Etoposide pharmacokinetics and survival in patients with small cell lung cancer: A multicentre study

SummaryPurposeTo investigate the prognostic value of systemic exposure to etoposide (Area Under the concentration Curve (AUCVP16)) on overall survival (OS) in patients with small cell lung cancer (SCLC).Patients and methodsData from 52 patients with limited stage (n = 17) or metastatic (n = 35) SCLC were analysed. They received at least two courses of etoposide (120 mg/(m2 day) on 3 days) combined with either doxorubicin–ifosfamide (AVI, n = 29) or platinum compounds (carboplatin: n = 16; cisplatin: n = 7). Population pharmacokinetic–pharmacodynamic (PK–PD) study was performed using NON-linear Mixed Effect Model (NONMEM) and Splus software with univariate and multivariate analyses.ResultsEtoposide plasma concentration vs. time was described by a two compartment model. Etoposide clearance (CL) was significantly dependant on serum creatinine (Scr). Ifosfamide (IFO) coadministration increased etoposide clearance by 28% (median CLVP16: 2.42 L/h vs. 1.89 L/h, p < 0.0005) leading to a reduced systemic exposure (median AUCVP16: 260 mg h/L vs. 339 mg h/L). No influence of body surface area (BSA) on CLVP16 was observed.Median percent decrease of absolute neutrophil count (ANC) after the first chemotherapy course was greater when etoposide 24 h concentration was above 0.33 mg/L (88% vs. 0%, p = 0.028). Median OS was significantly longer in patients treated without ifosfamide (11.0 months vs. 7.0 months, p = 0.049) and in patients with CLVP16 < 2.22 L/h (14 months vs. 7 months, p = 0.013) and AUCVP16 > 254.8 mg h/L (11 months vs. 7 months, p = 0.048). The independent prognostic factors regarding OS were LDH, CLVP16 and AUCVP16.ConclusionIn this study it was found that CLVP16 is reduced in patients with elevated serum creatinine, whilst ifosfamide coadministration increases CLVP16 and reduces AUCVP16, demonstrating the interaction between VP16 and ifosfamide. CLVP16 and AUCVP16 correlate significantly with overall survival of patients with SCLC patients receiving etoposide regimens.