Prolonged infusion of etoposide in patients with advanced non-small cell lung cancer.

We assessed the efficacy and toxicity of two etoposide infusional schedules in patients with advanced non-small cell lung cancer (NSCLC). Twenty-six patients were treated with a 21-day infusion every 28 days at a dose of 25-40 mg/m2/d, and six patients with a 7-day infusion every 21 days at a dose of 45-75 mg/m2/d. Sixty-three percent of patients had a Karnofsky status of 80% or better, and only five (15%) patients had prior chemotherapy. Plasma etoposide concentrations were determined in 26 patients. Sixty-nine treatment cycles were administered. Two patients (6.3%; 90% confidence interval, 1.1-18.4%) had partial responses; with response durations of 2 and 7 months, respectively. The median survival was 4 months. Grade 3 or 4 neutropenia occurred in 13 of 69 cycles (19%) and was associated with three toxic deaths. Ten patients required RBC transfusions. Nausea was common, but was associated with vomiting in only 7% of all cycles. The interpatient variability of etoposide concentrations at steady state was significant. We conclude that the antitumor activity of prolonged infusion of etoposide is not superior to standard dose and schedule in advanced NSCLC.

Phase I and pharmacologic study of 7- 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 pharmacokinetic/pharmacodynamic profile in patients with advanced cancer. METHODS: A group of 17 patients received a 7-day infusion of etoposide (schedule A) every 21 days at doses from 30 to 75 mg/m2 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/m2 per day. Patients had a median Karnofsky performance status (PS) of 80%, and 34 patients had no prior chemotherapy. Etoposide concentrations at steady state (Css) and other pharmacokinetic parameters (plasma clearance, CLp; area under the curve, AUC) were determined during the first treatment cycle. Correlation coefficients were calculated to measure the relationship between variables. RESULTS: Myelosuppression was the major toxicity, and was associated with three deaths. The maximum tolerated dose due to neutropenia was 75 mg/m2 per day for schedule A and 40 mg/m2 per day for schedule B. There was significant interpatient pharmacokinetic variability in both infusional schedules. Even though etoposide dose levels did not significantly correlate with plasma levels, the Css was > or = 1 microgram/ml in the majority of the patients. A significant correlation between AUC and neutrophil absolute decrease was noted only in schedule B (r = 0.56, P = 0.003). There were several marginal relationships in schedule B: PS versus Css (r = 0.31, P = 0.058), PS versus AUC (r = -0.38; P = 0.058) and age versus CLp (r = -0.31, P = 0.057). CONCLUSION: Overall, significant correlations were found for several hematologic variables and etoposide dose levels, but not with the Css values. One major problem with the application of pharmacodynamic models to predict hematologic toxicity in clinical practice is the presence of significant interpatient variability.

Evaluation of the methemoglobinemia associated with sulofenur.

A new class of antineoplastic agents, the diarylsulfonylureas entered clinical trials with the testing of Sulofenur (LY186641). Phase I trials and preclinical studies showed the dose limiting toxicity to be methemoglobinemia. We studied the incidence of methemoglobinemia, sulfhemoglobinemia and cytochrome b5 reductase deficiency in nine consecutive patients enrolled in a phase II trials using Sulofenur. The specific Malloy method as well as clinically standard co-oximeter measurements were used to determine methemoglobin levels and marked discrepancies were noted. One patient with symptomatic methemoglobinemia had enzyme levels and family history consistent with a heterozygous state for a cytochrome b5 reductase deficiency. We conclude that the clinical incidence of methemoglobinemia will be overestimated by co-oximeter measurements but that Sulofenur does produce clinically significant methemoglobinemia in cytochrome b5 reductase deficient patients.