title: Prognostic reclassification of patients with intermediate-risk metastatic germ cell tumors: Implications for clinical practice, trial design, and molecular interrogation.
abstract: OBJECTIVE
  Approximately one-third of the metastatic germ cell tumors (GCT) in patients are classified as intermediate-risk metastatic GCT, and available guidelines recommend the same treatment of poor-risk cases. Yet the prognosis of these patients is heterogeneous, and consequently refining the intensity of treatment is warranted. We aimed to address the heterogeneity of this category by providing a proof of principle for reclassification attempt.
  
  
  METHODS
  Data on consecutive patients with intermediate-risk metastatic GCT and who received treatment at Fondazione INT Milano in the time frame between February 1980 and March 2014 were collected. Cox regression analyses were done, evaluating potential prognostic factors for overall survival (OS, primary end point) to first-line therapy. Each factor was evaluated in a multivariable model. Recursive partitioning was performed to define prognostic risk groups.
  
  
  RESULTS
  A total of 224 patients were suitable for the present analysis. Median age was 26 years (interquartile range: 22-31), 11 patients (4.9%) had a retroperitoneal primary tumor, 6 yielded seminomatous histology, 85 (37.9%) had lung metastases, and 58 (25.9%) had bulky (i.e.,≥ 10 cm) retroperitoneal lymph nodes. Patients received cisplatin, bleomycin, and etoposide (PEB, n = 199) or vinblastine (PVB, n = 23); however, 2 patients received other treatments. Median follow-up was 135 months (interquartile range: 81-223). Globally, 5-year progression-free survival and OS rates were 72.8% (95% CI: 67.1-79.0) and 86.2% (81.7-91.0), respectively. In the multivariable model for OS, elevated alfa fetoprotein (AFP) level was the only significant prognostic factor (hazard ratio = 1.48, 95% CI: 1.12-1.96). The 2 separate prognostic groups with differential OS outcomes were identified based on the cutoff level of 6,200 IU/ml. The 10-year OS rate was 55.6% (95% CI: 36.6-84.3), and it was 86.7% (95% CI: 82.0-91.7) for those with AFP levels more than (n = 19, 8.5%) and less than (n = 205, 91.5%) the cutoff, respectively.
  
  
  CONCLUSIONS
  A small fraction of patients with highly elevated AFP levels have an OS approximating the poor prognostic category, whereas most of them are close to good-risk cases. This might have implications to select outlier patients for clinical trials and molecular characterization.
authors.affiliation: Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Raggi
authors.affiliation: Clinical Epidemiology and Trials Organization Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Mariani
authors.affiliation: Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Giannatempo
authors.affiliation: Clinical Epidemiology and Trials Organization Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Lo Vullo
authors.affiliation: Clinical Epidemiology and Trials Organization Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Giardiello
authors.affiliation: Department of Surgery, Urology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Nicolai
authors.affiliation: Department of Surgery, Urology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Piva
authors.affiliation: Department of Surgery, Urology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Biasoni
authors.affiliation: Department of Surgery, Urology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Catanzaro
authors.affiliation: Department of Surgery, Urology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Tullio
authors.initials: T
authors.lastname: Torelli
authors.affiliation: Department of Surgery, Urology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Stagni
authors.affiliation: Department of Surgery, Urology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Maffezzini
authors.affiliation: Department of Radiology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Calareso
authors.affiliation: Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Magni
authors.affiliation: Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Di Nicola
authors.affiliation: Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Verzoni
authors.affiliation: Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Grassi
authors.affiliation: Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Procopio
authors.affiliation: Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: De Braud
authors.affiliation: Department of Surgery, Urology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Pizzocaro
authors.affiliation: Department of Surgery, Urology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Salvioni
authors.affiliation: Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. Electronic address: andrea.necchi@istitutotumori.mi.it.
authors.forename: Andrea
authors.initials: A
authors.lastname: Necchi
mesh_terms: D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D018572:Disease-Free Survival; D006801:Humans; D008297:Male; D009373:Neoplasms, Germ Cell and Embryonal / Q000145:classification* / Q000188:drug therapy / Q000401:mortality; D011379:Prognosis; D016016:Proportional Hazards Models; D012107:Research Design; D012186:Retroperitoneal Neoplasms / Q000145:classification* / Q000188:drug therapy / Q000401:mortality; D012189:Retrospective Studies; D055815:Young Adult; D000509:alpha-Fetoproteins / Q000378:metabolism
chemical_list: D000509:alpha-Fetoproteins
keywords: Germ cell tumor; Intermediate Risk; Prognosis; Survival; Testicular cancer