title: Phase I trial of low-dose continuous topotecan infusion in patients with cancer: an active and well-tolerated regimen.
abstract: OBJECTIVE
  The objective of this trial was to define the maximum-tolerated dose (MTD) of topotecan for a 21-day infusion schedule, repeated every 28 days, in patients with cancer.
  
  
  METHODS
  Cohorts of four patients received continuous ambulatory infusions of topotecan in escalated duration with doses beginning at 0.20 mg/m2/d for 7 days. Forty-four patients with a histologic diagnosis of cancer refractory to standard therapy were treated with infusions of topotecan for a total of 115 cycles and 1,780 patient-days of infusion. The median number of treatment cycles per patient was two (range, one to eight). All patients were heavily pretreated with chemotherapy and/or radiation.
  
  
  RESULTS
  The dose-limiting toxicity (DLT) was myelo-suppression, with thrombocytopenia greater than neutropenia seen at the dose level of 0.70 mg/m2/d for 21 days. At the MTD of 0.53 mg/m2, ten patients were treated for a total of 20 courses, resulting in one episode of grade 4 thrombocytopenia and leukopenia, one grade 3 thrombocytopenia, and two grade 3 leukopenias. This dose regimen was well tolerated, with minimal nonhematologic toxicity. Local infusion port complications developed in two patients and two had bacteremia, including one patient with repeated local skin infections. Objective responses were observed in this heavily pretreated population for patients with ovarian cancer (two partial responses and one mixed response in six patients), breast cancer (one partial response and one mixed response in two patients), and for one patient each with renal and non-small-cell lung cancer (two partial remissions).
  
  
  CONCLUSIONS
  Twenty-one-day topotecan infusion is well tolerated at 0.53 mg/m2, with dose-intensity exceeding other schedules for administration of topotecan. The DLT is hematologic, with thrombocytopenia somewhat exceeding leukopenia. Objective responses were observed in seven patients with breast, ovarian, renal, and non-small-cell lung cancer.
authors.affiliation: Kaplan Comprehensive Cancer Center, Division of Medical Oncology, New York University Medical Center, New York 10016.
authors.forename: H
authors.initials: H
authors.lastname: Hochster
authors.forename: L
authors.initials: L
authors.lastname: Liebes
authors.forename: J
authors.initials: J
authors.lastname: Speyer
authors.forename: J
authors.initials: J
authors.lastname: Sorich
authors.forename: B
authors.initials: B
authors.lastname: Taubes
authors.forename: R
authors.initials: R
authors.lastname: Oratz
authors.forename: J
authors.initials: J
authors.lastname: Wernz
authors.forename: A
authors.initials: A
authors.lastname: Chachoua
authors.forename: B
authors.initials: B
authors.lastname: Raphael
authors.forename: R Z
authors.initials: RZ
authors.lastname: Vinci
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001855:Bone Marrow Diseases / Q000139:chemically induced; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D019772:Topotecan; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D019772:Topotecan; D002166:Camptothecin