title: Phase I pharmacologic study of oral topotecan and intravenous cisplatin: sequence-dependent hematologic side effects.
abstract: OBJECTIVE
  In in vitro studies, synergism and sequence-dependent effects were reported for the combination of topotecan and cisplatin. Recently, an oral formulation of topotecan became available. This phase I study was performed to assess the feasibility of the combination of oral topotecan and cisplatin, the pharmacokinetic interaction, and sequence-dependent effects.
  
  
  METHODS
  Topotecan was administered orally (PO) daily for 5 days in escalating doses and cisplatin was given intravenously (IV) at a fixed dose of 75 mg/m(2) either before topotecan administration on day 1 (sequence CT) or after topotecan administration on day 5 (sequence TC) once every 3 weeks. Patients were treated in a randomized cross-over design.
  
  
  RESULTS
  Forty-nine patients were entered onto the study; one patient was not eligible. Sequence CT induced significantly more severe myelosuppression than did sequence TC, and the maximum-tolerated dosage of topotecan in sequence CT was 1.25 mg/m(2)/d x 5. In sequence TC, the maximum-tolerated dosage of topotecan was 2.0 mg/m(2)/d x 5. Dose-limiting toxicity consisted of myelosuppression and diarrhea. Pharmacokinetics of topotecan and cisplatin were linear over the dose range studied; no sequence-dependent effects were observed. In addition, topotecan did not influence the protein binding of cisplatin or the platinum-DNA adduct formation in peripheral leukocytes in either sequence.
  
  
  CONCLUSIONS
  The recommended dosages for phase II studies involving patients like the patients in our study are topotecan 1.25 mg/m(2)/d PO x 5 preceded by cisplatin 75 mg/m(2) IV day 1 once every 3 weeks, and topotecan 2.0 mg/m(2)/d PO followed by cisplatin 75 mg/m(2) IV day 5. No pharmacokinetic interaction could be discerned in our study. The antitumor efficacy of both schedules should be evaluated in a randomized phase II study.
authors.affiliation: Department of Medical Oncology, Rotterdam Cancer Institute, and University Hospital Rotterdam, the Netherlands. jonge@onch.azr.nl
authors.forename: M J
authors.initials: MJ
authors.lastname: de Jonge
authors.forename: W J
authors.initials: WJ
authors.lastname: Loos
authors.forename: H
authors.initials: H
authors.lastname: Gelderblom
authors.forename: A S
authors.initials: AS
authors.lastname: Planting
authors.forename: M E
authors.initials: ME
authors.lastname: van der Burg
authors.forename: A
authors.initials: A
authors.lastname: Sparreboom
authors.forename: E
authors.initials: E
authors.lastname: Brouwer
authors.forename: V
authors.initials: V
authors.lastname: van Beurden
authors.forename: M A
authors.initials: MA
authors.lastname: Mantel
authors.forename: E
authors.initials: E
authors.lastname: Doyle
authors.forename: S
authors.initials: S
authors.lastname: Hearn
authors.forename: G
authors.initials: G
authors.lastname: Ross
authors.forename: J
authors.initials: J
authors.lastname: Verweij
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002945:Cisplatin / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D004334:Drug Administration Schedule; D004347:Drug Interactions; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy; D009503:Neutropenia / Q000139:chemically induced; D013921:Thrombocytopenia / Q000139:chemically induced; D019772:Topotecan / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*
chemical_list: D019772:Topotecan; D002945:Cisplatin