Phase 2 study of dose-intense temozolomide in recurrent glioblastoma

Abstract

Background: Among patients with glioblastoma (GBM) who progress on standard temozolomide, the optimal therapy is unknown. Resistance to temozolomide is partially mediated by O(6)-methylguanine-DNA methyltransferase (MGMT). Because MGMT may be depleted by prolonged temozolomide administration, dose-intense schedules may overcome resistance.

Methods: This was a multicenter, phase 2, single-arm study of temozolomide (75-100 mg/m(2)/day) for 21 days of each 28-day cycle. Patients had GBM in first recurrence after standard therapy. The primary end point was 6-month progression-free survival (PFS6).

Results: Fifty-eight participants were accrued, 3 of whom were ineligible for analysis; one withdrew before response assessment. There were 33 men (61%), with a median age of 57 years (range, 25-79 years) and a median Karnofsky performance score of 90 (range, 60-100). Of 47 patients with MGMT methylation results, 36 (65%) had methylated tumors. There were 7 (13%) partial responses, and PFS6 was only 11%. Response and PFS did not depend on MGMT status; MSH2, MLH1, or ERCC1 expression; the number of prior temozolomide cycles; or the time off temozolomide. Treatment was well tolerated, with limited grade 3 neutropenia (n = 2) or thrombocytopenia (n = 2).

Conclusions: Dose-intense temozolomide on this schedule is safe in recurrent GBM. However, efficacy is marginal and predictive biomarkers are needed.

Keywords: MGMT promoter methylation; dose-intense temozolomide; recurrent glioblastoma.

Fig. 1.

Kaplan-Meier curve showing progression-free and overall survival for the full cohort.

Fig. 2.

Expression of DNA repair enzymes stratified by progression-free survival (PFS). MSH2 (A), MLH1 (B), and ERCC1 (C) intensities did not differ between PFS <4 and ≥4. H-scores for MSH2 (D), MLH1 (E), and ERCC1 (F) revealed no significant differences between PFS <4 and ≥4.

Fig. 3.

Correlations between MSH2 and MLH1. In cases with progression-free survival (PFS) < 4, the correlation between MSH2 and MLH1 (A) demonstrated an R² of 0.1178. In contrast, a more positively inflected correlation between MSH2 and MLH1 was seen in cases with PFS ≥ 4 had an R² of 0.3847.