title: Treatment of poor-prognosis extensive disease small-cell lung cancer with an all-oral regimen of etoposide and cyclophosphamide - a Southwest Oncology Group clinical and pharmacokinetic study.
abstract: OBJECTIVE
  An all-oral regimen of etoposide and cyclophosphamide was developed for use in poor-prognosis extensive disease small-cell lung cancer. Limited pharmacokinetic sampling was used to derive a pharmacodynamic model predictive of myelosuppression early in the course of therapy.
  
  
  METHODS
  Eligible patients were chemotherapy-naive and had extensive disease small-cell lung cancer with either SWOG performance status 2 or serum albumin <3.5 g/dl. The first cohort (n = 18) received etoposide orally at 50 mg daily and cyclophosphamide orally at 50 mg daily days 1-14 every 28 days. Due to good hematologic tolerance, the second cohort (n = 39) received both agents orally at 50 mg twice daily days 1-14 every 28 days. Plasma etoposide levels were determined in samples drawn at baseline, and at 1 h, 2 h, and 23.5 h (trough) after the first dose. Linear regression analysis was used to determine pharmacokinetic and demographic parameters predictive of myelosuppression.
  
  
  RESULTS
  A total of 173 treatment cycles were delivered. Patients on the daily regimen had a 22% response rate (complete and partial), a 22% unconfirmed response rate, and a 5-month median survival, while patients on the twice-daily regimen had a 28% response rate (complete and partial), a 13% unconfirmed response rate, and a 7-month median survival. Granulocytopenia and alopecia were the most common toxicities seen. Significant granulocytopenia could be predicted for the twice-daily regimen according to the formula ln(AGC nadir)=7.80 - 1.88(trough), with an increased incidence of granulocytopenia if the etoposide trough value was >/=1.49 microg/ml.
  
  
  CONCLUSIONS
  Oral etoposide and oral cyclophosphamide given days 1-14 every 28 days is well tolerated and results in an acceptable response rate and median survival in poor-prognosis (poor performance status or low serum albumin) extensive disease small-cell lung cancer. A trough etoposide level obtained within 24 h of starting therapy can predict severe granulocytopenia.
authors.affiliation: University of Vermont, Burlington, VT, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: Grunberg
authors.forename: J
authors.initials: J
authors.lastname: Crowley
authors.forename: K R
authors.initials: KR
authors.lastname: Hande
authors.forename: D
authors.initials: D
authors.lastname: Giroux
authors.forename: N
authors.initials: N
authors.lastname: Munshi
authors.forename: D H
authors.initials: DH
authors.lastname: Lau
authors.forename: L E
authors.initials: LE
authors.lastname: Schroder
authors.forename: M H
authors.initials: MH
authors.lastname: Zangmeister
authors.forename: S P
authors.initials: SP
authors.lastname: Balcerzak
authors.forename: H E
authors.initials: HE
authors.lastname: Hynes
authors.forename: D R
authors.initials: DR
authors.lastname: Gandara
mesh_terms: D000284:Administration, Oral; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D018288:Carcinoma, Small Cell / Q000188:drug therapy*; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000493:pharmacokinetics; D004334:Drug Administration Schedule; D005047:Etoposide / Q000008:administration & dosage / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D012044:Regression Analysis
chemical_list: D005047:Etoposide; D003520:Cyclophosphamide