Abstract
<div>Abstract<p><b>Purpose:</b> 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.</p><p><b>Experimental Design:</b> 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/m<sup>2</sup> per day)/one week off] or Arm B [3 weeks on (80 mg/m<sup>2</sup> 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. O<sup>6</sup>-methylguanine DNA methyltransferase (<i>MGMT</i>) promoter methylation was prospectively assessed by methylation-specific PCR.</p><p><b>Results:</b> 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 <i>MGMT</i>-methylated tumors was 3.2 months (95% CI, 1.8–7.4) versus 1.8 months (95% CI, 1.8–2) in <i>MGMT</i>-unmethylated glioblastoma. Progression-free survival rates at 6 months (PFS-6) were 39.7% with versus 6.9% without <i>MGMT</i> promoter methylation.</p><p><b>Conclusions:</b> Temozolomide rechallenge is a treatment option for <i>MGMT</i> promoter-methylated recurrent glioblastoma. Alternative strategies need to be considered for patients with progressive glioblastoma without <i>MGMT</i> promoter methylation. <i>Clin Cancer Res; 21(9); 2057–64. ©2015 AACR</i>.</p></div>
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