collected clinical and radiographic data from adult newly diagnosed MGMT promoter methylated IDH wildtype glioblastoma patients from five neuro-oncology centers in Germany. For inclusion in our analysis, treatment with CCNU and temozolomide had to be performed for at least six weeks (one course).

Results: Seventy patients were included. Median progression-free survival was 14.4 months and median overall survival 33.8 months. Patients with TTFields treatment for at least 8 weeks and CCNU plus temozolomide (n = 22, 31%) had a prolonged progression-free survival compared to those with TTFields treatment for less than eight weeks (n = 48, 69%) (21.5 versus 11.2 months; P = .0105). In a multivariable Cox regression analysis, TTFields treatment for eight weeks or longer together with CCNU plus temozolomide and a Karnofsky performance score ≥ 90% were independent prognostic factors for progression-free and overall survival. Pseudoprogression occurred in n = 16 (33%) of investigated n = 49 (70%) patients. In n = 31 (44%) patients high-grade hematotoxicity was observed.

Conclusions: The results from this multicentric trial indicate that-under real-life conditions-toxicity and survival estimates are comparable to the CeTeG/NOA-09 trial. TTFields therapy for at least eight weeks in combination with this regimen was independently associated with prolonged survival.

Keywords: CCNU and temozolomide; CeTeG; NOA-09; TTFields; glioblastoma.

Figure 1.

Kaplan–Meier curves and individual patient information. For the full multicentric cohort mPFS was 14.4 months at an event rate of 80% and mOS was 33.8 months at an event rate of 49% (a). The subgroup of patients ≥ 65 years of age did not perform significantly worse in respect to OS and PFS than the patients < 65 years of age (b). For KPS, overall survival appeared slightly longer in patients with a KPS ≥ 90% compared to those with a KPS < 70% (c). In (d) individual patient’s characteristics for all patients as well as comparatively for the subgroup of patients with < 8 weeks TTFields + CeTeG or no TTFields treatment and for the subgroup of patients with ≥ 8 weeks TTFields + CeTeG treatment are illustrated. Treatment in the latter subgroup resulted in a longer median progression-free and overall survival than in the subgroup of patients with < 8 weeks TTFields + CeTeG or no TTFields treatment (e). KPS, Karnofsky performance score; mOS, median overall survival; mPFS, median progression-free survival; No., number; OS, overall survival; PFS, progression-free survival; TTFields, tumor treating fields.

Figure 2.

Multivariable analysis for progression-free and overall survival. Combination of CeTeG + TTFields for at least 8 weeks emerged as the only statistically significant prognostic marker regarding PFS (a). Concerning OS, the combination of CeTeG + TTFields for at least 8 weeks and a KPS of at least 90% emerged as statistically significant prognostic markers. CI, confidence interval; KPS, Karnofsky performance score; No., number; PFS, progression-free survival; OS, overall survival; TTFields, tumor treating fields.