title: Sequential dose-intensive paclitaxel, ifosfamide, carboplatin, and etoposide salvage therapy for germ cell tumor patients.
abstract: OBJECTIVE
  To evaluate the efficacy and toxicity of sequential, dose-intensified chemotherapy with paclitaxel/ifosfamide and carboplatin/etoposide administered plus peripheral blood-derived stem-cell (PBSC) support for patients with germ cell tumors (GCT) who have unfavorable prognostic features in response to conventional-dose salvage programs. Carboplatin was dose escalated by target area under the curve (AUC; in [milligrams per milliliter] x minutes) among patient cohorts, and pharmacokinetic studies were performed for comparison.
  
  
  METHODS
  Thirty-seven previously treated patients who had cisplatin-resistant GCT and unfavorable prognostic features for response to conventional-dose salvage therapy were treated. Two cycles of paclitaxel 200 mg/m(2) plus ifosfamide 6 g/m(2) were given 2 weeks apart with leukapheresis, followed by three cycles of carboplatin plus etoposide given 14 to 21 days apart with reinfusion of PBSCs. The dose of etoposide was 1, 200 mg/m(2), and the carboplatin target AUC ranged among cohorts from 12 to 32 (mg/mL) x min. Pharmacokinetic studies of carboplatin were performed for comparison of target to measured AUC.
  
  
  RESULTS
  Twenty-one patients (57%) achieved a complete response and an additional two patients (5%) achieved a partial response with normal tumor markers; therefore, 23 (62%) achieved a favorable response. Eight patients relapsed, and 15 (41%) of the favorable responses remained durable at a median follow-up of 30 months. Myelosuppression was the major toxicity; 58% of carboplatin/etoposide cycles were associated with hospitalization for nadir fever. The AUC of carboplatin measured in serum was lower than the target AUC; this may be related to underestimation of the glomerular filtration rate used in the dosing formula.
  
  
  CONCLUSIONS
  Dose-intense therapy with sequential, accelerated chemotherapy of paclitaxel/ifosfamide and carboplatin/etoposide administered with PBSC support was relatively well tolerated. The durable complete response proportion was substantial in patients with unfavorable prognostic features for achieving durable complete response to conventional-dose salvage programs. Optimal dosing of carboplatin in the high-dose setting warrants further investigation.
authors.affiliation: Genitourinary Oncology, Nuclear Medicine, and Renal Services, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. motzerr@mskcc.org
authors.forename: R J
authors.initials: RJ
authors.lastname: Motzer
authors.forename: M
authors.initials: M
authors.lastname: Mazumdar
authors.forename: J
authors.initials: J
authors.lastname: Sheinfeld
authors.forename: D F
authors.initials: DF
authors.lastname: Bajorin
authors.forename: H A
authors.initials: HA
authors.lastname: Macapinlac
authors.forename: M
authors.initials: M
authors.lastname: Bains
authors.forename: L
authors.initials: L
authors.lastname: Reich
authors.forename: C
authors.initials: C
authors.lastname: Flombaum
authors.forename: T
authors.initials: T
authors.lastname: Mariani
authors.forename: W P
authors.initials: WP
authors.lastname: Tong
authors.forename: G J
authors.initials: GJ
authors.lastname: Bosl
mesh_terms: D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D019540:Area Under Curve; D016190:Carboplatin / Q000008:administration & dosage / Q000493:pharmacokinetics; D004334:Drug Administration Schedule; D005047:Etoposide / Q000008:administration & dosage; D005260:Female; D018237:Germinoma / Q000188:drug therapy*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007069:Ifosfamide / Q000008:administration & dosage; D007937:Leukapheresis; D008297:Male; D008875:Middle Aged; D017239:Paclitaxel / Q000008:administration & dosage; D011446:Prospective Studies; D016879:Salvage Therapy; D016019:Survival Analysis
chemical_list: D005047:Etoposide; D016190:Carboplatin; D017239:Paclitaxel; D007069:Ifosfamide