title: Preclinical and clinical evaluation of four gemcitabine plus carboplatin schedules as front-line treatment for stage IV non-small-cell lung cancer.
abstract: BACKGROUND
  To explore the activity and tolerability of gemcitabine (GEM) and carboplatin (CBDCA) in non-small-cell lung cancer (NSCLC) we tested four administration sequences on H460 NSCLC cells, and at the same time performed a randomized phase II trial using analogous schedules.
  
  
  METHODS
  GEM was given first in two in vitro sequences, and CBDCA first in the other two; interaction was quantified calculating a combination index. Eighty-eight chemotherapy-naïve, stage IV NSCLC patients were randomly assigned to receive either: GEM (1000 mg/m(2)) on days 1 and 8 and CBDCA (AUC 5 mg.min/ml) on day 1, 4 h before GEM (arm A); same as arm A except CBDCA given 4 h after GEM (arm B); GEM on days 1 and 8 and CBDCA on day 2 (arm C); GEM on days 2 and 9 and CBDCA on day 1 (arm D). Courses were repeated every 21 days.
  
  
  RESULTS
  In the preclinical study, CBDCA given before GEM produced a synergistic cytotoxic effect. Two complete and 29 partial responses occurred in 86 of 88 treated patients (intention-to-treat analysis 35%; 95% confidence interval 25.5% to 46.8%). One- and 2-year survivals were 44% and 11%, respectively. Grade 3/4 thrombocytopenia occurred in 11%; grade 3/4 neutropenia in 17%; and non-hematological toxicity was insignificant. Median survival was 11 months (range 7-18+), but better in patients receiving CBDCA first (arms A and D) (13 versus 9 months) than in patients receiving GEM first (arms B and C). The response was greater (50% versus 31%) in arm A than in the other arms.
  
  
  CONCLUSIONS
  The CBDCA/GEM combination is safe and active against stage IV NSCLC. Our preclinical and clinical findings suggest that administration of CBDCA before GEM gives the better outcome.
authors.affiliation: Medical Oncology Unit B, Unit of Experimental Oncology C, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy. emilio.bajetta@istitutotumori.mi.it
authors.forename: E
authors.initials: E
authors.lastname: Bajetta
authors.forename: S C
authors.initials: SC
authors.lastname: Stani
authors.forename: D
authors.initials: D
authors.lastname: De Candis
authors.forename: N
authors.initials: N
authors.lastname: Zaffaroni
authors.forename: N
authors.initials: N
authors.lastname: Zilembo
authors.forename: D
authors.initials: D
authors.lastname: Cortinovis
authors.forename: S
authors.initials: S
authors.lastname: Aglione
authors.forename: L
authors.initials: L
authors.lastname: Mariani
authors.forename: B
authors.initials: B
authors.lastname: Formisano
authors.forename: P
authors.initials: P
authors.lastname: Bidoli
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009503:Neutropenia / Q000139:chemically induced; D013534:Survival; D013921:Thrombocytopenia / Q000139:chemically induced; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured; D000093542:Gemcitabine
chemical_list: D003841:Deoxycytidine; D016190:Carboplatin; D000093542:Gemcitabine