title: Revised risk classification for pediatric extracranial germ cell tumors based on 25 years of clinical trial data from the United Kingdom and United States.
abstract: OBJECTIVE
  To risk stratify malignant extracranial pediatric germ cell tumors (GCTs).
  
  
  METHODS
  Data from seven GCT trials conducted by the Children's Oncology Group (United States) or the Children's Cancer and Leukemia Group (United Kingdom) between 1985 and 2009 were merged to create a data set of patients with stage II to IV disease treated with platinum-based therapy. A parametric cure model was used to evaluate the prognostic importance of age, tumor site, stage, histology, tumor markers, and treatment regimen and estimate the percentage of patients who achieved long-term disease-free (LTDF) survival in each subgroup of the final model. Validation of the model was conducted using the bootstrap method.
  
  
  RESULTS
  In multivariable analysis of 519 patients with GCTs, stage IV disease (P = .001), age ≥ 11 years (P < .001), and tumor site (P < .001) were significant predictors of worse LTDF survival. Elevated alpha-fetoprotein (AFP) ≥ 10,000 ng/mL was associated with worse outcome, whereas pure yolk sac tumor (YST) was associated with better outcome, although neither met criteria for statistical significance. The analysis identified a group of patients age > 11 years with either stage III to IV extragonadal tumors or stage IV ovarian tumors with predicted LTDF survival < 70%. A bootstrap procedure showed retention of age, tumor site, and stage in > 94%, AFP in 12%, and YST in 27% of the replications.
  
  
  CONCLUSIONS
  Clinical trial data from two large national pediatric clinical trial organizations have produced a new evidence-based risk stratification of malignant pediatric GCTs that identifies a poor-risk group warranting intensified therapy.
authors.affiliation: A. Lindsay Frazier and Carlos Rodriguez-Galindo, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, MA; Juliet P. Hale, Newcastle upon Tyne Hospitals National Health Service (NHS) Foundation Trust, Newcastle upon Tyne; Matthew J. Murray and James C. Nicholson, Cambridge University Hospitals NHS Foundation Trust; Matthew J. Murray, University of Cambridge, Cambridge; Claire Thornton, Royal Victoria Hospital, Belfast Health Trust, Belfast; G. Suren Arul, Birmingham Children's Hospital NHS Foundation Trust, Birgmingham; Sara Stoneham, Children's and Young Persons Cancer Services, University College London Hospital Trusts, London, United Kingdom; Ha Dang, Children's Oncology Group; Mark Krailo, University of Southern California, Los Angeles, CA; Thomas Olson, Children's Healthcare of Atlanta, Emory University, Atlanta, GA; James F. Amatruda, University of Texas Southwestern Medical Center and Children's Medical Center Dallas, Dallas, TX; Deborah Billmire, Riley Hospital for Children, Indianapolis, IN; Furqan Shaikh, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada; and Farzana Pashankar, Yale Cancer Center, New Haven, CT. lindsay_frazier@dfci.harvard.edu.
authors.forename: A Lindsay
authors.initials: AL
authors.lastname: Frazier
authors.affiliation: A. Lindsay Frazier and Carlos Rodriguez-Galindo, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, MA; Juliet P. Hale, Newcastle upon Tyne Hospitals National Health Service (NHS) Foundation Trust, Newcastle upon Tyne; Matthew J. Murray and James C. Nicholson, Cambridge University Hospitals NHS Foundation Trust; Matthew J. Murray, University of Cambridge, Cambridge; Claire Thornton, Royal Victoria Hospital, Belfast Health Trust, Belfast; G. Suren Arul, Birmingham Children's Hospital NHS Foundation Trust, Birgmingham; Sara Stoneham, Children's and Young Persons Cancer Services, University College London Hospital Trusts, London, United Kingdom; Ha Dang, Children's Oncology Group; Mark Krailo, University of Southern California, Los Angeles, CA; Thomas Olson, Children's Healthcare of Atlanta, Emory University, Atlanta, GA; James F. Amatruda, University of Texas Southwestern Medical Center and Children's Medical Center Dallas, Dallas, TX; Deborah Billmire, Riley Hospital for Children, Indianapolis, IN; Furqan Shaikh, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada; and Farzana Pashankar, Yale Cancer Center, New Haven, CT.
