title: Sequencing and schedule effects of cisplatin plus etoposide in small-cell lung cancer: results of a North Central Cancer Treatment Group randomized clinical trial.
abstract: OBJECTIVE
  The combination of etoposide (E) and cisplatin (P) is an accepted standard therapy for small-cell lung cancer (SCLC); however, the optimal sequencing and administration schedule has not been defined. This study was designed to evaluate different sequencing and administration schedules of E and P in the treatment of SCLC.
  
  
  METHODS
  Five hundred fifty-two eligible patients with limited-(LD) and extensive-stage (ED) SCLC were randomized to receive one of the following regimens: arm A, P 30 mg/m2 by intravenous (IV) bolus followed by E 130 mg/m2 bolus; arm B, E 130 mg/m2 bolus followed by P 30 mg/m2 bolus; arm C, E 130 mg/m2 by 24-hour infusion and P 30 mg/m2 bolus at the end of each 24-hour infusion of E; arm D, E 130 mg/m2 by 24-hour infusion and P 45 mg/m2 by 24-hour infusion on day 2 and 3 only. Two 3-day induction cycles of IV EP were administered 4 weeks apart. Subsequent therapy was the same for all arms, consisting of four cycles of cyclophosphamide, doxorubicin, and vincristine (CAV) at 4-week intervals. Consolidative thoracic radiation therapy (TRT) and prophylactic cranial irradiation (PCI) were administered to responders.
  
  
  RESULTS
  The overall response rate (84%) was similar in all treatment arms. Treatment arm A was associated with the best complete response (CR) rate (52%), the most favorable median survival time (MST) of 15 months, and a 26% 2-year survival rate. Patients with LD on arm A had a MST of 20 months and a 42% 2-year survival rate. Multivariate analysis indicated that extent of disease, performance status, arm of therapy, and sex were significant independent factors influencing survival. Toxicity of the four regimens was similar, except for greater thrombocytopenia on arm D.
  
  
  CONCLUSIONS
  The bolus administration of EP with E following P for the first two cycles of chemotherapy was the most effective regimen, with especially encouraging survival for LD patients.
authors.affiliation: Saskatchewan Cancer Foundation-Saskatoon Cancer Centre, Canada.
authors.forename: A W
authors.initials: AW
authors.lastname: Maksymiuk
authors.forename: J R
authors.initials: JR
authors.lastname: Jett
authors.forename: J D
authors.initials: JD
authors.lastname: Earle
authors.forename: J Q
authors.initials: JQ
authors.lastname: Su
authors.forename: F A
authors.initials: FA
authors.lastname: Diegert
authors.forename: J A
authors.initials: JA
authors.lastname: Mailliard
authors.forename: C G
authors.initials: CG
authors.lastname: Kardinal
authors.forename: J E
authors.initials: JE
authors.lastname: Krook
authors.forename: M H
authors.initials: MH
authors.lastname: Veeder
authors.forename: M
authors.initials: M
authors.lastname: Wiesenfeld
mesh_terms: D000206:Actuarial Analysis; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D018288:Carcinoma, Small Cell / Q000188:drug therapy*; D002945:Cisplatin / Q000008:administration & dosage; D004334:Drug Administration Schedule; D005047:Etoposide / Q000008:administration & dosage; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D011446:Prospective Studies; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D005047:Etoposide; D002945:Cisplatin