title: Phase I trial and pharmacologic trial of sequences of paclitaxel and topotecan in previously treated ovarian epithelial malignancies: a Gynecologic Oncology Group study.
abstract: OBJECTIVE
  A phase I and pharmacologic study to evaluate the feasibility of administering paclitaxel (PTX) in combination with topotecan (TPT) without and with granulocyte colony-stimulating factor (G-CSF) in women with recurrent or refractory ovarian cancer.
  
  
  METHODS
  TPT was administered as a 30-minute infusion daily for 5 days and PTX was given as a 24-hour infusion (PTX-24) either before TPT on day 1 or after TPT on day 5. Each patient received both schedules on an alternating basis every 3 weeks. Sequential dose escalation of TPT or PTX-24 without and with G-CSF resulted in five dosage permutations of TPT/PTX (mg/ m2): 0.75/135 without G-CSF and 0.75/135, 1.25/135, 1.50/135, and 1.25/170 with G-CSF.
  
  
  RESULTS
  Twenty-two patients received 109 courses of therapy. Dose-limiting myelosuppression consistently occurred at the first TPT/PTX-24 dose level (0.75/135 mg/m2) in the absence of G-CSF support. Although the addition of G-CSF resulted in reduced rates of complicated neutropenia, the incidences of dose-limiting neutropenia and thrombocytopenia were unacceptably high after the doses of either TPT or PTX-24 were increased. Paired analysis showed similar hematologic toxicities between the two sequences of drug administration. The pharmacologic behavior of both TPT and PTX-24 was not altered by drug sequencing. Major antitumor responses occurred in 40% of patients with measurable and assessable disease, including 45% and 9% of patients with potentially cisplatin-sensitive and -resistant tumors, respectively.
  
  
  CONCLUSIONS
  The recommended doses of TPT on a daily times-five schedule combined with PTX-24 in these patients were 0.75 mg/m2/d and 135 mg/m2, respectively, with G-CSF support. Although this dose of PTX has significant single-agent activity in ovarian cancer, the dose of TPT is much lower than the TPT dose at which single-agent activity has been observed. Due to the inability to administer near relevant single-agent doses of both drugs in combination, as well as the requirement for G-CSF support, further evaluations of this regimen in women with refractory or recurrent ovarian cancer are necessary before it can be recommended for previously treated patients in this setting.
authors.affiliation: Department of Oncology, Johns Hopkins Oncology Center, Baltimore, MD, USA.
authors.forename: S
authors.initials: S
authors.lastname: O'Reilly
authors.forename: G F
authors.initials: GF
authors.lastname: Fleming
authors.forename: S D
authors.initials: SD
authors.lastname: Barker
authors.forename: J R
authors.initials: JR
authors.lastname: Walczak
authors.forename: M A
authors.initials: MA
authors.lastname: Bookman
authors.forename: W P
authors.initials: WP
authors.lastname: McGuire
authors.forename: R J
authors.initials: RJ
authors.lastname: Schilder
authors.forename: R D
authors.initials: RD
authors.lastname: Alvarez
authors.forename: D K
authors.initials: DK
authors.lastname: Armstrong
authors.forename: I R
authors.initials: IR
authors.lastname: Horowitz
authors.forename: R F
authors.initials: RF
authors.lastname: Ozols
authors.forename: E K
authors.initials: EK
authors.lastname: Rowinsky
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D004334:Drug Administration Schedule; D005240:Feasibility Studies; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage; D006801:Humans; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009503:Neutropenia / Q000139:chemically induced; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects; D013921:Thrombocytopenia / Q000139:chemically induced; D019772:Topotecan; D014839:Vomiting / Q000139:chemically induced
chemical_list: D016179:Granulocyte Colony-Stimulating Factor; D019772:Topotecan; D017239:Paclitaxel; D002166:Camptothecin