Etoposide is an increasingly used and well-tolerated drug in cancer medicine. Its cytotoxic action is phase-specific and it has demonstrated schedule dependency in both in vitro and animal studies, but clinical evidence of the importance of drug scheduling is uncertain. The two administration schedules of etoposide that have been compared in this randomized study of 39 patients with previously untreated extensive small-cell lung cancer treated with single-agent etoposide were 500 mg/m2 as a continuous intravenous (IV) infusion over 24 hours or five consecutive daily 2-hour infusions each of 100 mg/m2. Both regimens were repeated every 3 weeks, for a maximum of six cycles. Patients received combination chemotherapy with vincristine, doxorubicin, and cyclophosphamide (VAC) or radiotherapy on failure to respond or at relapse, depending on their Karnofsky performance status. The same therapy was used in both arms of the study. All patients are evaluable for response to etoposide. In the 24-hour arm, two patients achieved a partial remission, resulting in an overall response rate of 10%. In the 5-day schedule, 16 patients had a partial response and one had a complete remission, producing an overall response rate of 89%, which was significantly superior to that in the 24-hour arm (P less than .001). The median duration of remission to etoposide in the 5-day arm was 4.5 months. Bone marrow toxicity was similar in both schedules. Etoposide pharmacokinetics were measured in all patients, and total areas under the concentration versus time curves (AUCs) were equivalent in both regimens. This study has clearly demonstrated the importance of etoposide scheduling in humans, and the superiority of five daily infusions over a 24-hour continuous infusion. The response rate to single-agent etoposide using an efficacious schedule in extensive small-cell lung cancer has been determined to be in excess of 80%.

Summary There is no information on the effect of food or concurrent drug administration on the bioavailability of oral etoposide, despite the fact that treatment is frequently administered over several days and most often in combination with other cytotoxic agents. The influence of these factors has been studied in 11 Etoposide was introduced into clinical trials in the early 1970s (Issell, 1982) and is established in the treatment of several malignancies, including small cell lung cancer, germ cell tumours and lymphomas (Arnold, 1979; Issell & Crooke, 1979;Vogelzang et al., 1982).The demonstration of schedule dependency in both experimental systems (Dombernowsky & Nissen, 1973;Rozencweig et al., 1977;D'Incalci & Garattini, 1982) and possibly also in man (Cavalli et al., 1978;Pedersen & Hansen, 1983) has led to most schedules of therapy being given over several (usually 3-5) days (Arnold, 1979;Nissen et al., 1980;Issell, 1982).The bioavailability of the oral etoposide capsule has been shown to be approximately 50% but with large variation between patients Harvey et al., 1984a). Despite the widespread use of oral etoposide over 3-5 days and its predominant use as part of combination chemotherapy regimens (Arnold, 1979;Comis, 1982;Rivera et al., 1982;Williams & Einhorn, 1982), there are no data concerning the influence of food or other chemotherapy on etoposide bioavailability.The intestinal absorption of some drugs has been shown to be affected by both food (Melander, 1978;McLean et al., 1978;Pinkerton et al., 1980) and chemotherapy (Pinkerton et al., 1982). The effect of food and concomitant oral and intravenous chemotherapy on the bioavailability of etoposide has therefore been studied. Materials and methods PatientsEleven patients receiving chemotherapy for extensive small cell lung carcinoma were studied. All were ambulant (performance score > 60% Karnofsky et al., 1948) with normal bone marrow, hepatic and renal function. No patients had disturbance of the gastrointestinal tract. Eight patients receiving primary chemotherapy were studied on 3 separate occasions to assess the effect of food and concomitant oral chemotherapy on etoposide bioavailability (Study 1). Six patients (3 of whom had previously been part of the above study) were receiving therapy for relapsed extensive SCLC and were studied on 3 successive days to assess the effect of intravenous and oral chemotherapy on etoposide bioavailability (Study 2).