authors.forename: Juliet P
authors.initials: JP
authors.lastname: Hale
authors.affiliation: A. Lindsay Frazier and Carlos Rodriguez-Galindo, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, MA; Juliet P. Hale, Newcastle upon Tyne Hospitals National Health Service (NHS) Foundation Trust, Newcastle upon Tyne; Matthew J. Murray and James C. Nicholson, Cambridge University Hospitals NHS Foundation Trust; Matthew J. Murray, University of Cambridge, Cambridge; Claire Thornton, Royal Victoria Hospital, Belfast Health Trust, Belfast; G. Suren Arul, Birmingham Children's Hospital NHS Foundation Trust, Birgmingham; Sara Stoneham, Children's and Young Persons Cancer Services, University College London Hospital Trusts, London, United Kingdom; Ha Dang, Children's Oncology Group; Mark Krailo, University of Southern California, Los Angeles, CA; Thomas Olson, Children's Healthcare of Atlanta, Emory University, Atlanta, GA; James F. Amatruda, University of Texas Southwestern Medical Center and Children's Medical Center Dallas, Dallas, TX; Deborah Billmire, Riley Hospital for Children, Indianapolis, IN; Furqan Shaikh, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada; and Farzana Pashankar, Yale Cancer Center, New Haven, CT.
authors.forename: Carlos
authors.initials: C
authors.lastname: Rodriguez-Galindo
authors.affiliation: A. Lindsay Frazier and Carlos Rodriguez-Galindo, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, MA; Juliet P. Hale, Newcastle upon Tyne Hospitals National Health Service (NHS) Foundation Trust, Newcastle upon Tyne; Matthew J. Murray and James C. Nicholson, Cambridge University Hospitals NHS Foundation Trust; Matthew J. Murray, University of Cambridge, Cambridge; Claire Thornton, Royal Victoria Hospital, Belfast Health Trust, Belfast; G. Suren Arul, Birmingham Children's Hospital NHS Foundation Trust, Birgmingham; Sara Stoneham, Children's and Young Persons Cancer Services, University College London Hospital Trusts, London, United Kingdom; Ha Dang, Children's Oncology Group; Mark Krailo, University of Southern California, Los Angeles, CA; Thomas Olson, Children's Healthcare of Atlanta, Emory University, Atlanta, GA; James F. Amatruda, University of Texas Southwestern Medical Center and Children's Medical Center Dallas, Dallas, TX; Deborah Billmire, Riley Hospital for Children, Indianapolis, IN; Furqan Shaikh, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada; and Farzana Pashankar, Yale Cancer Center, New Haven, CT.
authors.forename: Ha
authors.initials: H
authors.lastname: Dang
authors.affiliation: A. Lindsay Frazier and Carlos Rodriguez-Galindo, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, MA; Juliet P. Hale, Newcastle upon Tyne Hospitals National Health Service (NHS) Foundation Trust, Newcastle upon Tyne; Matthew J. Murray and James C. Nicholson, Cambridge University Hospitals NHS Foundation Trust; Matthew J. Murray, University of Cambridge, Cambridge; Claire Thornton, Royal Victoria Hospital, Belfast Health Trust, Belfast; G. Suren Arul, Birmingham Children's Hospital NHS Foundation Trust, Birgmingham; Sara Stoneham, Children's and Young Persons Cancer Services, University College London Hospital Trusts, London, United Kingdom; Ha Dang, Children's Oncology Group; Mark Krailo, University of Southern California, Los Angeles, CA; Thomas Olson, Children's Healthcare of Atlanta, Emory University, Atlanta, GA; James F. Amatruda, University of Texas Southwestern Medical Center and Children's Medical Center Dallas, Dallas, TX; Deborah Billmire, Riley Hospital for Children, Indianapolis, IN; Furqan Shaikh, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada; and Farzana Pashankar, Yale Cancer Center, New Haven, CT.
