title: Dose and schedule-finding study of oral topotecan and weekly cisplatin in patients with recurrent ovarian cancer.
abstract: Both weekly cisplatin chemotherapy and single agent topotecan have proven to be effective in recurrent ovarian cancer. Preclinical data show synergism between cisplatin and topotecan. Side effects for this combination are drug sequence dependent and predominantly haematologic. Since preclinical data suggest that Cremophor EL (CrEL), the formulation vehicle of paclitaxel, has a protective effect on haematological toxicity of cisplatin, CrEL was added to the combination cisplatin and topotecan. In this phase I study, escalating doses of oral topotecan administered on day 1, 2, 8, 9, 15, 16, 29, 30, 36, 37, 43, 44 were combined with weekly cisplatin 70 mg m(-2) d(-1) on day 1, 8, 15, 29, 36, 43 (scheme A) or with the presumably less myelotoxic sequence weekly cisplatin day 2, 9, 16, 30, 37, 44 (scheme B). In scheme C, CrEL 12 ml was administered prior to cisplatin in the sequence of Scheme A. 18 patients have received a total of 85 courses. In scheme A 4/10 patients, all treated with topotecan 0.45 mg m(-2) d(-1), experienced DLT: 1 patient had vomiting grade 4, 1 patient had grade 4 neutropenia >5 days, 1 patient had >2 weeks delay due to thrombocytopenia and 1 patient due to neutropenia. Both patients in scheme B (topotecan 0.45 mg m(-2) d(-1)) had DLT due to a delay > 2 weeks because of prolonged haematological toxicity. No DLT was observed in the first 3 patients in scheme C (topotecan 0.45 mg m(-2) d(-1)). However, 2 out of 3 patients treated at dose level topotecan 0.60 mg m(-2)d(-1) in scheme C experienced DLT due to >2 weeks delay because of persistent thrombocytopenia or neutropenia. We conclude that there is a modest clinical effect of CrEL on haematological toxicity for this cisplatin-based combination regimen, which seems to reduce these side effects but does not really enable an increase of the oral topotecan dose.
authors.affiliation: Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek) and University Hospital Rotterdam, Rotterdam, AE, 3075, The Netherlands.
authors.forename: H
authors.initials: H
authors.lastname: Gelderblom
authors.forename: A
authors.initials: A
authors.lastname: Sparreboom
authors.forename: M J
authors.initials: MJ
authors.lastname: de Jonge
authors.forename: W J
authors.initials: WJ
authors.lastname: Loos
authors.forename: E
authors.initials: E
authors.lastname: Wilms
authors.forename: M A
authors.initials: MA
authors.lastname: Mantel
authors.forename: B
authors.initials: B
authors.lastname: Hennis
authors.forename: I
authors.initials: I
authors.lastname: Camlett
authors.forename: J
authors.initials: J
authors.lastname: Verweij
authors.forename: M E
authors.initials: ME
authors.lastname: van der Burg
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002945:Cisplatin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004334:Drug Administration Schedule; D005260:Female; D005990:Glycerol / Q000008:administration & dosage / Q000031:analogs & derivatives*; D006801:Humans; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D019772:Topotecan / Q000008:administration & dosage* / Q000493:pharmacokinetics
chemical_list: C000515:cremophor EL; D019772:Topotecan; D005990:Glycerol; D002945:Cisplatin