title: A Phase I-II study of 96-hour infusional topotecan and paclitaxel for patients with recurrent Müllerian tumors.
abstract: BACKGROUND
  Topotecan and paclitaxel are schedule dependent chemotherapeutic agents with activity against ovarian carcinoma. A Phase I-II study in which both drugs were administered concurrently by 96-hour, continuous, intravenous infusion was performed to determine the maximum tolerated dose (MTD), toxicities, pharmacokinetics, and efficacy of the combination.
  
  
  METHODS
  Women with ovarian or primary peritoneal carcinoma and documented recurrent disease were eligible for the study. The dose of topotecan was escalated from 1.6 mg/m(2) while maintaining the paclitaxel dose constant at 100 mg/m(2). Plasma concentrations of both drugs were monitored daily during the first cycle of therapy.
  
  
  RESULTS
  Forty-five patients with a median age of 54 years (range, 42-70 years) received 181 cycles of therapy. Five patients were recruited to each of four dose levels (topotecan 1.6 mg/m(2), 2.0 mg/m(2), 2.8 mg/m(2), and 3.6 mg/m(2)), and an additional 25 patients were treated at the MTD (Phase II). Neutropenia and thrombocytopenia became dose limiting toxicities (DLT) at the fourth dose level. Emesis, mucositis, peripheral neuropathy, diarrhea, and alopecia were mild. Twenty patients (44%) had line-related occlusion, thrombosis, or infection. The mean values (+/- standard deviation) of the apparent steady-state plasma concentrations at the Phase II doses were 2.3 nM +/- 0.5 nM for topotecan lactone, 5.6 nM +/- 2.1 nM for total topotecan, and 40.1 nM +/- 16.8 nM for paclitaxel. There were seven partial responses (Phase II) contributing to an objective response rate of 28% and a median survival time of 11.7 months (range, 0.6-20.1 months).
  
  
  CONCLUSIONS
  Topotecan at a dose of 2.8 mg/m(2) and paclitaxel at a dose of 100 mg/m(2) administered by concurrent, 96-hour, continuous intravenous infusions shows activity against tumors of Müllerian origin.
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114-2617, USA.
authors.forename: R T
authors.initials: RT
authors.lastname: Penson
authors.forename: J G
authors.initials: JG
authors.lastname: Supko
authors.forename: M V
authors.initials: MV
authors.lastname: Seiden
authors.forename: A F
authors.initials: AF
authors.lastname: Fuller
authors.forename: R S
authors.initials: RS
authors.lastname: Berkowitz
authors.forename: A
authors.initials: A
authors.lastname: Goodman
authors.forename: S M
authors.initials: SM
authors.lastname: Campos
authors.forename: K M
authors.initials: KM
authors.lastname: MacNeill
authors.forename: S
authors.initials: S
authors.lastname: Cook
authors.forename: U A
authors.initials: UA
authors.lastname: Matulonis
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage / Q000493:pharmacokinetics; D010534:Peritoneal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D018709:Statistics, Nonparametric; D015996:Survival Rate; D019772:Topotecan / Q000008:administration & dosage / Q000493:pharmacokinetics
chemical_list: D019772:Topotecan; D017239:Paclitaxel