authors.forename: Thomas
authors.initials: T
authors.lastname: Olson
authors.affiliation: A. Lindsay Frazier and Carlos Rodriguez-Galindo, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, MA; Juliet P. Hale, Newcastle upon Tyne Hospitals National Health Service (NHS) Foundation Trust, Newcastle upon Tyne; Matthew J. Murray and James C. Nicholson, Cambridge University Hospitals NHS Foundation Trust; Matthew J. Murray, University of Cambridge, Cambridge; Claire Thornton, Royal Victoria Hospital, Belfast Health Trust, Belfast; G. Suren Arul, Birmingham Children's Hospital NHS Foundation Trust, Birgmingham; Sara Stoneham, Children's and Young Persons Cancer Services, University College London Hospital Trusts, London, United Kingdom; Ha Dang, Children's Oncology Group; Mark Krailo, University of Southern California, Los Angeles, CA; Thomas Olson, Children's Healthcare of Atlanta, Emory University, Atlanta, GA; James F. Amatruda, University of Texas Southwestern Medical Center and Children's Medical Center Dallas, Dallas, TX; Deborah Billmire, Riley Hospital for Children, Indianapolis, IN; Furqan Shaikh, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada; and Farzana Pashankar, Yale Cancer Center, New Haven, CT.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Murray
authors.affiliation: A. Lindsay Frazier and Carlos Rodriguez-Galindo, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, MA; Juliet P. Hale, Newcastle upon Tyne Hospitals National Health Service (NHS) Foundation Trust, Newcastle upon Tyne; Matthew J. Murray and James C. Nicholson, Cambridge University Hospitals NHS Foundation Trust; Matthew J. Murray, University of Cambridge, Cambridge; Claire Thornton, Royal Victoria Hospital, Belfast Health Trust, Belfast; G. Suren Arul, Birmingham Children's Hospital NHS Foundation Trust, Birgmingham; Sara Stoneham, Children's and Young Persons Cancer Services, University College London Hospital Trusts, London, United Kingdom; Ha Dang, Children's Oncology Group; Mark Krailo, University of Southern California, Los Angeles, CA; Thomas Olson, Children's Healthcare of Atlanta, Emory University, Atlanta, GA; James F. Amatruda, University of Texas Southwestern Medical Center and Children's Medical Center Dallas, Dallas, TX; Deborah Billmire, Riley Hospital for Children, Indianapolis, IN; Furqan Shaikh, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada; and Farzana Pashankar, Yale Cancer Center, New Haven, CT.
authors.forename: James F
authors.initials: JF
authors.lastname: Amatruda
authors.affiliation: A. Lindsay Frazier and Carlos Rodriguez-Galindo, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, MA; Juliet P. Hale, Newcastle upon Tyne Hospitals National Health Service (NHS) Foundation Trust, Newcastle upon Tyne; Matthew J. Murray and James C. Nicholson, Cambridge University Hospitals NHS Foundation Trust; Matthew J. Murray, University of Cambridge, Cambridge; Claire Thornton, Royal Victoria Hospital, Belfast Health Trust, Belfast; G. Suren Arul, Birmingham Children's Hospital NHS Foundation Trust, Birgmingham; Sara Stoneham, Children's and Young Persons Cancer Services, University College London Hospital Trusts, London, United Kingdom; Ha Dang, Children's Oncology Group; Mark Krailo, University of Southern California, Los Angeles, CA; Thomas Olson, Children's Healthcare of Atlanta, Emory University, Atlanta, GA; James F. Amatruda, University of Texas Southwestern Medical Center and Children's Medical Center Dallas, Dallas, TX; Deborah Billmire, Riley Hospital for Children, Indianapolis, IN; Furqan Shaikh, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada; and Farzana Pashankar, Yale Cancer Center, New Haven, CT.
authors.forename: Claire
authors.initials: C
authors.lastname: Thornton
authors.affiliation: A. Lindsay Frazier and Carlos Rodriguez-Galindo, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, MA; Juliet P. Hale, Newcastle upon Tyne Hospitals National Health Service (NHS) Foundation Trust, Newcastle upon Tyne; Matthew J. Murray and James C. Nicholson, Cambridge University Hospitals NHS Foundation Trust; Matthew J. Murray, University of Cambridge, Cambridge; Claire Thornton, Royal Victoria Hospital, Belfast Health Trust, Belfast; G. Suren Arul, Birmingham Children's Hospital NHS Foundation Trust, Birgmingham; Sara Stoneham, Children's and Young Persons Cancer Services, University College London Hospital Trusts, London, United Kingdom; Ha Dang, Children's Oncology Group; Mark Krailo, University of Southern California, Los Angeles, CA; Thomas Olson, Children's Healthcare of Atlanta, Emory University, Atlanta, GA; James F. Amatruda, University of Texas Southwestern Medical Center and Children's Medical Center Dallas, Dallas, TX; Deborah Billmire, Riley Hospital for Children, Indianapolis, IN; Furqan Shaikh, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada; and Farzana Pashankar, Yale Cancer Center, New Haven, CT.
