Near-continuous temozolomide and low-dose weekly CCNU: A novel chemotherapy regimen with activity in malignant gliomas resistant to dose-dense temozolomide alone.

Abstract

e12544 Background: Alkylating chemotherapy with CCNU is active in recurrent glioma, but may be antagonized by anti-alkylating MGMT. Here, we present feasibility and activity of a novel regimen aiming at depletion of MGMT with lower dose, near-continuous temozolomide followed by low-dose weekly CCNU to treat recurrent malignant gliomas resistant to dose-dense temozolomide. Methods: 11 consecutive patients with recurrent malignant gliomas (4 glioblastomas, 3 gliosarkomas, 4 anaplastic gliomas) were treated: 6 males (55%), 5 females (45%); mean age at first diagnosis was 55.9 (19-76) years; median Karnofsky Performance Status 70%; nine patients were treated for a second, two for first recurrence. All patients were pretreated with dose-dense temozolomide (day 1-21/28 or 1-5/7, initial dose 100 mg/m2). Nine of the 11 patients were switched without delay from dose-dense temozolomide monotherapy to combined near-continuous temozolomide (50-60 mg/m2 day 1-5/7) plus weekly low-dose CCNU (40mg fix dose at day 6/7). Results: in total, 32 cycles of chemotherapy were applied. The combination was well tolerated in terms of nausea and fatigue. Blood counts decreased continuously, enabling a gradual dose adaptation. Hematological WHO grade 3+4 toxicity occurred in 5/11 patients (45%), two of them were symptomatic. One patient had a prolonged elevation of liver enzymes which improved partially after termination of levetiracetam. Best responses after ≥ 2 months were: 1 complete and 2 partial remissions (27%), 3 stable diseases (27%), 5 progressive diseases (46%). Median overall survival after start of chemotherapy was 4.5 months, progression-free survival at six months (PFS 6) was 18%, overall survival from first diagnosis 23.5 months. Conclusions: In spite of adverse prognostic signs, the objective remissions indicate activity of combined near-continuous temozolomide and low-dose weekly CCNU after failure of dose-dense temozolomide alone. Hematotoxicity, though, has to be controlled vigorously. The results have to be controlled in a larger, prospective series. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Schering-Plough Medac Schering-Plough