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


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Meghan Cupp1,Margarita Cariolou1,Ioanna Tzoulaki1,Evangelou Evangelos1,Antonio Berlanga-Taylor1
1MRC-PHE Centre for Environment and Health, Department of Epidemiology & Biostatistics, School of Public Health, Faculty of Medicine, Imperial College London, St Mary's Campus, Norfolk Place, LONDON W2 1PG

Abstract

Background

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 explore the association between neutrophil counts and cancer prognosis, contributing 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.

Method

For this umbrella review we searched Medline, EMBASE, and the Cochrane Database of Systematic Reviews for meta-analyses of observational studies evaluating the association between neutrophil to lymphocyte ratio (NLR) or tumour associated neutrophils (TAN) and specific cancer outcomes related to prognosis. 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

Ultimately, 81 meta-analyses from 36 studies met the criteria for inclusion. All meta-analyses suggested a hazard ratio in the same 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 overall survival and progression-free survival 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 meta-analyses 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.