authors.forename: G Suren
authors.initials: GS
authors.lastname: Arul
authors.affiliation: A. Lindsay Frazier and Carlos Rodriguez-Galindo, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, MA; Juliet P. Hale, Newcastle upon Tyne Hospitals National Health Service (NHS) Foundation Trust, Newcastle upon Tyne; Matthew J. Murray and James C. Nicholson, Cambridge University Hospitals NHS Foundation Trust; Matthew J. Murray, University of Cambridge, Cambridge; Claire Thornton, Royal Victoria Hospital, Belfast Health Trust, Belfast; G. Suren Arul, Birmingham Children's Hospital NHS Foundation Trust, Birgmingham; Sara Stoneham, Children's and Young Persons Cancer Services, University College London Hospital Trusts, London, United Kingdom; Ha Dang, Children's Oncology Group; Mark Krailo, University of Southern California, Los Angeles, CA; Thomas Olson, Children's Healthcare of Atlanta, Emory University, Atlanta, GA; James F. Amatruda, University of Texas Southwestern Medical Center and Children's Medical Center Dallas, Dallas, TX; Deborah Billmire, Riley Hospital for Children, Indianapolis, IN; Furqan Shaikh, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada; and Farzana Pashankar, Yale Cancer Center, New Haven, CT.
authors.forename: Deborah
authors.initials: D
authors.lastname: Billmire
authors.affiliation: A. Lindsay Frazier and Carlos Rodriguez-Galindo, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, MA; Juliet P. Hale, Newcastle upon Tyne Hospitals National Health Service (NHS) Foundation Trust, Newcastle upon Tyne; Matthew J. Murray and James C. Nicholson, Cambridge University Hospitals NHS Foundation Trust; Matthew J. Murray, University of Cambridge, Cambridge; Claire Thornton, Royal Victoria Hospital, Belfast Health Trust, Belfast; G. Suren Arul, Birmingham Children's Hospital NHS Foundation Trust, Birgmingham; Sara Stoneham, Children's and Young Persons Cancer Services, University College London Hospital Trusts, London, United Kingdom; Ha Dang, Children's Oncology Group; Mark Krailo, University of Southern California, Los Angeles, CA; Thomas Olson, Children's Healthcare of Atlanta, Emory University, Atlanta, GA; James F. Amatruda, University of Texas Southwestern Medical Center and Children's Medical Center Dallas, Dallas, TX; Deborah Billmire, Riley Hospital for Children, Indianapolis, IN; Furqan Shaikh, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada; and Farzana Pashankar, Yale Cancer Center, New Haven, CT.
authors.forename: Furqan
authors.initials: F
authors.lastname: Shaikh
authors.affiliation: A. Lindsay Frazier and Carlos Rodriguez-Galindo, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, MA; Juliet P. Hale, Newcastle upon Tyne Hospitals National Health Service (NHS) Foundation Trust, Newcastle upon Tyne; Matthew J. Murray and James C. Nicholson, Cambridge University Hospitals NHS Foundation Trust; Matthew J. Murray, University of Cambridge, Cambridge; Claire Thornton, Royal Victoria Hospital, Belfast Health Trust, Belfast; G. Suren Arul, Birmingham Children's Hospital NHS Foundation Trust, Birgmingham; Sara Stoneham, Children's and Young Persons Cancer Services, University College London Hospital Trusts, London, United Kingdom; Ha Dang, Children's Oncology Group; Mark Krailo, University of Southern California, Los Angeles, CA; Thomas Olson, Children's Healthcare of Atlanta, Emory University, Atlanta, GA; James F. Amatruda, University of Texas Southwestern Medical Center and Children's Medical Center Dallas, Dallas, TX; Deborah Billmire, Riley Hospital for Children, Indianapolis, IN; Furqan Shaikh, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada; and Farzana Pashankar, Yale Cancer Center, New Haven, CT.
