Treatment of recurrent malignant glioma, which has a poor patient prognosis, has not been standardised. Moreover, it is unclear whether repeated treatment with temozolomide is effective in patients who received previous temozolomide treatment before developing a recurrence. Here, we present the results of a high-dose individually adapted 21-day regimen demonstrating that rechallenge is effective even in patients expressing O6-methylguanine-DNA methyltransferase (MGMT) in the tumor. Twenty-one patients with recurrent malignant gliomas pre-treated with temozolomide, 18 WHO IV glioblastoma (GBM) and 3 WHO III patients, received 100 mg/m2 temozolomide on days 1-21/28. The GBM patients had a median Karnofsky performance status of 60% and a median age of 54.8 years. Blood counts decreased continuously, enabling a gradual dose adaptation. When blood counts dropped below normal values, temozolomide was applied on days 1-5/7. Dosage was reduced to 50-75 mg/m2 in 11 patients and gradually increased up to 130 mg/m2 in 3 patients. WHO grade 3/4 toxicity was hematological in 3 patients and non-hematological in 3 patients. In GBM patients (n=18), response after >3 months was complete in 3 patients, partial in 1 (22%), stable disease in 7 (39%) and progressive disease in 7 (39%). Progression-free survival at 6 months (PFS-6M) was 39%. Median survival was 9.1 months from relapse and 17.9 months overall. Of the patients with unmethylated MGMT promoter, 2/7 were progression-free for >6 (15 and 19) months. The data indicate that rechallenge with near-continuous, higher-dose temozolomide (100 mg/m2 on days 1-21/28 or days 1-5/7 with individual dose adaptation) is also feasible in patients with critical blood counts. Objective responses can be achieved even after relapse during a conventional 5/28-day regimen. The resistance of tumors characterized by unmethylated MGMT promoter may be overcome by near continuous temozolomide administration, which is probably most effective with a 5/7-day schedule. In spite of the relatively poor clinical prognosis, the data indicate that rechallenge with temozolomide with a dose-dense and long-lasting administration protocol is tolerable and comparable with other reported treatment protocols involving temozolomide.

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