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DOI: 10.1055/s-0028-1086680
Tegwondo – development of a novel near-continuous dose-dense temozolomide regimen for the treatment of recurrent gliomas
Background: We report on activity and feasibility of a rechallenge of recurrent gliomas with temozolomide (TMZ) in a dose-dense 21/28-day regimen and development of a novel 5/7-day schedule.
Methods: 40 recurrent glioma-patients received TMZ 100mg/m2 with individual dose adaptation: 21 pts. received 148 cycles day 1–21/28 (18 WHO IV [GBM], 3 WHO III). GBM-pts. had a mean age of 54.4y, median KPS was 60%.
Patients with critical blood counts (˜50%) were switched to a 1 5/7-day regimen. Better tolerability led us to treat 19 subsequent patients initially day 1–5/7: 13 GBM, 2 WHO-III, 4 WHO-II; 55.5 y, KPS 70%, total 61 cycles.
All malignant gliomas were pretreated with temozolomide.
Results: nausea and fatigue were less frequent than with the 5/28-day schedule. Blood counts usually decreased continuously. Dosage was reduced in approx. 50% of patients and increased to up to 130mg/m2 in 3 patients. Hematotoxicity grade ¾ (asymptomatic): 2/21 pts. (21/28-day) and 2/19 pts. (5/7-day); nonhematological ¾°: 4/21 Pts. (21/28), 0/19 (5/7).
Efficacy of 21/28-day application in GBM was: 2 CR (11%), 2 PR (11%), 7 SD (39%) and 7 PD (39%) at ≥3 months. 38.8% were progression-free at 6 months. Survival after relapse was 34.8 weeks, overall 17.9 months. MGMT-status was available from 7 tumors: 2/4 pts. with unmethylated MGMT were progression-free ≥12 months, but only 1/3 with methylated MGMT.
Conclusions: Rechallenge of recurrent gliomas with dose-dense temozolomide at 100mg/m2 and individual dose adaptation is feasible and active. 22% objective long-term responses demonstrate that this strategy is effective even with unfavorable prognostic criteria. Dose adaptation is most appropriate with a near-continuous application day 1–5/7, which is expected to cause permanent depletion of the alkylation-resistance factor MGMT. In fact, also patients with unmethylated MGMT had long-term responses, indicating that chemotherapy resistance may be overcome with this strategy. We therefore consider TEGWONDO (TEmozolomide in the Glioma WOrkiNgday DOse-dense regimen) to be active and feasible also in TMZ-pretreated patients with critical blood counts.