title: High-dose sequential chemotherapy (HDS) versus PEB chemotherapy as first-line treatment of patients with poor prognosis germ-cell tumors: mature results of an Italian randomized phase II study.
abstract: BACKGROUND
  In the late 1990s, the use of high-dose chemotherapy (HDCT) and stem-cell rescue held promise for patients with advanced and poor prognosis germ-cell tumors (GCT). We started a randomized phase II trial to assess the efficacy of sequential HDCT compared with cisplatin, etoposide, and bleomycin (PEB).
  
  
  METHODS
  Patients were randomly assigned to receive four cycles of PEB every 3 weeks or two cycles of PEB followed by a high-dose sequence (HDS) comprising HD-cyclophosphamide (7.0 g/m(2)), 2 courses of cisplatin and HD-etoposide (2.4 g/m(2)) with stem-cell support, and a single course of HD-carboplatin [area under the curve (AUC) 27 mg/ml × min] with autologous stem-cell transplant. Postchemotherapy surgery was planned on responding residual disease in both arms. The primary end point was progression-free survival (PFS). The study was designed to detect a 30% improvement of 5-year PFS (from 40% to 70%), with 80% power and two-sided α at 5%.
  
  
  RESULTS
  From December 1996 to March 2007, 85 patients were randomized: 43 in PEB and 42 in HDS arm. Median follow-up was 114.2 months [interquartile range (IQR): 87.7-165.8]. Complete or partial response with normal markers (PRm-) were obtained in 28 (65.1%) and 29 (69.1%) patients, respectively. Five-year PFS was 55.8% [95% confidence interval (CI) 42.8-72.8] and 54.8% (95% CI 41.6%-72.1%) in PEB and HDS arm, respectively (log-rank test P = 0.726). Five-year overall survival was 62.8% (95% CI 49.9-79.0) and 59.3% (95% CI 46.1-76.3). One toxic death (PEB arm) was recorded.
  
  
  CONCLUSIONS
  The study failed to meet the primary end point. Furthermore, survival estimates of conventional-dose chemotherapy higher than expected should be accounted for and will likely limit further improvements in the first-line setting. CLINICALTRIALS.GOV: NCT02161692.
authors.affiliation: Department of Medical Oncology. Electronic address: andrea.necchi@istitutotumori.mi.it.
authors.forename: A
authors.initials: A
authors.lastname: Necchi
authors.affiliation: Clinical Epidemiology and Trials Organization Unit.
authors.forename: L
authors.initials: L
authors.lastname: Mariani
authors.affiliation: Department of Medical Oncology.
authors.forename: M
authors.initials: M
authors.lastname: Di Nicola
authors.affiliation: Clinical Epidemiology and Trials Organization Unit.
authors.forename: S
authors.initials: S
authors.lastname: Lo Vullo
authors.affiliation: Department of Surgery, Urology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan.
authors.forename: N
authors.initials: N
authors.lastname: Nicolai
authors.affiliation: Department of Medical Oncology.
authors.forename: P
authors.initials: P
authors.lastname: Giannatempo
authors.affiliation: Department of Medical Oncology.
authors.forename: D
authors.initials: D
authors.lastname: Raggi
authors.affiliation: Department of Medical Oncology.
authors.forename: E
authors.initials: E
authors.lastname: Farè
authors.affiliation: Department of Medical Oncology.
authors.forename: M
authors.initials: M
authors.lastname: Magni
authors.affiliation: Department of Surgery, Urology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan.
authors.forename: L
authors.initials: L
authors.lastname: Piva
authors.affiliation: Department of Medical Oncology.
authors.forename: P
authors.initials: P
authors.lastname: Matteucci
authors.affiliation: Department of Surgery, Urology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan.
authors.forename: M
authors.initials: M
authors.lastname: Catanzaro
authors.affiliation: Department of Surgery, Urology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan.
authors.forename: D
authors.initials: D
authors.lastname: Biasoni
authors.affiliation: Department of Surgery, Urology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan.
authors.forename: T
authors.initials: T
authors.lastname: Torelli
authors.affiliation: Department of Surgery, Urology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan.
authors.forename: S
authors.initials: S
authors.lastname: Stagni
authors.affiliation: Department of Medical Oncology, Ospedale Misericordia, Grosseto.
authors.forename: C
authors.initials: C
authors.lastname: Bengala
authors.affiliation: Department of Medical Oncology, Oncologia Medica ASL TO5 Ospedale di Carmagnola, Turin.
authors.forename: C
authors.initials: C
authors.lastname: Barone
authors.affiliation: Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, Milan.
authors.forename: I
authors.initials: I
authors.lastname: Schiavetto
authors.affiliation: Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, Milan.
authors.forename: S
authors.initials: S
authors.lastname: Siena
authors.affiliation: Department of Oncology and Hematology, Humanitas Cancer Center, Humanitas Clinical and Research Center, Rozzano; Department of Medical Biotechnology and Translational Medicine.
authors.forename: C
authors.initials: C
authors.lastname: Carlo-Stella
authors.affiliation: Department of Surgery, Urology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan.
authors.forename: G
authors.initials: G
authors.lastname: Pizzocaro
authors.affiliation: Department of Surgery, Urology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan.
authors.forename: R
authors.initials: R
authors.lastname: Salvioni
authors.affiliation: Department of Medical Oncology; Department of Pathophysiology and Transplantation, University of Milano, Milan, Italy.
authors.forename: A M
authors.initials: AM
authors.lastname: Gianni
mesh_terms: D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D001761:Bleomycin / Q000008:administration & dosage; D016190:Carboplatin / Q000008:administration & dosage / Q000627:therapeutic use; D002945:Cisplatin / Q000008:administration & dosage; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000627:therapeutic use; D018572:Disease-Free Survival; D004338:Drug Combinations; D005047:Etoposide / Q000008:administration & dosage; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D009373:Neoplasms, Germ Cell and Embryonal / Q000188:drug therapy* / Q000401:mortality; D013736:Testicular Neoplasms / Q000188:drug therapy* / Q000401:mortality; D055815:Young Adult
chemical_list: D004338:Drug Combinations; D001761:Bleomycin; D005047:Etoposide; D003520:Cyclophosphamide; D016190:Carboplatin; D002945:Cisplatin
keywords: germ-cell cancer; high-dose chemotherapy; poor prognosis; testicular neoplasms; transplantation