PHASE-I AND PHARMACOLOGICAL STUDY OF 7-DAY AND 21-DAY CONTINUOUS ETOPOSIDE INFUSION IN PATIENTS WITH ADVANCED CANCER

Purpose. This phase I study was undertaken to evaluate the safety and tolerability of prolonged infusional etoposide, and to evaluate its ph armacokinetic/pharmacodynamic profile in patients with advanced cancer . Methods. A group of 17 patients received a 7-day infusion of etoposi de (schedule A) every 21 days at doses from 30 to 75 mg/m(2) per day, and a second group of 37 patients a 21-day infusion (schedule B) every 28 days at doses from 18 to 40 mg/m(2) per day. Patients had a median Karnofsky performance status (PS) of 80%, and 34 patients had no prio r chemotherapy. Etoposide concentrations at steady state (Css) and oth er pharmacokinetic parameters (plasma clearance, CLp; area under the c urve, AUG) were determined during the first treatment cycle. Correlati on coefficients were calculated to measure the relationship between va riables. Results. Myelosuppression was the major toxicity, and was ass ociated with three deaths. The maximum tolerated dose due to neutropen ia was 75 mg/m(2) per day for schedule A and 40 mg/m(2) per day for sc hedule B. There was significant interpatient pharmacokinetic variabili ty in both infusional schedules. Even though etoposide dose levels did not significantly correlate with plasma levels, the Css was 1 greater than or equal to g/ml in the majority of the patients. A significant correlation between AUC and neutrophil absolute decrease was noted onl y in schedule B (r = 0.56, P = 0.003). There were several marginal rel ationships in schedule B: PS versus Css (r = 0.31, P = 0.058), PS vers us AUC (r = -0.38; P = 0.058) and age versus CLp (r = -0.31, P = 0.057 ). Conclusion. Overall, significant correlations were found for severa l hematologic variables and etoposide dose levels, but not with the Cs s values. One major problem with the application of pharmacodynamic mo dels to predict hematologic toxicity in clinical practice is the prese nce of significant interpatient variability.