title: A phase I study of dose-dense topotecan given upfront to standard therapy in patients with small cell lung cancer.
abstract: OBJECTIVE
  To determine the feasibility and maximum tolerated dose of dose-dense topotecan as induction chemotherapy before standard therapy (carboplatin plus etoposide alone or in combination with radiotherapy) in patients with small cell lung cancer (SCLC).
  
  
  METHODS
  Chemotherapy-naive patients with SCLC and good performance status were eligible. Three 2-week cycles of dose-dense topotecan administered on days 1-3 with granulocyte colony-stimulating factor support were followed by four cycles of standard carboplatin plus etoposide therapy alone (extensive-stage SCLC) or with radiotherapy (limited-stage SCLC). The dose of topotecan was escalated from 1.5 mg/m2/day to 2.5 mg/m2/day in increments of 0.25 mg/m2/day within cohorts of 3-5 patients each. Dose-limiting toxicity was defined as any grade 3 or 4 toxicity resulting in a treatment reduction or a delay of >3 days.
  
  
  RESULTS
  Twenty-two patients with SCLC (5 limited-stage, 17 extensive-stage) were enrolled. Treatment was well tolerated. The dose-limiting toxicities were thrombocytopenia and neutropenia, and the maximum tolerated dose of dose-dense topotecan induction therapy was 2.25 mg/m2/day. Overall, topotecan-related grade 3/4 haematological toxicities included neutropenia (n = 4), thrombocytopenia (n = 3) and febrile neutropenia (n = 1). No grade 4 non-haematological toxicities occurred. Grade 3 adverse events included nausea (n = 2), renal toxicity (n = 1) and anorexia (n = 1). Toxicity during the carboplatin plus etoposide +/- radiotherapy phase of therapy was consistent with that reported in previous trials. The overall response rate was 80% for limited-stage and 76% for extensive-stage SCLC. Median survival was 8 months in patients with limited-stage SCLC and 13.5 months for patients with extensive-stage SCLC.
  
  
  CONCLUSIONS
  The results of this phase I study suggest that a regimen of sequential dose-dense topotecan and carboplatin plus etoposide is feasible, and the preliminary activity observed in patients with SCLC warrants further investigation at a starting dose of topotecan 2.25 mg/m2/day.
authors.affiliation: Duke University Medical Center, Durham, North Carolina 27710, USA. garst001@mc.duke.edu
authors.forename: Jennifer
authors.initials: J
authors.lastname: Garst
authors.forename: James E
authors.initials: JE
authors.lastname: Herndon
authors.forename: Timothy
authors.initials: T
authors.lastname: Shafman
authors.forename: Lara
authors.initials: L
authors.lastname: Campagna
authors.forename: Susan
authors.initials: S
authors.lastname: Blackwell
authors.forename: Karen
authors.initials: K
authors.lastname: Padilla
authors.forename: Toni
authors.initials: T
authors.lastname: Bjurstrom
authors.forename: Carolyn
authors.initials: C
authors.lastname: Andrews
authors.forename: Diana
authors.initials: D
authors.lastname: Maravich-May
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Anderson
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Crawford
mesh_terms: D000855:Anorexia / Q000139:chemically induced; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage / Q000009:adverse effects; D018288:Carcinoma, Small Cell / Q000188:drug therapy* / Q000401:mortality / Q000532:radiotherapy; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005047:Etoposide / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage; D006402:Hematologic Diseases / Q000139:chemically induced; D006801:Humans; D017567:Karnofsky Performance Status; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000532:radiotherapy; D008297:Male; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009367:Neoplasm Staging; D018714:Radiotherapy, Adjuvant / Q000379:methods; D012074:Remission Induction; D015996:Survival Rate; D019772:Topotecan / Q000008:administration & dosage / Q000009:adverse effects; D016896:Treatment Outcome
chemical_list: D016179:Granulocyte Colony-Stimulating Factor; D005047:Etoposide; D019772:Topotecan; D016190:Carboplatin