title: Reduction of chemotherapy-induced febrile leucopenia by prophylactic use of ciprofloxacin and roxithromycin in small-cell lung cancer patients: an EORTC double-blind placebo-controlled phase III study.
abstract: BACKGROUND
  CDE (cyclophosphamide, doxorubicin, etoposide) is one of the standard chemotherapy regimens in the treatment of small-cell lung cancer (SCLC), with myelosuppression as dose-limiting toxicity. In this trial the impact of prophylactic antibiotics on incidence of febrile leucopenia (FL) during chemotherapy for SCLC was evaluated.
  
  
  METHODS
  Patients with chemo-naïve SCLC were randomized to standard-dose CDE (C 1,000 mg/m2 day 1, D 45 mg/m2 day 1, E 100 mg/m2 days 1-3. i.v., q 3 weeks, x5) or to intensified CDE chemotherapy (125% dose, q 2 weeks, x4, with filgrastim 5 microg/kg/day days 4-13) to assess the impact on survival (n = 240 patients). Patients were also randomized to prophylactic antibiotics (ciprofloxacin 750 mg plus roxithromycin 150 mg, bid. days 4-13) or to placebo in a 2 x 2 factorial design (first 163 patients). This manuscript focuses on the antibiotics question.
  
  
  RESULTS
  The incidence of FL during the first cycle was 25% of patients in the placebo and 11% in the antibiotics arm (P = 0.010; 1-sided), with an overall incidence through all cycles of 43% vs. 24% respectively (P = 0.007; 1-sided). There were less Gram-positive (12 vs. 4), Gram-negative (20 vs. 5) and clinically documented (38 vs. 15) infections in the antibiotics arm. The use of therapeutic antibiotics was reduced (P = 0.013; 1-sided), with less hospitalizations due to FL (31 vs. 17 patients, P = 0.013: 1-sided). However, the overall number of days of hospitalization was not reduced (P = 0.05; 1-sided). The number of infectious deaths was nil in the antibiotics vs. five (6%) in the placebo arm (P = 0.022; 2-sided).
  
  
  CONCLUSIONS
  Prophylactic ciprofloxacin plus roxithromycin during CDE chemotherapy reduced the incidence of FL, the number of infections, the use of therapeutic antibiotics and hospitalizations due to FL by approximately 50%, with reduced number of infectious deaths. For patients with similar risk for FL, the prophylactic use of antibiotics should be considered.
authors.affiliation: Department of Medical Oncology, University Medical Center Nijmegen,The Netherlands. V.Tjan@onco.azn.nl
authors.forename: V C
authors.initials: VC
authors.lastname: Tjan-Heijnen
authors.forename: P E
authors.initials: PE
authors.lastname: Postmus
authors.forename: A
authors.initials: A
authors.lastname: Ardizzoni
authors.forename: C H
authors.initials: CH
authors.lastname: Manegold
authors.forename: J
authors.initials: J
authors.lastname: Burghouts
authors.forename: J
authors.initials: J
authors.lastname: van Meerbeeck
authors.forename: S
authors.initials: S
authors.lastname: Gans
authors.forename: M
authors.initials: M
authors.lastname: Mollers
authors.forename: E
authors.initials: E
authors.lastname: Buchholz
authors.forename: B
authors.initials: B
authors.lastname: Biesma
authors.forename: C
authors.initials: C
authors.lastname: Legrand
authors.forename: C
authors.initials: C
authors.lastname: Debruyne
authors.forename: G
authors.initials: G
authors.lastname: Giaccone
mesh_terms: D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000890:Anti-Infective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D019072:Antibiotic Prophylaxis; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use*; D018288:Carcinoma, Small Cell / Q000188:drug therapy*; D003520:Cyclophosphamide / Q000008:administration & dosage; D004311:Double-Blind Method; D004317:Doxorubicin / Q000008:administration & dosage; D005047:Etoposide / Q000008:administration & dosage; D005260:Female; D005334:Fever / Q000139:chemically induced* / Q000517:prevention & control*; D024841:Fluoroquinolones; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage; D006760:Hospitalization; D006801:Humans; D007239:Infections / Q000139:chemically induced; D007262:Infusions, Intravenous; D008175:Lung Neoplasms / Q000188:drug therapy*; D018942:Macrolides; D008297:Male; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced* / Q000517:prevention & control*; D010919:Placebos; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents; D024841:Fluoroquinolones; D018942:Macrolides; D010919:Placebos; D016179:Granulocyte Colony-Stimulating Factor; D005047:Etoposide; D004317:Doxorubicin; D003520:Cyclophosphamide