Amifostine pretreatment for protection against topotecan-induced hematologic toxicity: results of a multicenter phase III trial in patients with advanced gynecologic malignancies☆

Abstract Objective. To determine if amifostine could reduce the hematologic toxicity associated with topotecan. Methods Thirty patients with recurrent/refractory gynecologic malignancies were randomized to receive topotecan (TOPO) (1.5 mg/m 2 /day days 1–5) with or without amifostine (AMI/TOPO) (500 mg/m 2 /day days 1–5) every 3 weeks for six cycles. The primary study endpoints were the incidence of grade 3 and 4 neutropenia. Results Fifteen patients were randomized to each arm for a total of 49 TOPO and 53 AMI/TOPO cycles. Patient characteristics and pretreatment ANC were similar between groups. Topotecan 1.5 mg/m 2 /day days 1–5 was initially administered to seven patients. Five developed neutropenic fevers, one an uncomplicated grade 4 neutropenia, and the other an uncomplicated grade 3 neutropenia. There were two treatment-related deaths due to sepsis (one in each treatment arm). The starting dose was thereafter reduced to 1.25 mg/m 2 /day days 1–5 every 21 days. No treatment related deaths occurred after this dose reduction. The incidence of combined grade 3/4 neutropenia was reduced from 67% (33/49 cycles) to 38% (20/53 cycles) with the addition of amifostine ( P = 0.003; OR 0.29; 95% CI 0.12–0.71). Conclusions Topotecan at 1.5 mg/m 2 /day days 1–5 in heavily pretreated patients resulted in excessive toxicity not manageable with amifostine. At the reduced topotecan dose (1.25 mg/m 2 × 5 days), pretreatment with amifostine reduced the hematologic toxicity associated with topotecan chemotherapy in women with recurrent/refractory gynecologic malignancies.