title: A randomised, concentration-controlled, comparison of standard (5-day) vs. prolonged (15-day) infusions of etoposide phosphate in small-cell lung cancer.
abstract: OBJECTIVE
  This randomised trial was designed to investigate the activity and toxicity of continuous infusion etoposide phosphate (EP), targeting a plasma etoposide concentration of either 3 micrograms/ml for five days (5d) or 1 microgram/ml for 15 days (15d), in previously untreated SCLC patients with extensive disease.
  
  
  METHODS
  EP was used as a single agent. Plasma etoposide concentration was monitored on days 2 and 4 in patients receiving 5d EP and on days 2, 5, 8 and 11 in patients receiving 15d EP, with infusion modification to ensure target concentrations were achieved. Treatment was repeated every 21 days for up to six cycles, with a 25% reduction in target concentration in patients with toxicity.
  
  
  RESULTS
  The study has closed early after entry of 29 patients (14 with 5d EP, 15 with 15d EP). Objective responses were seen in seven of 12 (58%, confidence interval (CI): 27%-85%) evaluable patients after 5d EP, and two of 14 (14%, CI: 4%-42%) evaluable patients after 15d EP (P = 0.038). Grade 3 or 4 neutropenia or leucopenia during the first cycle of treatment was observed in six of 12 patients after 5d EP and 0/14 patients after 15d EP (P = 0.004), with median nadir WBC count of 2.6 x 10(9)/1 after 5d and 5.0 x 10(9)/1 after 15d EP (P = 0.017). Only one of 49 cycles of 15d EP was associated with grade 3 or worse haematological toxicity, compared to 14 of 61 cycles of 5d EP.
  
  
  CONCLUSIONS
  Although the number of patients entered into this trial was small, the low activity seen at 1 microgram/ml in the 15d arm suggests that this concentration is below the therapeutic window in this setting. Further concentration-controlled studies with prolonged EP infusions are required.
authors.affiliation: ICRF Department of Medical Oncology, St. Bartholomew's Hospital, West Smithfield, London, UK.
authors.forename: S
authors.initials: S
authors.lastname: Joel
authors.forename: K
authors.initials: K
authors.lastname: O'Byrne
authors.forename: R
authors.initials: R
authors.lastname: Penson
authors.forename: D
authors.initials: D
authors.lastname: Papamichael
authors.forename: A
authors.initials: A
authors.lastname: Higgins
authors.forename: H
authors.initials: H
authors.lastname: Robertshaw
authors.forename: R
authors.initials: R
authors.lastname: Rudd
authors.forename: D
authors.initials: D
authors.lastname: Talbot
authors.forename: M
authors.initials: M
authors.lastname: Slevin
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D018288:Carcinoma, Small Cell / Q000188:drug therapy*; D004334:Drug Administration Schedule; D005047:Etoposide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009943:Organophosphorus Compounds / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D009943:Organophosphorus Compounds; C061400:etoposide phosphate; D005047:Etoposide