title: A phase I trial defining the maximum tolerated systemic exposure of topotecan in combination with Carboplatin and Etoposide in extensive stage small cell lung cancer.
abstract: OBJECTIVE
  Topotecan is active in relapsed small cell lung cancer; thus, its addition to the standard carboplatin-etoposide regimen may improve outcomes in extensive-stage small cell lung cancer (ES-SCLC) patients. Significant interpatient variability in the topotecan systemic exposure results when it is dosed based on body surface area (mg/m2). The purpose of this Phase I trial was to determine the maximally tolerated systemic exposure (MTSE) of topotecan in combination with carboplatin and etoposide.
  
  
  METHODS
  Thirty-four chemotherapy-naïve ES-SCLC patients received topotecan in combination with carboplatin AUC 5 mg/mL*min and oral etoposide 100 mg/m2/day. Topotecan was administered as a 30-minute infusion either on Days 1-5 or Days 1-3 and the dosage was individualized to attain a topotecan lactone AUC range (ng/mL*hr) in successive patient cohorts from 7 to 23; 24 to 36; 37 to 53; 54 to 66.
  
  
  RESULTS
  The majority (67 percent) of the measured topotecan AUCs were within target range. Overall, 8 of 34 patients experienced Cycle 1 dose-limiting toxicity (DLT), either neutropenia or thrombocytopenia. Carboplatin administration prior to topotecan resulted in 2 of 6 patients having Cycle 1 DLT. When the administration sequence was changed (topotecan, carboplatin, etoposide), Cycle 1 hematologic toxicity decreased; however, the maximum topotecan lactone AUC of 24-36 ng/mL*hr (median dose 0.82 mg/m2) had significant cumulative hematologic toxicity. The number of topotecan doses were reduced from 5 to 3, which resulted in a maximum topotecan lactone AUC of 37 to 53 ng/mL*hr with only 1 of 6 patients having Cycle 1 DLT. Overall response rate was 71 percent with median survival of 10.8 months.
  
  
  CONCLUSIONS
  It is feasible to target topotecan lactone AUC in adult ES-SCLC patients. However, this triplet regimen resulted in considerable hematologic toxicity and has a median survival comparable to carboplatin-etoposide. Alternative, less toxic regimens should be investigated for improving survival in ES-SCLC.
authors.affiliation: The Multidisciplinary Thoracic Oncology Program, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA. hhg6f@virginia.edu
authors.forename: Heidi H
authors.initials: HH
authors.lastname: Gillenwater
authors.forename: Jeannine S
authors.initials: JS
authors.lastname: McCune
authors.forename: Celeste
authors.initials: C
authors.lastname: Lindley
authors.forename: Stephanie
authors.initials: S
authors.lastname: Faucette
authors.forename: Stacy
authors.initials: S
authors.lastname: Shord
authors.forename: Angela
authors.initials: A
authors.lastname: Donahue
authors.forename: Mark A
authors.initials: MA
authors.lastname: Socinski
authors.forename: Clinton F
authors.initials: CF
authors.lastname: Stewart
authors.forename: William C
authors.initials: WC
authors.lastname: Zamboni
authors.forename: Mark N
authors.initials: MN
authors.lastname: Kirstein
authors.forename: Dominic
authors.initials: D
authors.lastname: Moore
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D019540:Area Under Curve; D016190:Carboplatin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D018288:Carcinoma, Small Cell / Q000188:drug therapy* / Q000401:mortality; D004334:Drug Administration Schedule; D005047:Etoposide / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D013534:Survival; D019772:Topotecan / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D005047:Etoposide; D019772:Topotecan; D016190:Carboplatin