Neutrophil counts and cancer prognosis: an umbrella review of systematic reviews and meta-analyses of observational studies

ABSTRACT OBJECTIVE To evaluate the strength and validity of evidence on the association between the neutrophil to lymphocyte ratio (NLR) or tumour-associated neutrophils (TAN) and cancer prognosis. DESIGN Umbrella review of systematic reviews and meta-analyses of observational studies. DATA SOURCES Medline, EMBASE, and Cochrane Database of Systematic Reviews. ELIGIBILITY CRITERIA Systematic reviews or meta-analyses of observational studies evaluating the association between NLR or TAN and specific cancer outcomes related to disease progression or survival. DATA SYNTHESIS The available evidence was graded as strong, highly suggestive, suggestive, or weak through the application of pre-set grading criteria. For each included meta-analysis, the grading criteria considered the significance of the random effects estimate, the significance of the largest included study, the number of studies and individuals included, the heterogeneity between included studies, the 95% prediction intervals, presence of small study effects, excess significance and credibility ceilings. RESULTS 239 meta-analyses investigating the association between NLR or TAN and cancer outcomes were identified from 57 published studies meeting the eligibility criteria, with 81 meta-analyses from 36 studies meeting the criteria for inclusion. No meta-analyses found a hazard ratio (HR) in the opposite direction of effect (HR<1). When assessed for significance and bias related to heterogeneity and small study effects, only three (4%) associations between NLR and outcomes in gastrointestinal and nasopharyngeal cancers were supported by strong evidence. CONCLUSION Despite many publications exploring the association between NLR and cancer prognosis, the evidence is limited by significant heterogeneity and small study effects. There is a lack of evidence on the association between TAN and cancer prognosis, with all nine associations identified arising from the same study. Further research is required to provide strong evidence for associations between both TAN and NLR and poor cancer prognosis. REGISTRATION This umbrella review is registered on PROSPERO (CRD42017069131) FUNDING Medical Research Council COPYRIGHT Open access article under terms of CC BY SHORT TITLE Neutrophils and cancer prognosis: an umbrella review KEY RESULT When assessed for significance and bias related to heterogeneity and small study effects, only three (4%) associations between NLR and overall survival and progression-free survival in gastrointestinal and nasopharyngeal cancers were supported by strong evidence. WHAT THIS PAPER ADDS WHAT IS ALREADY KNOWN ON THE TOPIC Neutrophil counts have been linked to the progression of cancer due to their tumourigenic role in the cancer microenvironment. Numerous meta-analyses and individual studies have explored the association between neutrophil counts and cancer outcomes for a variety of cancer sites, leading to a large body of evidence with variable strength and validity. Uncertainty exists around the association between neutrophils and cancer outcomes, depending on the site, outcome and treatments considered. WHAT THIS STUDY ADDS All meta-analyses included in this review indicated an association between high neutrophil counts and poor cancer prognosis. There is strong evidence supporting the association between the neutrophil to lymphocyte ratio and poor cancer prognosis in some respiratory and gastrointestinal cancers. Further research is required to strengthen the existing body of evidence, particularly for the association between tumour-associated neutrophils and cancer outcomes.