Phase II Study of Fractionated Daily Doses of Oral Etoposide in Patients With Stage IV Breast Cancer Refractory to Multiple Chemotherapy Regimens

Abstract

Etoposide is an inhibitor of the nuclear topoisomerase II enzyme, which produces objective tumor responses in about 10% of patients with metastatic breast cancer failing to standard chemotherapy regimens. Fractionated oral administration of etoposide causes significant increase in tissue drug exposure, leading to a better therapeutic index. In this paper, the outcomes of a Phase II trial of fractionated oral daily doses of etoposide conducted in 20 women with metastatic breast cancer, who progressed following multiple chemotherapy regimens, are described. Eligible patients were those between 18-75 years old, ECOG performance status between 0-2, confirmed histopathological diagnosis of breast cancer, presence of visceral involvement, no vital organs dysfunction and no CNS involvement. A written informed consent was required, in accordance with the local IRB and the Ministry of Health of Brazil. The content of an ampoule for IV use was administered orally, at the dose of 20 mg/m2, every eight hours, diluted in a low pH fluid (orange or grape juice), daily for 14 consecutive days, followed by a 7-day rest. Patients were reviewed every 21 days for toxicity (NCI-CTC criteria), and every 42 days for tumoral response (RECIST criteria). Patients were treated until tumor progression, dose-limiting toxicity or own desire to interrupt the treatment. Twenty patients were included in the trial, and a total of 55 treatment cycles administered with a median of two cycles per patient (1-10) was evaluated. The most common side-effects were nausea (36%), vomiting (24%), mucositis (16%) and neutropenia (14%). Febrile neutropenia was documented in one case (2%) only. No objective response was documented. However, nine patients showed stable disease (45%), in some cases with prolonged duration (30+, 21+ and 18 weeks). The median duration of stable disease was 15 weeks (9-30+). In summary, this daily fractionated regimen of oral etoposide was well tolerated, producing long-lasting stable disease in some cases. However, no clear advantage in terms of objective tumor responses could be documented, when compared with previous data on its classical single oral administration.