Phase II and pharmacologic study of topotecan administered as a 21-day continuous infusion to patients with colorectal cancer

PURPOSE: Topotecan is a specific inhibitor of topoisomerase I. Preclinical data have indicated that topoisomerase I inhibitors demonstrate more efficacy and have a greater therapeutic index with prolonged continuous exposure. The feasibility of this concept in humans using a 21-day continuous infusion of topotecan has been reported. We conducted a phase II study of this 21-day continuous topotecan administration schedule in patients with locally advanced, unresectable or metastatic colorectal cancer. PATIENTS AND METHODS: Topotecan, initially applied at a dose of 0.6 mg/m2/d, was administered as a continuous infusion via an ambulatory pump for 21 days repeated every 4 weeks. The starting dose was reduced to 0.5 mg/m2/d, because in five of the first 11 patients, the second course had to be delayed due to prolonged myelosuppression. Forty-two patients entered the study; one patient was ineligible and was excluded from further analyses. RESULTS: The overall response rate was 10%, with one complete and three partial responses. The median response duration was 7 months (range, 4 to 11). With this schedule, the major toxicity was prolonged cumulative myelosuppression, including a marked inhibition of erythropoiesis. A total transfusion of 250 U of erythrocytes was needed to maintain a hemoglobin level greater than 6.0 mmol/L. Other side effects were mild, and included alopecia (47%), periodic nausea (40%)/vomiting (22%), and fatigue (16%). Pharmacokinetic evaluation showed a mean steady-state plasma concentration (Css) of topotecan of 0.62 ng/mL (range, 0.33 to 1.1), with a significant relationship between the Css of topotecan and common cytotoxicity criteria (CTC) grade of leukocytopenia. CONCLUSION: Topotecan administered as a 21-day continuous infusion exerts minor activity as single-agent therapy in patients with metastatic colorectal cancer.