Phase II Trial of Continuous Dose-Intense Temozolomide in Recurrent Malignant Glioma: RESCUE Study

Abstract

PURPOSE Concomitant temozolomide (TMZ)/radiotherapy followed by adjuvant TMZ has increased survival in patients with glioblastoma multiforme (GBM). However, few options are effective for patients who experience treatment failure. We conducted a multicenter, phase II study to assess the efficacy and safety of continuous dose-intense TMZ for recurrent GBM. PATIENTS AND METHODS Patients with malignant glioma at progression after standard TMZ 150 to 200 mg/m(2) x 5 days in a 28-day cycle for three or more cycles were stratified by tumor type (anaplastic glioma group A, GBM, group B). Ninety-one patients with GBM were prospectively divided into three groups (early [B1], extended [B2], and rechallenge [B3]) according to the timing of progression during adjuvant therapy. All patients received continuous dose-intense TMZ 50 mg/m(2)/d for up to 1 year or until progression occurred. Response was assessed by using RECIST (Response Evaluation Criteria in Solid Tumors). Results A total of 116 of 120 patients were evaluable for efficacy. For patients with GBM, 6-month progression-free survival (PFS) was 23.9% (B1, 27.3%; B2, 7.4%; B3, 35.7%). One-year survival from time of study entry was 27.3%, 14.8%, and 28.6% for the B1, B2 and B3 groups, respectively. For patients with anaplastic glioma, 6-month PFS was 35.7%; 1-year survival was 60.7%. The most common grades 3 and 4 nonhematologic toxicities were nausea/vomiting (6.7%) and fatigue (5.8%). Grades 3 and 4 hematologic toxicities were uncommon. CONCLUSION Rechallenge with continuous dose-intense TMZ 50 mg/m(2)/d is a valuable therapeutic option for patients with recurrent GBM. Patients who experience progression during the first six cycles of conventional adjuvant TMZ therapy or after a treatment-free interval get the most benefit from therapy.

EANO guideline for the diagnosis and treatment of anaplastic gliomas and glioblastoma

“…The activity of CCNU has been confirmed in the standard arms of randomized trials exploring the activity of the protein kinase C-β inhibitor, enzastaurin, 46 or the vascular endothelial growth factor (VEGF) receptor inhibitor, cediranib, 47 with progression-free survival rates at 6 months of 20%. Somewhat better control rates at 6 months have been reported with a continuous dosing regimen of TMZ, 48 but not in recent phase II trial exploring a 21 out of 28 days schedule. 49 The BR12 trial which enrolled recurrent, TMZ-naïve malignant glioma patients provided no evidence for superiority of dose-intensified TMZ over standard-dosed TMZ, 50 but these data are of limited value in assessing the role of TMZ rechallenge for patients pre-exposed to TMZ.…”

Therapeutic options in recurrent glioblastoma—An update

“…on angiogenesis. The main alternative schedules (Table 2) cycles of adjuvant TMZ and those patients with a treatment-free interval longer than 2 months showed comparable PFS-6 rates of 27.3 and 35.7% (median PFS 3.6 and 3.7 months) deriving more benefit than those patients receiving TMZ beyond the standard 6 adjuvant cycles but without a treatment-free interval (PFS-6 7.4%, median PFS 1.8 months) [68].…”

Standard Therapy for Glioblastoma- A Review of Where We Are

“…20,33) Due to its usage as the first-line treatment of GBM, TMZ has been no longer considered by many investigators to be a reasonable choice for patients with recurrent GBM. However, alternative schedules of TMZ addressing different pathophysiological mechanisms could be effective even after progression during standard TMZ regimens.…”