Rechallenge of malignant gliomas with Temozolomide – can it be effective?

No standard treatment of recurrent malignant glioma is established. Moreover, it is unclear if rechallenge with Temozolomide is effective. We present here feasibility and first treatment results of a dose dense, individually dose adapted 21-day regimen with Temozolomide for recurrent malignant gliomas.

18 consecutive patients with recurrent malignant gliomas (15 glioblastomas [GBM], 2 anaplastic astrocytomas, 1 anaplastic oligodendroglioma) were treated. The basic data are: median time to first relapse 9.1 months; median Karnofsky Performance Status 60% (9×50+60%; 9×70–100%); median age 51 (32–73) years; gender: 11 males (61%), 7 females (39%). All patients were pretreated with Radiochemotherapy and Temozolomide 200mg/m² days 1–5/28 in first line. In eight of the 18 patients, therapy was switched without delay from the conventional 5/28-day regimen to the dose-dense schedule: Temozolomide 100mg/m² day 1 21/28. The dosage was adapted individually, aiming towards total leukocyte counts of approximately 4,000/µL.

Results: The 21/28 days regimen was better tolerated than the 5/28 days schedule in terms of nausea and fatigue. Blood counts decreased continuously, enabling a gradual dose adaptation. The dosage was kept at 100mg/m² in 10 patients, reduced to 75mg/m² in 7 and gradually increased to 130mg/m² in 1 patient. Hematotoxicity was WHO grade 3 in 2 patients and grade 4 in 1 patient without clinical signs. One patient had a pneumonia WHO grade 4 in the terminal stage of the disease several weeks after discontinuation of the chemotherapy. One other patient had a prolonged constipation.

Response after 3 months in 11 GBM patients was: 1 partial and 1 complete remission (18%), 4 stable diseases (36%), 5 progressive diseases (45%). In the 9 glioblastoma patients with an observation period of more than 6 months, the progression free survival at 6 months (PFS 6) was 44%; the median PFS after relapse was 17.4 weeks; median survival after relapse was 33.6 weeks; median overall survival 13.4+ months.

Second-line treatment with dose-dense Temozolomide at 100mg/m² day 1–21/28 and individual dose adaptation is feasible for recurrent malignant gliomas. Even in this series with relatively unfavourable prognostic criteria, the rate of objective responses and PFS 6 compare well with other series. We conclude that rechallenge with a dose-dense schedule of Temozolomide can be effective. The results will be controlled in a prospective study.