Phase II trial of 7 days on/7 days off temozolmide for recurrent high-grade glioma

Abstract

Background: A phase II trial was performed to evaluate the efficacy of a dose-dense, 7 days on/7 days off schedule of temozolomide for patients with recurrent high-grade gliomas (HGG).

Methods: Sixty patients with recurrent HGG received temozolomide at 150 mg/m(2)/day on days 1-7 and days 15-21 during each 4-week cycle. The primary endpoint was 6-month progression-free survival (PFS-6), with a secondary endpoint of overall survival (OS). A further exploratory objective included the investigation of whether methylation status of the O(6)-methylguanine-DNA methyltransferase (MGMT) promoter within tumor tissue predicted outcomes.

Results: Among patients with glioblastoma (n = 40), PFS-6 was 10% (95% CI, 3%-24%) with median OS of 21.6 weeks (95% CI, 16.9-30.6 weeks). PFS-6 for grade III glioma patients (n = 20) was 50% (95% CI, 27%-73%), and median OS was 100.6 weeks (95% CI, 67 weeks to not reached). There were trends towards longer PFS and OS with MGMT promoter methylation (log-rank test; P = .06 for PFS; P = .07 for OS). Additionally, bevacizumab-naïve glioblastoma patients had significantly longer PFS and OS (median PFS was 8.07 weeks [95% CI, 8 weeks to not reached] vs 7.57 weeks [95% CI, 7.29-8.29 weeks], log-rank test, P < .001; median OS was 62 weeks [26.1 weeks to not reached] vs 18.2 weeks [13.9-27.3 weeks], log-rank test, P < .001).

Conclusions: The dose-dense temozolomide regimen was well tolerated, although it has no significant activity in this population. Clinical trials.gov identified. NCT00619112 (available at https://ichgcp.net/clinical-trials-registry/NCT00619112).

Keywords: bevacizumab; chemotherapy; glioblastoma; glioma; temozolomide.

© The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Figures

Fig. 1.

Progression-free survival (PFS) for grade III and glioblastoma cohorts. Median PFS for grade III was 31.3 weeks (95% CI, 8.43–73.9 weeks); median PFS for glioblastoma was 8.0 weeks (95% CI, 7.57–8.29 weeks). P = .007.

Fig. 2.

Overall survival (OS) for grade III and glioblastoma cohorts. Median OS for grade III was 100.6 weeks (95% CI, 67 weeks to not reached); median OS for glioblastoma was 21.6 weeks (95% CI, 16.9–0.6 weeks). P < .001.

Fig. 3.

Progression-free survival (PFS) for recurrent glioblastoma patients (n = 40) who were bevacizumab naïve (n = 14) and those who had previously failed bevacizumab (n = 26). Median PFS for bevacizumab naïve was 8.07 weeks (95% CI, 8 weeks to not reached); median PFS for bevacizumab-failed was 7.57 weeks (95% CI, 7.29–8.29 weeks). P = .02.

Fig. 4.

Overall survival (OS) for recurrent glioblastoma patients (n = 40) who were bevacizumab naïve (n = 14) and those who had failed bevacizumab (n = 26). Median OS for bevacizumab-failed was 18.2 weeks (95% CI, 13.9–27.3 weeks); median OS for bevacizumab-naïve was 62 weeks (95% CI, 26.1 weeks to not reached). P =.001.

Fig. 5.

Progression-free survival (PFS) based on tumor MGMT promoter methylation status. Median PFS for methylated MGMT:was 11.6 weeks (95% CI, 8.14–49.6 weeks); median PFS for unmethylated MGMT was 7.57 weeks (95% CI, 7.29–9.00 weeks). P = .06.

Fig. 6.

Overall survival (OS) based on tumor MGMT promoter methylation status. Median OS for methylated MGMT was 65.3 weeks (95% CI, 40.4 weeks to not reached); median OS for unmethylated MGMT was 19.4 weeks (95% CI, 16.1–55.3 weeks). P = .07.

Fig. 7.

Progression-free survival (PFS) based on grade III tumor MGMT promoter methylation status. Median PFS for methylated MGMT was 38.1 weeks (95% CI, 10.71 weeks to not reached); median PFS for unmethylated MGMT was 48.6 weeks (95% CI, 6.86 weeks to not reached). P = .79.

Fig. 8.

Overall survival (OS) based on grade III tumors MGMT promoter methylation status. Median OS for methylated MGMT was 94.6 weeks (95% CI, 65.3 weeks to not reached); median OS for unmethylated MGMT was 100.6 weeks (No CI due to small sample size). P = .46.

Fig. 9.

Progression-free survival (PFS) based on GB tumor MGMT promoter methylation status. Median PFS for methylated MGMT was 8.14 weeks (95% CI, 7.71 weeks to not reached); median PFS for unmethylated MGMT was 7.57 weeks (95% CI, 7.29–9 weeks). P = .22.

Fig. 10.

Overall survival (OS) based on GB tumors MGMT promoter methylation status. Median OS for methylated MGMT was 28.9 weeks (95% CI, 2.34 weeks to not reached); median OS for unmethylated MGMT was 16.9 weeks (95% CI, 14.0–42.4 weeks). P = .33.