Prolonged temozolomide for treatment of glioblastoma: preliminary clinical results and prognostic value of p53 overexpression

Abstract

We report retrospective data on the feasibility and efficacy of prolonging adjuvant temozolomide (TMZ) more than 6 months after chemoradiotherapy completion in patients with glioblastoma (GBM). Molecular prognostic factors were assessed. Data from 46 patients were reviewed. Patients received postoperative irradiation, 60 Gy in 30 fractions, combined with concurrent TMZ, 75 mg/m(2). Four weeks later, adjuvant TMZ was prescribed, 150-200 mg/m(2) for a total of 24 cycles unless there was progression or toxicity. Tumor samples were tested for the following prognostic factors: EGFR overexpression, 1p19q deletion, p53 overexpression and proliferation index. Overall survival (OS) was 84.8% at 6 months, 54.3% at 12 months, 26.1% at 18 months, and 21.7% at 24 months. Progression-free survival (PFS) was 73.9% at 6 months, 34.8% at 12 months, 15.2% at 18 months and 10.4% at 24 months. In the adjuvant phase, no treatment disruption for toxicity was necessary but eight patients required dose adaptation because of side effects. No significant molecular prognostic factor was evidenced for OS. We found that p53 overexpression was the only significant prognostic factor for PFS, with a median PFS of 9.3 months versus 7 months for patients without p53 overexpression (P = 0.031). This study suggests that delivering adjuvant TMZ therapy for more than 6 months is feasible in patients with GBM. Efficacy data warrant further prospective assessment with the focus on molecular prognostic factors, such as p53 overexpression, which was found to be the only significant molecular prognostic factor for outcome.

Carnitine-induced senescence in glioblastoma cells

“…Although initially identified in tumors following radiation or genotoxic chemotherapy (9-11), TIS might also be induced at lower drug doses, in contrast to the higher doses at which DNA damage and apoptotic responses are elicited. Temozolomide is widely used for the treatment of glioblastoma (22,23), and has been reported to induce senescence without apoptosis in melanoma cells (24). The present study demonstrated that carnitine induced senescence in glioma cells.…”

A practical review of prognostic correlations of molecular biomarkers in glioblastoma

“…Some studies support an effect of p53 status on improving prognosis, 31,39,40 while others show a limited impact on clinical outcome. 13,19,45 One study of 46 patients who had received adjuvant radiochemotherapy showed im-biomarkers in glioblastoma proved median PFS (9.3 vs 7 months) in samples without p53 overexpression; however, another study of 220 GBMs did not show a significant difference in median survival between wild-type and mutant p53 GBM tumors (17.0 vs 14.7 months).…”

Pseudoprogression after glioma therapy: a comprehensive review

“…Stricter adherence to adjuvant TMZ in the setting of early post-chemoRT imaging changes (some of which represents PsP) may in part have contributed to the improved outcomes on recent NABTT Phase II studies [16]. However, even with continuation of adjuvant TMZ beyond 6 months, only approximately 35% of the patients remain without progression at 12 months [20]. Patients with progressive HGG should ideally be enrolled in clinical trials.…”