title: Pharmacokinetically guided phase I trial of topotecan and etoposide phosphate in recurrent ovarian cancer.
abstract: A pharmacokinetically guided phase I study of topotecan and etoposide phosphate was conducted in recurrent ovarian cancer. The scheduling of the topoisomerase I and II inhibitors was determined using in vitro activity data. All patients had recurrent disease following prior platinum-containing chemotherapy. Patients had a World Health Organisation performance status of 0-2 and adequate bone marrow, renal and hepatic function. Treatment was with topotecan intravenously for 5 days followed immediately by a 5-day intravenous infusion of etoposide phosphate (EP), with pharmacokinetically guided dose adjustment. Plasma etoposide levels were measured on days 2 and 4 of the infusion. A total of 21 patients entered the study. In all, 48% were platinum resistant and 71% had received prior paclitaxel. The main toxicities were haematological, short lived and reversible. A total of 29% of patients experienced grade 4 thrombocytopenia and 66% grade 4 neutropenia after the first cycle. Neutropenia and thrombocytopenia was dose limiting. The maximum-tolerated dose was topotecan 0.85 mg m(-2) day(-1) days 1-5 followed immediately by a 5-day infusion of EP at a plasma concentration of 1 mug ml(-1). The response rate (RR) was 28% in 18 evaluable patients. There was marked interpatient variability in topoisomerase IIalpha levels measured from peripheral lymphocytes, with no observed increase following topotecan. This regimen of topotecan followed by EP demonstrated good activity in recurrent ovarian cancer and was noncrossresistant with paclitaxel. Both the toxicity and RR was higher than would be expected from the single agent data, in keeping with synergy of action.
authors.affiliation: Cancer Research UK Cancer Centre, Churchill Hospital, Oxford OX3 7LJ, UK.
authors.forename: N C
authors.initials: NC
authors.lastname: Levitt
authors.forename: D J
authors.initials: DJ
authors.lastname: Propper
authors.forename: S
authors.initials: S
authors.lastname: Madhusudan
authors.forename: J P
authors.initials: JP
authors.lastname: Braybrooke
authors.forename: C
authors.initials: C
authors.lastname: Echeta
authors.forename: R
authors.initials: R
authors.lastname: Te Poele
authors.forename: S L
authors.initials: SL
authors.lastname: Davies
authors.forename: E
authors.initials: E
authors.lastname: Flanagan
authors.forename: I D
authors.initials: ID
authors.lastname: Hickson
authors.forename: S
authors.initials: S
authors.lastname: Joel
authors.forename: T S
authors.initials: TS
authors.lastname: Ganesan
mesh_terms: D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm / Q000097:blood; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D004250:DNA Topoisomerases, Type II / Q000097:blood; D004268:DNA-Binding Proteins / Q000097:blood; D005047:Etoposide / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D008875:Middle Aged; D009943:Organophosphorus Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D011788:Quality of Life; D012008:Recurrence; D019772:Topotecan / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D000951:Antigens, Neoplasm; D004268:DNA-Binding Proteins; D009943:Organophosphorus Compounds; C061400:etoposide phosphate; D005047:Etoposide; D019772:Topotecan; D004250:DNA Topoisomerases, Type II