Amifostine does not protect against the ototoxicity of high-dose cisplatin combined with etoposide and bleomycin in pediatric germ-cell tumors - A children's Oncology Group study

Background. High-dose cisplatin combined with etoposide and bleomycin (HDPEB) improves event-free survival (EFS) in advanced pediatric germ-cell tumors (PGCT), but has significant ototoxicity. Amifostine appears to protect against toxicity. The authors combined amifostine with HDPEB and evaluated the efficacy and toxicity, specifically whether ototoxicity decreased. Methods. Eligibility criteria included age <15 years and unresectable Stage III/IV extracranial, extragonadal PGCT. Patients received bleomycin 15 IU/m(2) on Day 1, then etoposide 100 mg/m(2) per day, amifostine 825 mg/m(2) per day, and cisplatin 40 mg/m(2) per day on Days 1-5, intravenously. The cycles were repeated every 3-4 weeks with imaging evaluation after 4 cycles. Patients with residual radiographic abnormalities underwent resection. Patients with residual tumor received two additional HDPEB cycles. Hearing evaluations were required at diagnosis and after two and four cycles. Audiologic results were reviewed and compared with historical controls treated with HDPEB. Results. Twenty-five eligible patients were enrolled between April 2000 and April 2002. Their median age was 1.6 years (range, 0.64-13.9 years), 17 patients were female, 11 had metastases, and 24 had a yolk sac carcinoma component histologically. Primary sites included sacrococcygeal area/pelvis (n=15), vagina (n=5), and other (n=5). Two-year EFS and overall survival were 83.5%+/- 12.8% and 85.6%+/- 12.3%, respectively. Eight patients were removed from the study (four had progressive disease/disease recurrence and four had ototoxicity). Grade 3/4 toxicities included neutropenia (n=20), thrombocytopenia (n=14), electrolyte imbalances (n=14), and gastrointestinal toxicity (n=12). Twenty-four of 25 patients received hearing evaluations, and 75% had significant hearing loss. Conclusions. Amifostine did not protect against HDPEB-associated ototoxicity.