PHASE-II TRIAL OF HIGH-DOSE CARBOPLATIN AND ETOPOSIDE WITH AUTOLOGOUSBONE-MARROW TRANSPLANTATION IN 1ST-LINE THERAPY FOR PATIENTS WITH POOR-RISK GERM-CELL TUMORS

Background: Between 20% and 30% of patients with advanced germ cell tu mors (GCTs) fail to have durable complete response to conventional cis platin-based induction chemotherapy. However, third-line therapy with high-dose carboplatin and etoposide plus autologous bone marrow transp lantation (AuBMT) has induced durable complete response in 10%-20% of patients with cisplatin-resistant GCT. Purpose: We conducted a phase I I trial of first-line therapy that included high-dose carboplatin and etoposide plus AuBMT in untreated men with advanced GCTs and unfavorab le prognosis (i.e., ''poor-risk'' patients). Methods: Twenty-eight pat ients were treated with a conventional-dose, cisplatin-containing regi men (VAB-6 [cisplatin, vinblastine, bleomycin, cyclophosphamide, dacti nomycin]) with or without high-dose carboplatin (1500 mg/m2) and etopo side (1200 mg/m2) plus AuBMT. Twenty-two of these patients were select ed for treatment with two cycles of high-dose carboplatin and etoposid e plus AuBMT when reduced clearance of serum tumor markers (alpha-feto protein [AFP] or human chorionic gonadotropin [HCG]), as evidenced by prolonged half-life (>7 days for AFP and >3 days for HCG), was observe d after two cycles of conventional treatment. Results: Fifteen (56%) o f 27 patients considered assessable for response achieved a complete r esponse (12 treated with high-dose chemotherapy plus AuBMT). Sixteen ( 57%) are alive; 13 (46%) are free of disease at a median follow-up of 31.2 months. For 36 cycles of high-dose chemotherapy, the median durat ion from bone marrow infusion until a granulocyte count of 0.5/mm3 and a platelet count of 50000/mm3 was 16 days (range, 7-41 days and 8-30 days, respectively). Analysis showed a trend toward improved survival (P = .07) in patients treated with high-dose chemotherapy in this stud y, compared with 68 poor-risk patients with GCT treated with conventio nal-dose therapy alone in two earlier studies. Toxicity was not cumula tive, and recovery of blood counts after AuBMT was generally rapid. Co nclusions: Inclusion of high-dose carboplatin-containing chemotherapy in treatment of poor-risk GCT patients is feasible when serum tumor ma rker half-life is used to predict resistance to standard cisplatin-bas ed therapy. High-dose therapy in this setting was well tolerated. Impl ications: Early use of a dose-intensive regimen may increase survival compared with conventional-dose therapy alone. Further studies with st andard induction therapy and intensive high-dose therapy using hematop oietic growth factor support are warranted, followed by a randomized t rial comparing this strategy with standard therapy.