title: A Novel System for the Surgical Staging of Primary High-grade Osteosarcoma: The Birmingham Classification.
abstract: BACKGROUND
  Chemotherapy response and surgical margins have been shown to be associated with the risk of local recurrence in patients with osteosarcoma. However, existing surgical staging systems fail to reflect the response to chemotherapy or define an appropriate safe metric distance from the tumor that will allow complete excision and closely predict the chance of disease recurrence. We therefore sought to review a group of patients with primary high-grade osteosarcoma treated with neoadjuvant chemotherapy and surgical resection and analyzed margins and chemotherapy response in terms of local recurrence.
  
  
  OBJECTIVE
  (1) What predictor or combination of predictors available to the clinician can be assessed that more reliably predict the likelihood of local recurrence? (2) Can we determine a better predictor of local recurrence-free survival than the currently applied system of surgical margins? (3) Can we determine a better predictor of overall survival than the currently applied system of surgical margins?
  
  
  METHODS
  This retrospective study included all patients with high-grade conventional osteosarcomas without metastasis at diagnosis treated at one center between 1997 and 2012 with preoperative chemotherapy followed by resection or amputation of the primary tumor who were younger than age 50 years with minimum 24-month followup for those still alive. A total of 389 participants matched the inclusion criteria. Univariate log-rank test and multivariate Cox analyses were undertaken to identify predictors of local recurrence-free survival (LRFS). The Birmingham classification was devised on the basis of two stems: the response to chemotherapy (good response = ≥ 90% necrosis; poor response = < 90% necrosis) and margins (< 2 mm or ≥ 2 mm). The 5-year overall survival rate was 67% (95% confidence interval [CI], 61%-71%) and 47 patients developed local recurrence (12%).
  
  
  RESULTS
  Intralesional margins (hazard ratio [HR], 9.9; 95% CI, 1.2-82; p = 0.03 versus radical margin HR, 1) and a poor response to neoadjuvant chemotherapy (HR, 3.8; 95% CI, 1.7-8.4; p = 0.001 versus good response HR, 1) were independent risk factors for local recurrence (LR). The best predictor of LR, however, was a combination of margins ≤ 2 mm and a less than 90% necrosis response to chemotherapy (Birmingham 2b HR, 19.6; 95% CI, 2.6-144; p = 0.003 versus Birmingham 1a; margin >2 mm and more than 90% necrosis HR, 1). Two-stage Cox regression model and higher Harrell's C statistic demonstrate that the Birmingham classification was superior to the Musculoskeletal Tumor Society (MSTS) margin classification for predicting LR (Harrell's C statistic Birmingham classification 0.68, MSTS criteria 0.59). A difference in overall survival was seen between groups of the Birmingham classification (log-rank test p < 0.0001), whereas the MSTS margin system was not discriminatory (log-rank test p = 0.14).
  
  
  CONCLUSIONS
  Based on these observations, we believe that a combination of the recording of surgical margins in millimeters and the response to neoadjuvant chemotherapy can more accurately predict the risk of local recurrence than the current MSTS system. A multicenter collaboration study initiated by the International Society of Limb Salvage is recommended to test the validity of the proposed classification and if these findings are confirmed, this classification system might be considered the standard practice in oncology centers treating patients with osteosarcomas and allow more effective communication of margin status for research.
  
  
  METHODS
  Level IV, prognostic study.
authors.affiliation: School of Life and Health Sciences, Aston University, Birmingham, UK. lee.jeys@nhs.net.|The Royal Orthopaedic Hospital NHS Foundation Trust, Bristol Road South, Birmingham, B31 2AP, UK. lee.jeys@nhs.net.
authors.forename: Lee M
authors.initials: LM
authors.lastname: Jeys
authors.affiliation: School of Clinical and Experimental Medicine, University of Birmingham, Edgbaston, UK.|The Royal Orthopaedic Hospital NHS Foundation Trust, Bristol Road South, Birmingham, B31 2AP, UK.
authors.forename: Chris J
authors.initials: CJ
authors.lastname: Thorne
authors.affiliation: The Royal Orthopaedic Hospital NHS Foundation Trust, Bristol Road South, Birmingham, B31 2AP, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Parry
authors.affiliation: The Royal Orthopaedic Hospital NHS Foundation Trust, Bristol Road South, Birmingham, B31 2AP, UK.
authors.forename: Czar Louie L
authors.initials: CL
authors.lastname: Gaston
authors.affiliation: The Royal Orthopaedic Hospital NHS Foundation Trust, Bristol Road South, Birmingham, B31 2AP, UK.
authors.forename: Vaiyapuri P
authors.initials: VP
authors.lastname: Sumathi
authors.affiliation: The Royal Orthopaedic Hospital NHS Foundation Trust, Bristol Road South, Birmingham, B31 2AP, UK.
authors.forename: J Robert
authors.initials: JR
authors.lastname: Grimer
mesh_terms: D000293:Adolescent; D000671:Amputation, Surgical / Q000009:adverse effects / Q000401:mortality; D001859:Bone Neoplasms / Q000145:classification / Q000401:mortality / Q000473:pathology* / Q000628:therapy*; D017024:Chemotherapy, Adjuvant / Q000009:adverse effects / Q000401:mortality; D016208:Databases, Factual; D003661:Decision Support Techniques; D018572:Disease-Free Survival; D004739:England; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D023821:Limb Salvage; D008297:Male; D000072662:Margins of Excision; D015999:Multivariate Analysis; D009336:Necrosis; D020360:Neoadjuvant Therapy / Q000009:adverse effects / Q000401:mortality; D060787:Neoplasm Grading; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging / Q000379:methods*; D012516:Osteosarcoma / Q000145:classification / Q000401:mortality / Q000473:pathology* / Q000628:therapy*; D010027:Osteotomy / Q000009:adverse effects / Q000401:mortality; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D015203:Reproducibility of Results; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D009626:Terminology as Topic; D013997:Time Factors; D016896:Treatment Outcome