title: Assessing the Prognostic Significance of Histologic Response in Osteosarcoma: A Comparison of Outcomes on CCG-782 and INT0133-A Report From the Children's Oncology Group Bone Tumor Committee.
abstract: The prognostic value of histologic response for osteosarcoma may have changed with induction chemotherapy schedules over time. We hypothesized that the increased intensity of induction therapy provided on INT0133 compared to the Children's Cancer Group study CCG-782 would diminish the impact of histologic response on the risk of events after definitive surgery.
  
  
  
  Retrospective analysis was performed for patients aged <22 with newly diagnosed nonmetastatic osteosarcoma enrolled on CCG-782 and INT0133. Clinical factors were evaluated for association with response and outcome. Good response was defined as <5% viable tumor at resection. Associations of response, study, and postdefinitive surgery event-free survival (EFS-DS) were determined using Cox proportional hazard models. EFS-DS was estimated by Kaplan-Meier methodology.
  
  
  
  Data were available for 814 patients (206 CCG-782, 608 INT0133). For good responders, 10-year EFS-DS (±SE) was 75.4% ± 7.7% for CCG-782 and 70.8% ± 3.1% for INT0133. For poor responders, 10-year EFS-DS was 39.9% ± 4.9% for CCG-782 and 58.4% ± 3.1% for INT0133. Histologic response predicted outcome across studies (P < 0.0001). Significant interaction between study and histologic response was observed for EFS-DS (P = 0.011). Using proportional hazards regression, INT0133 poor responders had less risk of events compared to CCG-782 poor responders (relative hazard ratio (RHR) = 0.6:1), but good responders on INT0133 had a greater risk of events compared to CCG-782 good responders (RHR = 1.53:1).
  
  
  
  We observed an inverse relationship between the predictive value of tumor necrosis and intensity of induction therapy, raising questions about the true prognostic value of histologic response. This highlights the need for novel markers to develop strategies for treatment in future trials.
authors.affiliation: Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee.|Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Bishop
authors.affiliation: Department of Preventive Medicine, University of Southern California, Los Angeles, California.
authors.forename: Yu-Chen
authors.initials: YC
authors.lastname: Chang
authors.affiliation: Department of Preventive Medicine, University of Southern California, Los Angeles, California.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Krailo
authors.affiliation: Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Meyers
authors.affiliation: Division of Pediatric Hematology-Oncology, Children's Hospital of Memorial University Medical Center, Savannah, Georgia.
authors.forename: Arthur J
authors.initials: AJ
authors.lastname: Provisor
authors.affiliation: Division of Pediatrics, M.D. Anderson Cancer Center, Houston, Texas.
authors.forename: Cindy L
authors.initials: CL
authors.lastname: Schwartz
authors.affiliation: Department of Pediatric Hematology-Oncology, Lucile Packard Children's Hospital at Stanford, Palo Alto, California.
authors.forename: Neyssa M
authors.initials: NM
authors.lastname: Marina
authors.affiliation: Department of Pathology, Boston Children's Hospital, Boston, Massachusetts.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Teot
authors.affiliation: Department of Orthopaedic Surgery, Boston Children's Hospital, Boston, Massachusetts.
authors.forename: Mark C
authors.initials: MC
authors.lastname: Gebhardt
authors.affiliation: Division of Pediatric Hematology/Oncology, The Children's Hospital at Montefiore, Bronx, New York.
authors.forename: Richard
authors.initials: R
authors.lastname: Gorlick
authors.affiliation: Department of Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Janeway
authors.affiliation: Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Chou
mesh_terms: D000293:Adolescent; D000328:Adult; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D060828:Induction Chemotherapy; D007223:Infant; D008297:Male; D012516:Osteosarcoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D016896:Treatment Outcome
keywords: biomarker; chemotherapy; histologic response; necrosis; osteosarcoma