authors.forename: Farzana
authors.initials: F
authors.lastname: Pashankar
authors.affiliation: A. Lindsay Frazier and Carlos Rodriguez-Galindo, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, MA; Juliet P. Hale, Newcastle upon Tyne Hospitals National Health Service (NHS) Foundation Trust, Newcastle upon Tyne; Matthew J. Murray and James C. Nicholson, Cambridge University Hospitals NHS Foundation Trust; Matthew J. Murray, University of Cambridge, Cambridge; Claire Thornton, Royal Victoria Hospital, Belfast Health Trust, Belfast; G. Suren Arul, Birmingham Children's Hospital NHS Foundation Trust, Birgmingham; Sara Stoneham, Children's and Young Persons Cancer Services, University College London Hospital Trusts, London, United Kingdom; Ha Dang, Children's Oncology Group; Mark Krailo, University of Southern California, Los Angeles, CA; Thomas Olson, Children's Healthcare of Atlanta, Emory University, Atlanta, GA; James F. Amatruda, University of Texas Southwestern Medical Center and Children's Medical Center Dallas, Dallas, TX; Deborah Billmire, Riley Hospital for Children, Indianapolis, IN; Furqan Shaikh, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada; and Farzana Pashankar, Yale Cancer Center, New Haven, CT.
authors.forename: Sara
authors.initials: S
authors.lastname: Stoneham
authors.affiliation: A. Lindsay Frazier and Carlos Rodriguez-Galindo, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, MA; Juliet P. Hale, Newcastle upon Tyne Hospitals National Health Service (NHS) Foundation Trust, Newcastle upon Tyne; Matthew J. Murray and James C. Nicholson, Cambridge University Hospitals NHS Foundation Trust; Matthew J. Murray, University of Cambridge, Cambridge; Claire Thornton, Royal Victoria Hospital, Belfast Health Trust, Belfast; G. Suren Arul, Birmingham Children's Hospital NHS Foundation Trust, Birgmingham; Sara Stoneham, Children's and Young Persons Cancer Services, University College London Hospital Trusts, London, United Kingdom; Ha Dang, Children's Oncology Group; Mark Krailo, University of Southern California, Los Angeles, CA; Thomas Olson, Children's Healthcare of Atlanta, Emory University, Atlanta, GA; James F. Amatruda, University of Texas Southwestern Medical Center and Children's Medical Center Dallas, Dallas, TX; Deborah Billmire, Riley Hospital for Children, Indianapolis, IN; Furqan Shaikh, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada; and Farzana Pashankar, Yale Cancer Center, New Haven, CT.
authors.forename: Mark
authors.initials: M
authors.lastname: Krailo
authors.affiliation: A. Lindsay Frazier and Carlos Rodriguez-Galindo, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, MA; Juliet P. Hale, Newcastle upon Tyne Hospitals National Health Service (NHS) Foundation Trust, Newcastle upon Tyne; Matthew J. Murray and James C. Nicholson, Cambridge University Hospitals NHS Foundation Trust; Matthew J. Murray, University of Cambridge, Cambridge; Claire Thornton, Royal Victoria Hospital, Belfast Health Trust, Belfast; G. Suren Arul, Birmingham Children's Hospital NHS Foundation Trust, Birgmingham; Sara Stoneham, Children's and Young Persons Cancer Services, University College London Hospital Trusts, London, United Kingdom; Ha Dang, Children's Oncology Group; Mark Krailo, University of Southern California, Los Angeles, CA; Thomas Olson, Children's Healthcare of Atlanta, Emory University, Atlanta, GA; James F. Amatruda, University of Texas Southwestern Medical Center and Children's Medical Center Dallas, Dallas, TX; Deborah Billmire, Riley Hospital for Children, Indianapolis, IN; Furqan Shaikh, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada; and Farzana Pashankar, Yale Cancer Center, New Haven, CT.
authors.forename: James C
authors.initials: JC
authors.lastname: Nicholson
mesh_terms: D000293:Adolescent; D000367:Age Factors; D014408:Biomarkers, Tumor / Q000032:analysis; D002648:Child; D002675:Child, Preschool; D002986:Clinical Trials as Topic; D018572:Disease-Free Survival; D018240:Endodermal Sinus Tumor / Q000453:epidemiology / Q000209:etiology; D019317:Evidence-Based Medicine; D005260:Female; D006801:Humans; D008297:Male; D015233:Models, Statistical; D009367:Neoplasm Staging; D009373:Neoplasms, Germ Cell and Embryonal / Q000453:epidemiology* / Q000209:etiology* / Q000401:mortality / Q000473:pathology; D011237:Predictive Value of Tests; D011379:Prognosis; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D006113:United Kingdom / Q000453:epidemiology; D014481:United States / Q000453:epidemiology; D000509:alpha-Fetoproteins / Q000032:analysis
chemical_list: D014408:Biomarkers, Tumor; D000509:alpha-Fetoproteins