title: Phase I/II trial of carboplatin dose escalation in combination chemotherapy with etoposide, bleomycin and GM-CSF support for poor prognosis nonseminomatous germ cell tumors patients.
abstract: To determine the maximum tolerated dose (MTD), and therapeutic efficacy of carboplatin (CBDCA) in combination with etoposide and bleomycin (CEB) as initial chemotherapy for poor prognosis germ cell tumors, a CBDCA dose escalation supported with GM-CSF had been performed. Twenty four untreated patients were treated with CBDCA 400 mg/m2 on day 1, etoposide 100 mg/m2 on days 1 to 5 and bleomycin 30 mg on days 1, 3, 5. Four cycles were scheduled at 21-day interval. The first cohort of 6 patients received only initial chemotherapy regimen. In the subsequent cohorts of six patients, the CBDCA dose was increased by 100 mg/m2. A fixed dose and schedule of GM-CSF at 5 micrograms/kg subcutaneously was given on days 6 through 15. Myelosuppression, with neutropenic fever and hemorrhages, was the dose-limiting toxicity at the 600 mg/m2 dose level. The recommended dose of CBDCA is 500 mg/m2. Overall complete response (CR) rate was 71% and with median follow up of 25 (16-34) months, 58% of patients are alive and have no evidence of disease (NED). A higher number of CR was achieved with CBDCA dose higher than 400 mg/m2 compared with CBDCA dose of 400 mg/m2 (92 vs. 50%, p = 0.03), as well as a higher proportion of patients who are alive and with NED (75 vs. 42%, p = 0.1). Despite GM-CSF support, the MTD of CBDCA could not be increased beyond 500 mg/m2 (50% of the dose escalation), due to severe myelosuppression. The treatment outcomes obtained with CEB in our study are no better than the standard cisplatin-based chemotherapy. Further studies of this regimen, where CBDCA dose should be calculated according to the patients glomerular filtration rate are warranted.
authors.affiliation: Department of Clinical Pharmacology and Chemotherapy, Cancer Research Center, Moscow, Russia.
authors.forename: S A
authors.initials: SA
authors.lastname: Tjulandin
authors.forename: M B
authors.initials: MB
authors.lastname: Stenina
authors.forename: N J
authors.initials: NJ
authors.lastname: Sidorova
authors.forename: F G
authors.initials: FG
authors.lastname: Delgado
authors.forename: A V
authors.initials: AV
authors.lastname: Sokolov
authors.forename: G V
authors.initials: GV
authors.lastname: Molchanov
authors.forename: N V
authors.initials: NV
authors.lastname: Ljubimova
authors.forename: A M
authors.initials: AM
authors.lastname: Garin
mesh_terms: D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D001761:Bleomycin / Q000008:administration & dosage; D016190:Carboplatin / Q000008:administration & dosage; D005047:Etoposide / Q000008:administration & dosage; D018237:Germinoma / Q000188:drug therapy*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000627:therapeutic use; D006801:Humans; D009503:Neutropenia / Q000139:chemically induced / Q000517:prevention & control; D011379:Prognosis
chemical_list: D001761:Bleomycin; D005047:Etoposide; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D016190:Carboplatin