title: Dose-intensity of a four-drug chemotherapy regimen with or without recombinant human granulocyte-macrophage colony-stimulating factor in extensive-stage small-cell lung cancer: a multicenter randomized phase III study.
abstract: OBJECTIVE
  We investigated whether a high-dose chemotherapy regimen of cyclophosphamide 1,800 mg/m2, 4'-epidoxorubicin 60 mg/m2, etoposide 330 mg/m2, and cisplatin 120 mg/m2 given monthly for four cycles with recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) support (5 micrograms/kg daily for 10 days) could improve the survival of patients with extensive-stage small-cell lung cancer (SCLC) compared with a standard-dose regimen (cyclophosphamide 1,200 mg/m2, 4'-epidoxorubicin 40 mg/m2, etoposide 225 mg/m2, and cisplatin 100 mg/m2) given monthly for six cycles. Planned cumulative doses of the drugs were the same in both treatment arms except for cisplatin (which was 80% in the higher-dose plus rhGM-CSF group).
  
  
  RESULTS
  At the time of the preplanned interim analysis, 125 patients, 60 in the standard-dose group and 65 in the higher-dose plus rhGM-CSF group, had entered the study; 116 were eligible, 55 in the standard-dose group and 61 in the higher-dose group. All patients were included in the analyses. The cumulative doses of each drug actually delivered were significantly higher in the standard-dose group. No difference in response rates was observed between the two groups. There were significantly greater hematologic toxicities, documented infections, and transfusions of RBCs and platelets in the higher-dose plus rhGM-CSF group. Patients in this group proved to have a shorter survival duration and a shorter time to relapse than patients in the standard-dose group (median overall survival: standard-dose, 10.8 months; higher-dose, 8.9 months; log-rank test with adjustment for prognostic variables, P = .0005; respective probabilities of relapse at 1 year, 77 +/- 0.6 and 96 +/- 2.2; log-rank test, P = .013).
  
  
  CONCLUSIONS
  A 50% increase in dose-intensity for this four-drug regimen could not be achieved with GM-CSF due to excessive toxicity in patients with extensive-stage SCLC.
authors.affiliation: Hôpital Universitaire Arnaud de Villeneuve, Montpellier, France.
authors.forename: J L
authors.initials: JL
authors.lastname: Pujol
authors.forename: J Y
authors.initials: JY
authors.lastname: Douillard
authors.forename: A
authors.initials: A
authors.lastname: Rivière
authors.forename: E
authors.initials: E
authors.lastname: Quoix
authors.forename: J L
authors.initials: JL
authors.lastname: Lagrange
authors.forename: P
authors.initials: P
authors.lastname: Berthaud
authors.forename: M
authors.initials: M
authors.lastname: Bardonnet-Comte
authors.forename: V
authors.initials: V
authors.lastname: Polin
authors.forename: V
authors.initials: V
authors.lastname: Gautier
authors.forename: B
authors.initials: B
authors.lastname: Milleron
authors.forename: F
authors.initials: F
authors.lastname: Chomy
authors.forename: P
authors.initials: P
authors.lastname: Chomy
authors.forename: D
authors.initials: D
authors.lastname: Spaeth
authors.forename: T
authors.initials: T
authors.lastname: Le Chevalier
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D018288:Carcinoma, Small Cell / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000009:adverse effects; D004334:Drug Administration Schedule; D015251:Epirubicin / Q000008:administration & dosage / Q000009:adverse effects; D005047:Etoposide / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011994:Recombinant Proteins; D016019:Survival Analysis
chemical_list: D011994:Recombinant Proteins; D015251:Epirubicin; D005047:Etoposide; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D003520:Cyclophosphamide; D002945:Cisplatin