title: Refining the definition of mandibular osteoradionecrosis in clinical trials: The cancer research UK HOPON trial (Hyperbaric Oxygen for the Prevention of Osteoradionecrosis).
abstract: Mandibular osteoradionecrosis (ORN) is a common and serious complication of head and neck radiotherapy for which there is little reliable evidence for prevention or treatment. The diagnosis and classification of ORN have been inconsistently and imprecisely defined, even in clinical trials.
  
  
  
  A systematic review of diagnosis and classifications of ORN with specific focus on clinical trials is presented. The most suitable classification was evaluated for consistency using blinded independent review of outcome data (clinical photographs and radiographs) in the HOPON trial.
  
  
  
  Of 16 ORN classifications found, only one (Notani) appeared suitable as an endpoint in clinical trials. Clinical records of 217 timepoints were analysed amongst 94 randomised patients in the HOPON trial. The only inconsistency in classification arose where minor bone spicules (MBS) were apparent, which occurred in 19% of patients. Some trial investigators judged MBS as clinically unimportant and not reflecting ORN, others classified as ORN based on rigid definitions in common clinical use. When MBS was added as a distinct category to the Notani classification this ambiguity was resolved and agreement between observers was achieved.
  
  
  
  Most definitions and clinical classifications are based on retrospective case series and may be unsuitable for prospective interventional trials of ORN prevention or treatment. When ORN is used as a primary or secondary outcome in prospective clinical trials, the use of Notani classification with the additional category of MBS is recommended as it avoids subjectivity and enhances reliability and consistency of reporting.
authors.affiliation: Department of Molecular and Clinical Cancer Medicine, University of Liverpool & Head & Neck Division, Aintree University Hospital NHS Foundation Trust, Liverpool L9 7AL, UK; Cancer Research UK Liverpool Cancer Trials Unit, University of Liverpool Cancer Research Centre, University of Liverpool, Block C Waterhouse Building, 1-3 Brownlow Street, L69 3GL, UK. Electronic address: richard.shaw@liverpool.ac.uk.
authors.forename: Richard
authors.initials: R
authors.lastname: Shaw
authors.affiliation: Cancer Research UK Liverpool Cancer Trials Unit, University of Liverpool Cancer Research Centre, University of Liverpool, Block C Waterhouse Building, 1-3 Brownlow Street, L69 3GL, UK.
authors.forename: Binyam
authors.initials: B
authors.lastname: Tesfaye
authors.affiliation: Cancer Research UK Liverpool Cancer Trials Unit, University of Liverpool Cancer Research Centre, University of Liverpool, Block C Waterhouse Building, 1-3 Brownlow Street, L69 3GL, UK.
authors.forename: Matt
authors.initials: M
authors.lastname: Bickerstaff
authors.affiliation: Cancer Research UK Liverpool Cancer Trials Unit, University of Liverpool Cancer Research Centre, University of Liverpool, Block C Waterhouse Building, 1-3 Brownlow Street, L69 3GL, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Silcocks
authors.affiliation: Department of Molecular and Clinical Cancer Medicine, University of Liverpool & Head & Neck Division, Aintree University Hospital NHS Foundation Trust, Liverpool L9 7AL, UK; Department of Restorative Dentistry, Liverpool University Dental Hospital, Pembroke Place, Liverpool L3 5PS, UK.
authors.forename: Christopher
authors.initials: C
authors.lastname: Butterworth
mesh_terms: D002986:Clinical Trials as Topic; D006258:Head and Neck Neoplasms / Q000532:radiotherapy*; D006801:Humans; D008334:Mandible / Q000528:radiation effects*; D010025:Osteoradionecrosis / Q000209:etiology*; D006113:United Kingdom
keywords: Classification; Clinical trial; Definition; Mandible; Osteoradionecrosis