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.