Phase I and pharmacokinetic study of preirradiation chemotherapy with BCNU, cisplatin, etoposide, and accelerated radiation therapy in patients with high-grade glioma

Abstract

Purpose: We conducted a Phase I study of bischloroethylnitrosourea (BCNU), cisplatin, and oral etoposide administered prior to and during accelerated hyperfractionated radiation therapy in newly diagnosed high-grade glioma. Pharmacokinetic studies of oral etoposide were also done.Methods and Materials: Patients started chemotherapy after surgery but prior to definitive radiation therapy (160 cGy twice daily × 15 days; 4800 cGy total). Initial chemotherapy consisted of BCNU 40 mg/m2 days 1–3, cisplatin 30 mg/m2 days 1–3 and 29–31, and etoposide 50 mg orally days 1–14 and 29–42, repeated in 8 weeks concurrent with radiation therapy. BCNU 200 mg/m2 every 8 weeks × 4 cycles was given after radiation therapy.Results: Sixteen patients, 5 with grade 3 anaplastic astrocytoma and 11 with glioblastoma were studied. Grade 3–4 leukopenia (38%) and thrombocytopenia (31%) were dose-limiting. Other toxicities were anorexia (81%), nausea (94%), emesis (56%), alopecia (88%), and ototoxicity (38%). The maximum tolerated dose was BCNU 40 mg/m2 days 1–3, cisplatin 20 mg/m2 days 1–3 and 29–31, and oral etoposide 50 mg days 1–21 and 29–49 prior to radiation therapy and repeated in 8 weeks with the start of radiation therapy followed by BCNU 200 mg/m2 every 8 weeks for 4 cycles. Median time to progression and survival were 13 and 14 months respectively. Responses occurred in 2 of 9 (22%) patients with evaluable disease. In pharmacokinetic studies, all patients achieved plasma concentrations of >0.1 μg/ml etoposide (the in vitro radiosensitizing threshold), following a 50 mg oral dose. The mean ± SD 2 hr and 6 hr plasma concentrations were 0.92 ± 0.43 μg/ml and 0.36 ± 0.12 μg/ml, respectively. Estimated duration of exposure to >0.1 μg/ml etoposide was 10–17 hr.Conclusions: Preirradiation chemotherapy with BCNU, cisplatin, and oral etoposide with accelerated hyperfractionated radiation therapy in high-grade gliomas is feasible and merits further investigation. Sustained radiosensitizing concentrations can be achieved with low oral doses of etoposide.