Tegwondo-CCNU: A novel combination of protracted, near-continuous temozolomide and CCNU with activity in recurrent malignant gliomas.

Abstract

2079 Background: Recent data have been raising doubt if dose-dense temozolomide is more efficient against malignant gliomas than with conventional dosing. We report here updated results of combined near-continuous temozolomide, aimed at depleting anti-alkylating MGMT, with once weekly application of low-dose lomustine (CCNU) at first or second relapse of malignant gliomas. Methods: 25 consecutive patients with recurrent malignant gliomas (12 anaplastic gliomas WHO III, 13 glioblastomas or gliosarkomas WHO IV) were treated: 15 males (60%), 10 females (40%); mean age at start of chemotherapy was 52 (20-78) years; Eight patients were treated at first, 15 at second and two at third recurrence. All patients were pretreated with temozolomide. Four patients received fractionated, stereotactically guided re-irradiation (FSRT). The treatment regimen consisted of near-continuous temozolomide 50mg/m2 day 1‑5/7 and low-dose CCNU 40mg absolute dose day 6/7. In cases of bone-marrow depression, temozolomide was reduced in steps of 20mg total dose or – in more severe cases – chemotherapy was interrupted until normalization of blood counts. Results: In total, 89 cycles (months) of chemotherapy were applied. The combination was well tolerated in terms of nausea and fatigue. Blood counts usually decreased continuously, enabling a gradual dose adaptation. Hematological WHO grade 3+4 toxicity occurred in 5/25 patients (20%), two of them were symptomatic. Three patients had prolonged elevation of liver enzymes. Best responses after ≥ 3 months (23 patients) were: 2 complete and 1 partial remissions (13%, ), 13 stable diseases (57%), and 7 progressive diseases (30%). Progression-free survival at six months from start of chemotherapy of the 16 patients treated > 6 months or deceased (PFS 6) was 37%, median overall survival 6.3 months. Conclusions: Although some hematotoxicity was observed, the regimen presented here is well tolerated and safe if carefully controlled. The objective responses and considerable rate of stable diseases indicate that this combination is active in malignant gliomas after pretreatment with temozolomide alone. The results have to be controlled in a prospective trial.