Prognostic role of pretreatment blood neutrophil-to-lymphocyte ratio in advanced cancer survivors: A systematic review and meta-analysis of 66 cohort studies

Highlights

• 66 cohorts with over 14 cancer types representing 24536 participants are included.

• High pretreatment NLR is associated with poor prognosis in advanced cancer.

• The impact of petreatment NLR remains consistent when adjusted for confounders.

• Large-scale prospective studies of specific cancer type are strongly advocated.

Abstract

Background

Neutrophil-to-lymphocyte ratio (NLR) is crucial for the incidence and mortality of various tumors. However, little is known on NLR and its association with prognosis in advanced tumors. Here we performed a meta-analysis to establish the prognostic significance of pretreatment blood NLR for advanced tumors.

Methods

A systematic literature search through April 2016 was performed to evaluate the association between pretreatment blood NLR and overall survival (OS) or progression-free survival (PFS) in patients with advanced tumors. Data were extracted from studies reporting hazard ratios (HRs) and 95% confidence interval (CI) and pooled using the Mantel–Haenszel random-effect model.

Results

Sixty-six studies with a total of 24536 individuals were included in the meta-analysis. Pooled analyses revealed that elevated pretreatment NLR was associated with worse OS (HR 1.70, 95% CI 1.57–1.84, P < 0.001) and PFS (HR 1.61, 95% CI 1.42–1.82, P < 0.001) in advanced tumors. Subgroup analysis stratified by tumor type demonstrated that pancreatic cancer patients with high pretreatment NLR had the worst OS (HR 1.94, 95% CI 1.55–2.54, P < 0.001) and colorectal cancer with the worst PFS (HR 1.74, 95% CI 1.04–2.90, P < 0.001). When stratified by cut-off value for NLR, we found that cut-off value being five indicated the worst PFS (HR 2.23, 95% CI 1.54–3.23, P = 0.019).

Conclusions

Overall, high pretreatment blood NLR could be an adverse prognostic indicator for advanced tumor. Large-scale prospective studies investigating its survival outcomes in specific cancer type are strongly advocated.

Introduction

Surgery remains the main option of curative therapy for most of the solid tumors. Nevertheless, there remain significant challenges for oncologists to stratify risk before giving any treatment preoperatively. In clinics, we mainly rely on the clinical and pathological staging based on preoperative imaging or biopsy to predict the outcomes of cancer patients, instead of considering the patient level data [1], [2], [3], [4], [5], [6]. In addition, current staging system cannot always accurately predict the risk of disease recurrence and benefit from adjuvant chemotherapy in advanced cancer patients [7], [8]. Therefore, some more effective and convenient indicators should be developed to assist clinicians with preoperative patient risk stratification, patient counseling, and guide clinical trial enrollment.

At present, there is increasing evidence that tumor-associated inflammation and tumor microenvironment play a more and more important role in the cancer development, progression and metastasis and might be related to systemic inflammation [9], [10], [11], [12]. Inflammatory responses in tumor microenvironment have been reflected by some common markers in peripheral blood, for example, some cytokines, leucocytes and their subtypes. Increased level of leucocytes, particularly lymphocytes, has been implicated to be a good indicator for cancer prognosis [13], [14], as it is indicated that lymphocyte-mediated cytotoxicity can result in the release of large amounts of cytokines which can inhibit the growth and metastasis of cancer cells [15]. The poorly understood mechanisms of this association may likely reflect more aggressive behavior in tumors with greater inflammation.

Numerous observational studies and meta-analyses have reported that elevated NLR is associated with poor prognosis in various cancers, such as gastric cancer, esophageal cancer, pancreatic cancer and osteosarcoma [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [115]. However, the prognostic impact of NLR in advanced cancers is still not determined. The purpose of this meta-analysis is to investigate the association between pretreatment blood NLR and the survival outcomes for metastatic cancers based on the current evidence.