title: A systematically structured review of biomarkers of dying in cancer patients in the last months of life; An exploration of the biology of dying.
abstract: BACKGROUND
  The Neuberger review made a number of recommendations to improve end of life care, including research into the biology of dying. An important aspect of the biology of dying is the identification of biomarkers as indices of disease processes. Biomarkers have the potential to inform the current, limited understanding of the dying process and assist clinicians in recognising dying, in particular how to distinguish dying from reversible acute deterioration.
  
  
  OBJECTIVE
  To critically appraise the literature on biological factors that may be used as prognostic indicators in advanced cancer patients and to identify candidate biomarkers of the dying process that can be measured serially in cancer patients' bodily fluids.
  
  
  METHODS
  A systematically structured review was conducted using three electronic databases. A hand search of six peer-reviewed journals and conference abstracts was also conducted. Studies reporting prognostic biomarkers in cancer patients with a median survival of ≤90 days and post-mortem studies were included. Final levels of evidence and recommendations were made using the Evidence Based Medicine modified GRADE system.
  
  
  RESULTS
  30 articles were included. Seven prognostic biological factors demonstrated Grade A evidence (lymphocyte count, white blood cell count, serum C-reactive protein, albumin, sodium, urea and alkaline phosphatase). An additional eleven prognostic factors were identified with Grade B evidence (platelet count, international normalised ratio, serum vitamin B12, prealbumin, bilirubin, cholesterol, aspartate aminotransferase, alanine transaminase, lactate dehydrogenase, pseudocholinesterase and urate). A number of biomarkers were specifically identified in the last two weeks of life but limitations exist. No post-mortem studies met the inclusion criteria.
  
  
  CONCLUSIONS
  The biology of dying is an important area for future research, with the evidence focused on signs, symptoms and prognostic factors. This review identifies a number of common themes shared amongst advanced cancer patients and highlights candidate biomarkers which may be indicative of a common biological process to dying.
authors.affiliation: The Marie Curie Palliative Care Institute Liverpool, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Victoria Louise
authors.identifier: http://orcid.org/0000-0003-2804-8308
authors.initials: VL
authors.lastname: Reid
authors.affiliation: Renal Medicine, Aintree University Hospital NHS Foundation Trust, Liverpool, United Kingdom.
authors.forename: Rachael
authors.initials: R
authors.lastname: McDonald
authors.affiliation: The Marie Curie Palliative Care Institute Liverpool, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Amara Callistus
authors.initials: AC
authors.lastname: Nwosu
authors.affiliation: The Marie Curie Palliative Care Institute Liverpool, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Mason
authors.affiliation: Department of Gastroenterology, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Chris
authors.initials: C
authors.lastname: Probert
authors.affiliation: The Marie Curie Palliative Care Institute Liverpool, University of Liverpool, Liverpool, United Kingdom.
authors.forename: John E
authors.initials: JE
authors.lastname: Ellershaw
authors.affiliation: The Marie Curie Palliative Care Institute Liverpool, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Séamus
authors.initials: S
authors.lastname: Coyle
mesh_terms: D015415:Biomarkers / Q000097:blood*; D006801:Humans; D009369:Neoplasms / Q000097:blood* / Q000401:mortality
chemical_list: D015415:Biomarkers