700 Phase II study with topotecan (T) administered as a 21-days continuous infusion to patients with colorectal cancer

T is a watersoluble semisynthetic analog of camptothecin which exerts cytotoxicity during the S-phase of the cell cycle through specific inhibition of topoisomerase I. Preclinical data have indicated that T is more effective with prolonged exposure. The clinical feasibility of this concept was recently reported by Hochster et al . (J.C.O. 1009: 12; 553–559) using a 21-days continuous infusion (c.i.). We performed a phase II study with T 0.6 mg/m 2 /d as a 21-days c.i. repeated every 28 days, in patients (pts) with metastatic colorectal cancer, not previously treated with chemotherapy. Dose reductions of 0.1 mg/m 2 /d were performed if myelosuppression persisted beyond day 28. If no toxicity worse than grade 2 occurred dose increases by 0.1 mg/m 2 /d were allowed. The starting dose was reduced to 0.5 mg/m 2 /d after in 5/11 pts the second course was delayed. Response was evaluated every 2 courses according to the WHO criteria, toxicity was scored according to the CTC criteria. To date, 41 pts have entered the study. Patient characteristics included: 22 females, 19 males; median age 57 years (range 37–68); median WHO performance score 1 (range 0–2). Two pts were unevaluable; 39 pts assessable for toxicity up to now received a total of 94 courses, median 3 per pt (range 1–9). The main toxicity was myelosuppression, with neutropenia grade 3–4 occurring in 26% of courses, median nadir of ANC occurring on day 25 (range 8–35), and thrombocytopenia being, relatively mild with the nadir also on day 25. Despite this mild myelotoxicity treatment had to be delayed in 24 courses (26%) mainly because of prolonged myelosuppression. As prescribed by protocol treatment delays mandated dose-reduction in the subsequent course. As a result of this median dose intensity (mg/m 2 /wk) decreased in the successive courses 1–9 from 2.62–2.62–2.62–2.1–2.1–1.92–2.1 to 2.1. In addition, a marked inhibition of the erythropoiesis was observed. Non-haematological disease effects were mild, nausea grade 1–2 occurred in 25 courses (26%), vomiting in 15 courses (16%), and asthenia and fatigue in 32 courses (34%). Alopecia being grade 2, except in one, was seen in 8 pts (20%). Steady-state (Css) levels of T were determined by HPLC during the first 2 courses and varied widely: 0.65 ± 0.15 ng/ml (range 0.37–6.91, N = 15). No significant correlation was found between Css and absolute dose. In the 30 pts presently evaluable for response 1 CR and 2 PRs were observed. In conclusion, this dosing schedule is relatively well tolerated but has only modest clinical activity in colorectal cancer.