Abstract
BackgroundAlthough neutrophils have been linked to the progression of cancer, uncertainty exists around their association with cancer outcomes, depending on the site, outcome and treatments considered. We aimed to evaluate the strength and validity of evidence on the association between either the neutrophil to lymphocyte ratio (NLR) or tumour-associated neutrophils (TAN) and cancer prognosis.MethodsWe searched MEDLINE, Embase and Cochrane Database of Systematic Reviews from inception to 29 May 2020 for systematic reviews and meta-analyses of observational studies on neutrophil counts (here NLR or TAN) and specific cancer outcomes related to disease progression or survival. The available evidence was graded as strong, highly suggestive, suggestive, weak or uncertain through the application of pre-set GRADE criteria.ResultsA total of 204 meta-analyses from 86 studies investigating the association between either NLR or TAN and cancer outcomes met the criteria for inclusion. All but one meta-analyses found a hazard ratio (HR) which increased risk (HR > 1). We did not find sufficient meta-analyses to evaluate TAN and cancer outcomes (N = 9). When assessed for magnitude of effect, significance and bias related to heterogeneity and small study effects, 18 (9%) associations between NLR and outcomes in composite cancer endpoints (combined analysis), cancers treated with immunotherapy and some site specific cancers (urinary, nasopharyngeal, gastric, breast, endometrial, soft tissue sarcoma and hepatocellular cancers) were supported by strong evidence.ConclusionIn total, 60 (29%) meta-analyses presented strong or highly suggestive evidence. Although the NLR and TAN hold clinical promise in their association with poor cancer prognosis, further research is required to provide robust evidence, assess causality and test clinical utility.Trial registrationPROSPERO CRD42017069131.
Highlights
Neutrophils have been linked to the progression of cancer, uncertainty exists around their association with cancer outcomes, depending on the site, outcome and treatments considered
Forty-two meta-analyses (21%) presented associations supported by highly suggestive evidence, including associations between increased neutrophil to lymphocyte ratio (NLR) and poor prognosis in composite cancer endpoints, cancers treated with immunotherapy, gastric, colorectal, colorectal liver metastasis (CLM), pancreatic, gynaecologic, breast, hepatocellular, biliary, non-small cell lung cancer (NSCLC), lung, head and neck, oral, renal, advanced renal cancer, upper urinary and bladder, soft tissue sarcoma (STS) and bladder
The quantitative evidence presented suggests an association between elevated NLR and poor outcomes in cancer patients across a wide spectrum of diagnoses, stages of disease and courses of treatment
Summary
Neutrophils have been linked to the progression of cancer, uncertainty exists around their association with cancer outcomes, depending on the site, outcome and treatments considered. Cancer incidence is increasing due, in part, to higher morbidity from chronic diseases and epidemiological transitions in developing countries [3] This increase highlights the importance of identifying prognostic indicators associated with cancer progression such as the neutrophil to lymphocyte ratio (NLR) [4]. The link between inflammation and cancer was first observed by Rudolf Virchow, who detected leukocytes within tumours and hypothesised that inflammation increased cellular proliferation [5]. Since this discovery in the nineteenth century, inflammation has been recognised as one of the six biological capabilities of tumour development and a hallmark of cancer [6], with links to cancer initiation, progression and metastasis [7]. The paradoxical role of neutrophils in both the prevention and facilitation of tumour progression has generated significant research interest around neutrophils in the tumour microenvironment [8]
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