Temozolomide administered daily for a total of five doses demonstrated marked activity against a panel of Mer+ xenografts despite marginal to moderate activity of 1,3-bis(2-chloroethyl)-1-nitrosourea. The growth delays produced by temozolomide in these xenografts were 1.8-7.5-fold greater than those produced by procarbazine. Although temozolomide demonstrated marginal activity against the Mer+ cell line D341 Med when a 5-day schedule was used, a high-dose 1-day schedule resulted in moderate activity. Temozolomide produced increases in median survival of 1285% (adult glioma D-54 MG), 323% (childhood glioma D-456 MG), and 68% (ependymoma D612 EP). Pretreatment of mice with O6-benzylguanine increased temozolomide-induced mortality, requiring reduction of the dosage from 1200 to 750 mg/m2 on the single-day regimen. O6-Benzylguanine pretreatment of mice bearing Mer+ D341 Med increased the growth delay of temozolomide, in duplicate experiments, from -3.1 to 4.8 and 1.1 to 4.9 days. These studies suggest that temozolomide may be active in the treatment of a broad spectrum of central nervous system cancers, including Mer+ tumors resistant to 1,3-bis(2-chloroethyl)-1-nitrosourea 1).
Eighteen patients (median age, 42 y), with either WHO grade III (10) or grade II (8) ependymoma were evaluable. Tumor location at diagnosis was supratentorial in 11 patients and infratentorial in 7. Progression before TMZ was local in 11 patients, local and spinal in 6 patients, and spinal only in one patient. A median of 8 cycles of TMZ (1-24) was administered. Response to TMZ consisted of complete response (CR) in one (5%) patient, partial response (PR) in 3 (17%) patients, stable disease (SD) in 7 (39%) patients, and progressive disease (PD) in 7 (39%) patients. Maximum response occurred after 3, 10, 14, and 15 cycles, respectively, with neurological improvement in 2 patients. All 4 responding patients were chemotherapy naïve. Both anaplastic (2) and grade II (2) tumors responded. Median progression-free survival and overall survival were 9.69 months (95% CI, 3.22-30.98) and 30.55 months (95% CI, 12.85-52.17), respectively. MGMT methylation was available in 11 patients and was not correlated with response or outcome.
TMZ has a role in recurrent chemo-naïve adult patients with intracranial ependymoma, regardless of tumor grade and MGMT methylation. We suggest that, after failure of surgery and radiotherapy, TMZ should be considered as a possible first-line treatment for recurrent ependymoma 2).
A total of 25 patients, ages 28 to 63 years, with recurrent ependymoma were treated. All patients had previously been treated with surgery, radiotherapy, and platinum-based chemotherapy (cisplatin in 15 patients and carboplatin in 10 patients). Nine patients underwent repeat surgery. Patients were treated at the time of second recurrence with TMZ (5 consecutive days), once every 4 weeks, which was defined as a single cycle. Neurologic evaluation was performed every 4 weeks and neuroradiographic assessment every 8 weeks.
A total of 68 cycles of TMZ (median, 2 cycles; range, 1-6 cycles) was administered. TMZ-related toxicity included leukopenia (7 patients; 1 with grade 3 [grade was determine according to National Cancer Institute Common Toxicity Criteria [version 3.0]), constipation (6 patients; none with grade 3), fatigue (5 patients; none with grade 3), anemia (2; none with grade 3), thrombocytopenia (2; none with grade 3), and deep vein thrombosis (2; none with grade 3). One patient (4%) demonstrated a partial radiographic response, 9 (36%) had stable disease, and 15 (60%) developed progressive disease after 2 cycles of TMZ. Time to tumor progression ranged from 1 to 7 months (median, 2 months). Survival ranged from 2 to 8 months (median, 3 months). The 6-month and 12-month PFS were 2% and 0%, respectively.
TMZ in this dose schedule demonstrated little efficacy in a cohort of adults with recurrent, intracranial, platinum-refractory ependymoma 3).
A 25-year-old female patient with multifocal recurrence of a supratentorial malignant ependymoma administered temozolomide as second-line therapy is reported. Currently, 5 months after initiation of temozolomide treatment, there is no evidence of radiographic progression 4).