title: Pre-treatment lymphocytopaenia is an adverse prognostic biomarker in muscle-invasive and advanced bladder cancer.
abstract: BACKGROUND
  Pre-treatment lymphocytopaenia may result from cytokines secreted by the tumour microenvironment in association with aggressive tumour biology. We sought to establish the prognostic significance of lymphocytopaenia in muscle-invasive and advanced bladder cancer.
  
  
  METHODS
  Seventy-four patients with muscle-invasive bladder cancer treated with radical chemoradiotherapy and 131 patients with advanced bladder cancer treated with palliative chemotherapy were included in the study. The absolute lymphocyte count on the first day of treatment was recorded. Invasive local or systemic recurrence in the muscle-invasive bladder cancer cohort and all-cause mortality in the advanced bladder cancer cohort were defined as survival end points. Receiver operating characteristic (ROC) curve analysis was utilized to determine the cut-off for defining lymphocytopaenia in the muscle-invasive bladder cancer cohort followed by multivariable analysis in a model evaluating the following variables: anaemia, neutrophilia, tumour stage, hydronephrosis and neoadjuvant chemotherapy. Subsequently, lymphocytopaenia was assessed in a multivariable model of the advanced bladder cancer cohort analysing the following prognostic variables: neutrophilia, anaemia, performance status and presence of bone or visceral metastases. A further analysis was carried out evaluating absolute lymphocyte count as a continuous variable.
  
  
  RESULTS
  An absolute lymphocyte count of 1.5 × 10(9)/l was determined as the cut-off on ROC curve analysis in the muscle-invasive bladder cancer cohort, and multivariate analysis revealed that only lymphocytopaenia was predictive for inferior outcome in this cohort. In the advanced bladder cancer cohort, lymphocytopaenia [hazard ratio (HR) 1.6, 95% confidence interval (CI) 1.1-2.4; P = 0.02] and performance status (HR 1.7, 95% CI 1.0-2.7; P = 0.047) were adverse prognostic factors in the binary variable multivariate model. Absolute lymphocyte count was the sole significant factor when analysed as a continuous variable (HR 0.66, 95% CI 0.5-0.87; P = 0.003).
  
  
  CONCLUSIONS
  Pre-treatment lymphocytopaenia is an independent adverse prognostic factor in both muscle-invasive and advanced bladder cancer. It may be a manifestation of cancer-induced immune suppression driving tumour progression.
authors.affiliation: Department of Clinical Oncology.
authors.forename: N
authors.initials: N
authors.lastname: Joseph
authors.affiliation: The University of Manchester, Manchester Academic Health Science Centre, The Christie NHS Foundation Trust, Manchester.
authors.forename: S J
authors.initials: SJ
authors.lastname: Dovedi
authors.affiliation: Department of Clinical Oncology, University Hospitals of Morecambe Bay NHS Foundation Trust, Morecambe, UK.
authors.forename: C
authors.initials: C
authors.lastname: Thompson
authors.affiliation: Department of Clinical Oncology.
authors.forename: J
authors.initials: J
authors.lastname: Lyons
authors.affiliation: Department of Clinical Oncology.
authors.forename: J
authors.initials: J
authors.lastname: Kennedy
authors.affiliation: Department of Clinical Oncology.
authors.forename: T
authors.initials: T
authors.lastname: Elliott
authors.affiliation: The University of Manchester, Manchester Academic Health Science Centre, The Christie NHS Foundation Trust, Manchester.
authors.forename: C M
authors.initials: CM
authors.lastname: West
authors.affiliation: Department of Clinical Oncology The University of Manchester, Manchester Academic Health Science Centre, The Christie NHS Foundation Trust, Manchester ananya.choudhury@christie.nhs.uk.
authors.forename: A
authors.initials: A
authors.lastname: Choudhury
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000740:Anemia / Q000150:complications; D014408:Biomarkers, Tumor / Q000097:blood*; D001859:Bone Neoplasms / Q000556:secondary*; D059248:Chemoradiotherapy; D015331:Cohort Studies; D005260:Female; D006801:Humans; D006869:Hydronephrosis / Q000150:complications; D018655:Lymphocyte Count; D008231:Lymphopenia / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D019042:Muscle Neoplasms / Q000556:secondary*; D009364:Neoplasm Recurrence, Local / Q000473:pathology; D009504:Neutrophils / Q000276:immunology; D011379:Prognosis; D012372:ROC Curve; D059016:Tumor Microenvironment; D001743:Urinary Bladder / Q000473:pathology; D001749:Urinary Bladder Neoplasms / Q000401:mortality / Q000473:pathology* / Q000628:therapy
chemical_list: D014408:Biomarkers, Tumor
keywords: biomarker; bladder cancer; hypoxia; immune suppression; lymphocytopaenia; prognosis