Purpose: Rechallenge with temozolomide (TMZ) at first progression of glioblastoma after temozolomide chemoradiotherapy (TMZ/RT→TMZ) has been studied in retrospective and single-arm prospective studies, applying temozolomide continuously or using 7/14 or 21/28 days schedules. The DIRECTOR trial sought to show superiority of the 7/14 regimen.
Patients and Methods: Patients with glioblastoma at first progression after TMZ/RT→TMZ and at least two maintenance temozolomide cycles were randomized to Arm A [one week on (120 mg/m2 per day)/one week off] or Arm B [3 weeks on (80 mg/m2 per day)/one week off]. The primary endpoint was median time-to-treatment failure (TTF) defined as progression, premature temozolomide discontinuation for toxicity, or death from any cause. O6-methylguanine DNA methyltransferase (MGMT) promoter methylation was prospectively assessed by methylation-specific PCR.
Results: Because of withdrawal of support, the trial was prematurely closed to accrual after 105 patients. There was a similar outcome in both arms for median TTF [A: 1.8 months; 95% confidence intervals (CI), 1.8–3.2 vs. B: 2.0 months; 95% CI, 1.8–3.5] and overall survival [A: 9.8 months (95% CI, 6.7–13.0) vs. B: 10.6 months (95% CI, 8.1–11.6)]. Median TTF in patients with MGMT-methylated tumors was 3.2 months (95% CI, 1.8–7.4) versus 1.8 months (95% CI, 1.8–2) in MGMT-unmethylated glioblastoma. Progression-free survival rates at 6 months (PFS-6) were 39.7% with versus 6.9% without MGMT promoter methylation.
Conclusions: Temozolomide rechallenge is a treatment option for MGMT promoter-methylated recurrent glioblastoma. Alternative strategies need to be considered for patients with progressive glioblastoma without MGMT promoter methylation. Clin Cancer Res; 1–8. ©2015 AACR.
Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).
M. Weller and G. Tabatabai share first authorship of this article.
G. Reifenberger and W. Wick share senior authorship of this article.
Note: Trial registration ID: NCT00941460.
- Received October 28, 2014.
- Revision received January 21, 2015.
- Accepted January 22, 2015.
- ©2015 American Association for Cancer Research.