title: The BIG 2.04 MRC/EORTC SUPREMO Trial: pathology quality assurance of a large phase 3 randomised international clinical trial of postmastectomy radiotherapy in intermediate-risk breast cancer.
abstract: BACKGROUND
  SUPREMO is a phase 3 randomised trial evaluating radiotherapy post-mastectomy for intermediate-risk breast cancer. 1688 patients were enrolled from 16 countries between 2006 and 2013. We report the results of central pathology review carried out for quality assurance.
  
  
  METHODS
  A single recut haematoxylin and eosin (H&E) tumour section was assessed by one of two reviewing pathologists, blinded to the originally reported pathology and patient data. Tumour type, grade and lymphovascular invasion were reviewed to assess if they met the inclusion criteria. Slides from potentially ineligible patients on central review were scanned and reviewed online together by the two pathologists and a consensus reached. A subset of 25 of these cases was double-reported independently by the pathologists prior to the online assessment.
  
  
  RESULTS
  The major contributors to the trial were the UK (75%) and the Netherlands (10%). There is a striking difference in lymphovascular invasion (LVi) rates (41.6 vs. 15.1% (UK); p = <0.0001) and proportions of grade 3 carcinomas (54.0 vs. 42.0% (UK); p = <0.0001) on comparing local reporting with central review. There was no difference in the locally reported frequency of LVi rates in node-positive (N+) and node-negative (N-) subgroups (40.3 vs. 38.0%; p = 0.40) but a significant difference in the reviewed frequency (16.9 vs. 9.9%; p = 0.004). Of the N- cases, 104 (25.1%) would have been ineligible by initial central review by virtue of grade and/or lymphovascular invasion status. Following online consensus review, this fell to 70 cases (16.3% of N- cases, 4.1% of all cases).
  
  
  CONCLUSIONS
  These data have important implications for the design, powering and interpretation of outcomes from this and future clinical trials. If critical pathology criteria are determinants for trial entry, serious consideration should be given to up-front central pathology review.
authors.affiliation: Department of Pathology, Western General Hospital, Edinburgh, EH4 2XU, UK. jeremy.thomas@nhslothian.scot.nhs.uk.
authors.forename: J S
authors.identifier: http://orcid.org/0000-0002-4652-610X
authors.initials: JS
authors.lastname: Thomas
authors.affiliation: Leeds Institute of Cancer and Pathology, St James's University Hospital, Leeds, LS9 7TF, UK.
authors.forename: A M
authors.initials: AM
authors.lastname: Hanby
authors.affiliation: Department of Radiation Oncology, Netherlands Cancer Institute, Postbus 90203, 1006 BE, Amsterdam, Netherlands.
authors.forename: N
authors.initials: N
authors.lastname: Russell
authors.affiliation: Academic Medical Center, University of Amsterdam, 1105 AZ, Amsterdam, Netherlands.
authors.forename: G
authors.initials: G
authors.lastname: van Tienhoven
authors.affiliation: Scottish Clinical Trials Research Unit, NHS National Services Scotland, Edinburgh, EH12 9EB, UK.
authors.forename: K
authors.initials: K
authors.lastname: Riddle
authors.affiliation: Centre of Population Health Sciences, Edinburgh University Medical School, Edinburgh, EH8 9AG, UK.
authors.forename: N
authors.initials: N
authors.lastname: Anderson
authors.affiliation: Edinburgh Cancer Centre, Western General Hospital, Edinburgh, EH4 2XU, UK.
authors.forename: D A
authors.initials: DA
authors.lastname: Cameron
authors.affiliation: Ontario Institute for Cancer Research, Toronto, ON, M5G0A3, Canada.
authors.forename: J M S
authors.initials: JM
authors.lastname: Bartlett
authors.affiliation: Edinburgh Cancer Centre, Western General Hospital, Edinburgh, EH4 2XU, UK.
authors.forename: T
authors.initials: T
authors.lastname: Piper
authors.affiliation: Edinburgh Cancer Centre, Western General Hospital, Edinburgh, EH4 2XU, UK.
authors.forename: C
authors.initials: C
authors.lastname: Cunningham
authors.affiliation: Beatson Oncology Centre, Gartnavel Campus, Glasgow, G12 0YN, UK.
authors.forename: P
authors.initials: P
authors.lastname: Canney
authors.affiliation: Edinburgh Cancer Centre, Western General Hospital, Edinburgh, EH4 2XU, UK.
authors.forename: I H
authors.initials: IH
authors.lastname: Kunkler
mesh_terms: D001943:Breast Neoplasms / Q000473:pathology* / Q000532:radiotherapy / Q000601:surgery; D005260:Female; D006801:Humans; D008408:Mastectomy; D060787:Neoplasm Grading; D015588:Observer Variation; D016896:Treatment Outcome
keywords: Breast cancer; Clinical trial; Pathology; Quality assurance; Radiation therapy