title: Febrile neutropenia in chemotherapy treated small-cell lung cancer patients.
abstract: BACKGROUND
  Chemotherapy with platinum agent and etoposide for small-cell lung cancer (SCLC) is supposed to be associated with intermediate risk (10-20%) of febrile neutropenia. Primary prophylaxis with granulocyte colony-stimulating factors (G-CSFs) is not routinely recommended by the treatment guidelines. However, in clinical practice febrile neutropenia is often observed with standard etoposide/platinum regimen. The aim of this analysis was to evaluate the frequency of neutropenia and febrile neutropenia in advanced SCLC patients in the first cycle of standard chemotherapy. Furthermore, we explored the association between severe neutropenia and etoposide peak plasma levels in the same patients.
  
  
  METHODS
  The case series based analysis of 17 patients with advanced SCLC treated with standard platinum/etoposide chemotherapy, already included in the pharmacokinetics study with etoposide, was performed. Grade 3/4 neutropenia and febrile neutropenia, observed after the first cycle are reported. The neutrophil counts were determined on day one of the second cycle unless symptoms potentially related to neutropenia occurred. Adverse events were classified according to Common Toxicity Criteria 4.0. Additionally, association between severe neutropenia and etoposide peak plasma concentrations, which were measured in the scope of pharmacokinetic study, was explored.
  
  
  RESULTS
  Two out of 17 patients received primary GCS-F prophylaxis. In 15 patient who did not receive primary prophylaxis the rates of both grade 3/4 neutropenia and febrile neutropenia were high (8/15 (53.3%) and 2/15 (13.3%), respectively), already in the first cycle of chemotherapy. One patient died due to febrile neutropenia related pneumonia. Neutropenic events are assumed to be related to increased etoposide plasma concentrations after a standard etoposide and cisplatin dose. While the mean etoposide peak plasma concentration in the first cycle of chemotherapy was 17.6 mg/l, the highest levels of 27.07 and 27.49 mg/l were determined in two patients with febrile neutropenia.
  
  
  CONCLUSIONS
  Our study indicates that there is a need to reduce the risk of neutropenic events in chemotherapy treated advanced SCLC, starting in the first cycle. Mandatory use of primary G-CSF prophylaxis might be considered. Alternatively, use of improved risk models for identification of patients with increased risk for neutropenia and individualization of primary prophylaxis based on not only clinical characteristics but also on etoposide plasma concentration measurement, could be a new, promising options that deserves further evaluation.
authors.affiliation: Krka, d.d., Novo mesto, Slovenia.
authors.forename: Renata Rezonja
authors.initials: RR
authors.lastname: Kukec
authors.affiliation: University of Ljubljana, Faculty of Pharmacy, Ljubljana, Slovenia.
authors.forename: Iztok
authors.initials: I
authors.lastname: Grabnar
authors.affiliation: University of Ljubljana, Faculty of Pharmacy, Ljubljana, Slovenia.
authors.forename: Tomaz
authors.initials: T
authors.lastname: Vovk
authors.affiliation: University of Ljubljana, Faculty of Pharmacy, Ljubljana, Slovenia.
authors.forename: Ales
authors.initials: A
authors.lastname: Mrhar
authors.affiliation: Institute of Oncology Ljubljana, Ljubljana, Slovenia.
authors.forename: Viljem
authors.initials: V
authors.lastname: Kovac
authors.affiliation: University Clinic Golnik, Golnik, Slovenia.
authors.forename: Tanja
authors.initials: T
authors.lastname: Cufer
keywords: etoposide; febrile neutropenia; plasma drug concentration; platinum-etoposide chemotherapy; small cell lung cancer