title: Individualised risk assessment for local recurrence and distant metastases in a retrospective transatlantic cohort of 687 patients with high-grade soft tissue sarcomas of the extremities: a multistate model.
abstract: This study investigates the effect of surgical margins and radiotherapy, in the presence of individual baseline characteristics, on survival in a large population of high-grade soft tissue sarcoma of the extremities using a multistate model.
  
  
  
  A retrospective multicentre cohort study.
  
  
  
  4 tertiary referral centres for orthopaedic oncology.
  
  
  
  687 patients with primary, non-disseminated, high-grade sarcoma only, receiving surgical treatment with curative intent between 2000 and 2010 were included.
  
  
  
  The risk to progress from 'alive without disease' (ANED) after surgery to 'local recurrence' (LR) or 'distant metastasis (DM)/death'. The effect of surgical margins and (neo)adjuvant radiotherapy on LR and overall survival was evaluated taking patients' and tumour characteristics into account.
  
  
  
  The multistate model underlined that wide surgical margins and the use of neoadjuvant radiotherapy decreased the risk of LR but have little effect on survival. The main prognostic risk factors for transition ANED to LR are tumour size (HR 1.06; 95% CI 1.01 to 1.11 (size in cm)) and (neo)adjuvant radiotherapy. The HRs for patients treated with adjuvant or no radiotherapy compared with neoadjuvant radiotherapy are equal to 4.36 (95% CI 1.34 to 14.24) and 14.20 (95% CI 4.14 to 48.75), respectively. Surgical resection margins had a protective effect for the occurrence of LR with HRs equal to 0.61 (95% CI 0.33 to 1.12), and 0.16 (95% CI 0.07 to 0.41) for margins between 0 and 2 mm and wider than 2 mm, respectively. For transition ANED to distant metastases/Death, age (HR 1.64 (95% CI 0.95 to 2.85) and 1.90 (95% CI 1.09 to 3.29) for 25-50 years and >50 years, respectively) and tumour size (1.06 (95% CI 1.04 to 1.08)) were prognostic factors.
  
  
  
  This paper underlined the alternating effect of surgical margins and the use of neoadjuvant radiotherapy on oncological outcomes between patients with different baseline characteristics. The multistate model incorporates this essential information of a specific patient's history, tumour characteristics and adjuvant treatment modalities and allows a more comprehensive prediction of future events.
authors.affiliation: Department of Orthopaedic Surgery, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Julie J
authors.initials: JJ
authors.lastname: Willeumier
authors.affiliation: Mathematical Institute, Leiden University, Leiden, The Netherlands.
authors.forename: Anja J
authors.initials: AJ
authors.lastname: Rueten-Budde
authors.affiliation: Department of Orthopaedic Surgery, Royal Orthopaedic Hospital, Birmingham, UK.
authors.forename: Lee M
authors.initials: LM
authors.lastname: Jeys
authors.affiliation: Department of Orthopaedic Surgery, Royal Orthopaedic Hospital, Birmingham, UK.
authors.forename: Minna
authors.initials: M
authors.lastname: Laitinen
authors.affiliation: Department of Orthopaedic Surgery, Royal National Orthopaedic Hospital, Stanmore, UK.
authors.forename: Rob
authors.initials: R
authors.lastname: Pollock
authors.affiliation: Department of Orthopaedic Surgery, Royal National Orthopaedic Hospital, Stanmore, UK.
authors.forename: Will
authors.initials: W
authors.lastname: Aston
authors.affiliation: Department of Orthopaedic Surgery, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: P D Sander
authors.initials: PD
authors.lastname: Dijkstra
authors.affiliation: Musculoskeletal Oncology Unit, Mount Sinai Hospital, Toronto, Canada.|Department of Surgery, University of Toronto, Toronto, Canada.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Ferguson
authors.affiliation: Musculoskeletal Oncology Unit, Mount Sinai Hospital, Toronto, Canada.|Department of Surgery, University of Toronto, Toronto, Canada.
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Griffin
authors.affiliation: Musculoskeletal Oncology Unit, Mount Sinai Hospital, Toronto, Canada.|Department of Surgery, University of Toronto, Toronto, Canada.
authors.forename: Jay S
authors.initials: JS
authors.lastname: Wunder
authors.affiliation: Mathematical Institute, Leiden University, Leiden, The Netherlands.|Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Marta
authors.initials: M
authors.lastname: Fiocco
authors.affiliation: Department of Orthopaedic Surgery, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Michiel A J
authors.initials: MA
authors.lastname: van de Sande
mesh_terms: D000328:Adult; D000368:Aged; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D000072662:Margins of Excision; D008875:Middle Aged; D015233:Models, Statistical; D020360:Neoadjuvant Therapy; D060787:Neoplasm Grading; D009364:Neoplasm Recurrence, Local / Q000517:prevention & control*; D016016:Proportional Hazards Models; D018714:Radiotherapy, Adjuvant; D012189:Retrospective Studies; D018570:Risk Assessment / Q000379:methods; D012307:Risk Factors; D012509:Sarcoma / Q000556:secondary / Q000628:therapy*; D012983:Soft Tissue Neoplasms / Q000473:pathology* / Q000628:therapy*; D015996:Survival Rate; D047368:Tumor Burden
keywords: Margins; Multi-state model; RADIOTHERAPY; STATISTICS & RESEARCH METHODS