title: Neurocognitive and Patient-Reported Outcomes in Adult Survivors of Childhood Osteosarcoma.
abstract: OBJECTIVE
  This study provides the first objective data documenting neurocognitive impairment in long-term survivors of childhood osteosarcoma.
  
  
  OBJECTIVE
  To examine neurocognitive, neurobehavioral, emotional, and quality-of-life outcomes in long-term survivors of childhood osteosarcoma.
  
  
  METHODS
  Cross-sectional cohort study at an academic research hospital, with prospective treatment and chronic health predictors. Outcome data were collected from June 2008 to August 2014. Data analysis was completed in April 2015. Survivors of osteosarcoma recruited from the St Jude Lifetime Cohort Study were compared with community controls.
  
  
  METHODS
  Neurocognitive function, neurobehavioral symptoms, emotional distress, and quality of life. Outcomes were examined in relation to pharmacokinetic indices of methotrexate exposure and current chronic health conditions, which were assessed through medical examination and coded according to Common Terminology Criteria for Adverse Events, Version 4.03.
  
  
  RESULTS
  Eighty survivors of osteosarcoma (mean [SD] age, 38.9 [7.6] years; time since diagnosis, 24.7 [6.6] years; 42% female) were compared with 39 community controls (age, 39.0 [11.7] years; 56% female). Survivors demonstrated lower mean scores in reading skills (-0.21 [95% CI, -0.32 to -0.10] vs 0.05 [95% CI, -0.13 to 0.23]; P = .01), attention (-0.78 [95% CI, -1.32 to -0.24] vs 0.24 [95% CI, -0.07 to 0.55]; P = .002), memory (-0.24 [95% CI, -0.48 to 0] vs 0.27 [95% CI, -0.08 to 0.62]; P = .01), and processing speed (-0.15 [95% CI, -0.35 to 0.05] vs 0.74 [95% CI, 0.44 to 1.03]; P < .001). Results of pharmacokinetic analysis showed that high-dose methotrexate maximum plasma concentration (estimate = 0; P = .48), median clearance (estimate = -0.11; P = .76), and median/cumulative exposure (estimate = 0; P = .45) were not associated with neurocognitive outcomes. Any grade 3 or 4 Common Terminology Criteria for Adverse Events cardiac, pulmonary, or endocrine condition was associated with poorer memory (t = 2.93; P = .006) and slower processing speed (t = 3.03; P = .002). Survivor-reported poor general health was associated with decreased sustained attention (estimate = 0.24; P = .05) and processing speed (estimate = 0.34; P = .005).
  
  
  CONCLUSIONS
  Long-term survivors of osteosarcoma are at risk for neurocognitive impairment, which is related to current chronic health conditions and not to original treatment with high-dose methotrexate. Prospective longitudinal studies are needed to identify onset and progression of impairment to inform optimal interventions.
authors.affiliation: Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Michelle N
authors.initials: MN
authors.lastname: Edelmann
authors.affiliation: Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Vinay M
authors.initials: VM
authors.lastname: Daryani
authors.affiliation: Department of Oncology, St Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Bishop
authors.affiliation: Department of Biostatistics, St Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, Tennessee5Department of Psychology, St Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Tara M
authors.initials: TM
authors.lastname: Brinkman
authors.affiliation: Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Clinton F
authors.initials: CF
authors.lastname: Stewart
authors.affiliation: Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, Tennessee3Department of Oncology, St Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Mulrooney
authors.affiliation: Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Cara
authors.initials: C
authors.lastname: Kimberg
authors.affiliation: Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Kirsten K
authors.initials: KK
authors.lastname: Ness
authors.affiliation: Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Yin Ting
authors.initials: YT
authors.lastname: Cheung
authors.affiliation: Department of Biostatistics, St Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Deo Kumar
authors.initials: DK
authors.lastname: Srivastava
authors.affiliation: Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Leslie L
authors.initials: LL
authors.lastname: Robison
authors.affiliation: Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, Tennessee3Department of Oncology, St Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Melissa M
authors.initials: MM
authors.lastname: Hudson
authors.affiliation: Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, Tennessee5Department of Psychology, St Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Krull
mesh_terms: D000328:Adult; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001288:Attention; D001859:Bone Neoplasms / Q000188:drug therapy*; D016022:Case-Control Studies; D003071:Cognition / Q000187:drug effects; D003072:Cognition Disorders / Q000139:chemically induced / Q000175:diagnosis / Q000523:psychology*; D003430:Cross-Sectional Studies; D004644:Emotions; D056344:Executive Function; D005260:Female; D006801:Humans; D008297:Male; D008568:Memory; D008727:Methotrexate / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008875:Middle Aged; D020258:Neurotoxicity Syndromes / Q000175:diagnosis / Q000209:etiology / Q000523:psychology*; D012516:Osteosarcoma / Q000188:drug therapy*; D011788:Quality of Life; D018570:Risk Assessment; D012307:Risk Factors; D017741:Survivors / Q000523:psychology*; D013997:Time Factors; D016896:Treatment Outcome; D014481:United States / Q000453:epidemiology
chemical_list: D000964:Antimetabolites, Antineoplastic; D008727:Methotrexate