title: The prognostic value of etoposide area under the curve (AUC) at first chemotherapy cycle in small cell lung cancer patients: a multicenter study of the groupe Lyon-Saint-Etienne d'Oncologie Thoracique (GLOT).
abstract: OBJECTIVE
  To assess the potential relationships between systemic exposure to doxorubicin, etoposide and ifosfamide at first chemotherapy cycle and therapeutic effect, tumor response, toxicity, and survival, in small cell lung cancer (SCLC) patients.
  
  
  METHODS
  Twenty-four patients referred to five different centers with either thorax-limited or metastatic SCLC entered the study. All but one received two induction courses of the 3 day-AVI (doxorubicin 50 mg/m(2) day 1, etoposide 120 mg/m(2) day 1, 2, 3, ifosfamide 2000 mg/m(2) day 1, 2) regimen. Individual plasma samples were collected at the first course and complete concentration data on 24 courses were available. Drugs exposures were estimated using a population pharmacokinetic method and expressed as clearance (Cl), area under the curve (AUC), and AUC-intensity (AUC/cycle duration). Responding patients received thoracic irradiation+concomitant cisplatinum-etoposide (limited disease) or four more courses of AVI (extensive disease). The impact of exposure parameters on haematological toxicity, tumor response and overall survival was assessed using linear regression, the Mann-Whitney U-test and the log-rank test/Kaplan-Meier estimation, respectively.
  
  
  RESULTS
  Twenty-three patients could be evaluated for response and survival. We found no relationship between drug exposure and haematological toxicity but all patients had received Granulocyte-Colony Stimulating Factor support. Tumor response was marginally influenced by ifosfamide AUC. In patients with etoposide AUC>254.8 mg h/l, 1-year survival was 50.0 vs. 9.1% in the other group (median 11.4 vs. 7.1 months, P=0.02), with respect to established prognostic factors. In patients with extensive disease only (n=15), 1-year survival was 42.9 vs. 0% (median 11.3 vs. 5.3 months, P=0.01).
  
  
  CONCLUSIONS
  This study strongly suggests that SCLC patients should benefit from sufficient etoposide exposure at first cycle to improve survival. Adaptative control based on plasma concentration measurements should be tested in further studies assessing various polychemotherapy regimens.
authors.affiliation: Medical Oncology Unit and EA 643, Centre Hospitalier Lyon-Sud, 69495 Pierre-Bénite, Cédex, France. gilles.freyer@chu-lyon.fr
authors.forename: G
authors.initials: G
authors.lastname: Freyer
authors.forename: B
authors.initials: B
authors.lastname: Ligneau
authors.forename: B
authors.initials: B
authors.lastname: Tranchand
authors.forename: C
authors.initials: C
authors.lastname: Ardiet
authors.forename: P J
authors.initials: PJ
authors.lastname: Souquet
authors.forename: I
authors.initials: I
authors.lastname: Court-Fortune
authors.forename: R
authors.initials: R
authors.lastname: Riou
authors.forename: P
authors.initials: P
authors.lastname: Rebattu
authors.forename: E
authors.initials: E
authors.lastname: Morignat
authors.forename: J P
authors.initials: JP
authors.lastname: Boissel
authors.forename: V
authors.initials: V
authors.lastname: Trillet-Lenoir
authors.forename: P
authors.initials: P
authors.lastname: Girard
mesh_terms: D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D019540:Area Under Curve; D018288:Carcinoma, Small Cell / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy; D002945:Cisplatin / Q000008:administration & dosage; D003131:Combined Modality Therapy; D004317:Doxorubicin / Q000008:administration & dosage; D005047:Etoposide / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D007069:Ifosfamide / Q000008:administration & dosage; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D011379:Prognosis; D016019:Survival Analysis
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D005047:Etoposide; D004317:Doxorubicin; D002945:Cisplatin; D007069:Ifosfamide