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

Author(s): Gold MA, Walker JL, Berek JS, Hallum AV 3rd, Garcia DJ, Alberts DS

Affiliation(s): University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA. michael-gold@ouhsc.edu

Publication date & source: 2003-08, Gynecol Oncol., 90(2):325-30.

Publication type: Clinical Trial; Clinical Trial, Phase III; Multicenter Study; Randomized Controlled Trial

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) x 5 days), pretreatment with amifostine reduced the hematologic toxicity associated with topotecan chemotherapy in women with recurrent/refractory gynecologic malignancies.