Background
Despite its declined incidence in recent decades, gastric cancer (GC) remains a major health problem around the world [
1]. It is the fifth most common cancer worldwide, with about one million (952,000) new cases diagnosed annually, and it was the third leading cause of cancer deaths (723,000 deaths) in 2012, according to the World Health Organization’s GLOBOCAN database [
2]. Despite rapid developments in surgery, chemotherapy and molecular therapy in the recent years, the clinical outcome of GC is still not promising. This is mainly due to local tumour recurrence or distal metastasis. The progression of tumour staging systems for GC can be used to predict prognosis and guide patient therapy; however, heterogeneity of prognosis still exists among patients in the same stage [
3]. It is increasingly recognised that variations within clinical outcomes in cancer patients are influenced by not only the oncological characteristics of the tumour but also the host-response factors [
4]. The possibility of combining multiple, clinically available host- and tumour-related factors is of great interest, as it might serve as an excellent basis for clinical decision-making, treatment planning and establishing follow-up schedules.
Several articles have suggested that GC could induce inflammation in the host [
5], revealing a close relationship between these tumours and chronic inflammation [
6]. This inflammatory response reflects a non-specific response to tumour hypoxia tissue injury and necrosis [
7,
8]. The complex and diverse neuroendocrinological and haemopoetic changes that occur during inflammation are thought to be responsible for the diminishment of the immune response and the increase in tumour proliferation [
9]. Work has been undertaken to identify components of this inflammatory response that might identify patients at risk of poorer outcomes. Generally speaking, lymphopenia is the surrogate of an impaired cell-mediated immunity, whereas neutrophilia is a response to systematic inflammation [
10]. NLR calculated as neutrophil counts divided by lymphocyte counts, is suggested as a marker for general immune responses to various stress stimuli [
11]. It is thought that a high NLR increased systemic inflammatory in the host and associated with a poorer prognostic outcome. Emerging evidence shows that NLR is a prognostic and predictive biomarker in patients with some cancers, including breast cancer, hepatocellular carcinoma and colon cancer [
12-
14]. Elevated NLR levels in GC patients may be independent predictors of poor OS [
15]. Due to variance in study design and sample size, some authors did not agree with the prognostic value of NLR in gastric cancer [
16]. The direct impact of the NLR level on patient survival and tumour clinicopathological variables remains inconclusive.
This study aimed to systematically review the literature and use meta-analysis to evaluate the prognostic utility of NLR in these patient groups. Additionally, the relationship between NLR and clinicopathological factors was investigated.
Discussion
The TNM staging system which mainly focuses on the biological behaviour and presentation of the tumour itself acts as the foundation for subdividing GC patients and determining suitable treatments. However, staging systems are inadequate methods to precisely predict prognosis and appropriately guide clinical practice because patients at the same stage may have various clinical outcomes. The introduction of the laboratory index as a supplementary item to the current tumour staging system has significant potential to help practitioners create personalised treatment strategies. So far, the prognostic significance of the marker of systematic inflammatory reaction to solid tumours has received relatively little attention in the pursuit of tumour-based molecular evaluations of outcome.
A simple marker of systemic inflammation is NLR. Elevated NLR has recently been shown associated with poorer prognosis in patients with various types of malignant tumours [
12-
14]. The cut-off value for defining high NLR has not been unified in our meta-analysis. Meanwhile, some authors defined cut-off value as 2, 3, 4 or 5 by analysing the ROC curve or just arbitrarily, which led to between-study heterogeneity [
28,
29]. However, the NLR’s prognostic value was not affected, as the majority of the subgroup analysis did not change the results substantially. In addition, sensitivity analysis did not draw different conclusions from the pooled estimate. A future large sample study is needed to give a definitive cut-off value of NLR with good sensitivity and specificity.
The present study analysed the association between NLR and prognosis as well as the clinicopathological parameters in GC. We showed that increased pre-treatment NLR, a systemic inflammation-based prognostic score, could predict OS in patients undergoing primary resections for GC and in patients undergoing palliative chemotherapy. We also found that NLR has a role in predicting PFS in patients undergoing palliative treatments for GC. HNLR was not only associated with a poorer prognosis when all patient groups were combined but also during subgroup analysis. Furthermore, subgroup analysis confirmed these findings in each of the groups and produced a significantly lower level of heterogeneity, as was expected. There was also a significant association between NLR and grade of tumour stage. Taking all these into consideration, NLR is a promising prognostic marker to assist in the clinical decision-making process regarding GC treatment and outcomes. Cancer-related inflammation has been shown to have adverse effects on cancer prognosis.
Our results have also identified a potential role for NLR as a predictor of survival during post-therapy follow-up particularly from between 1 and 3 years post-treatment. Paramanathan [
30] found that high NLR correlated with worse long-term outcomes following curative intent surgery on solid tumours. Median 5-year OS for higher NLR compared to lower NLR was 35.8%
versus 70.1%. These results provide evidence to support the hypothesis that the NLR potentially represents a simple and robust measurement of prognosis. However, this preliminary finding requires further investigation before NLR can be recommended for inclusion in GC surveillance programmes. It needs to be validated in larger prospective studies for it to be useful in risk stratification.
To date, there has been one previous meta-analysis examining the role of NLR in predicting overall survival and PFS [
31]. This study had similar aims to our own study and produced similar results, but differed in several key regards. First, it selected more patients for the meta-analysis (3,709
versus 2,952), making it significantly more powerful. Second, the subgroups of patient treatment type used in the previous study were not as well defined. Third, the subgroups of patient tumour stage used by the previous study were also not as well defined. Finally, our study also investigated the role of NLR in predicting survival as part of a GC surveillance programme. Based on our results, the significant value of NLR is that it can identify patients at high risk of disease progression and death as a clinically convenient and useful biomarker. Thus, it not only provides guidance for clinical follow-up care but also has the potential to be a stratification factor or a selection criterion in randomised clinical trials for metastatic GC.
The reason for the association between elevated NLR and progression of tumour growth is not fully understood. One possible mechanism for this association is that tumour-associated neutrophils remodel the tumour microenvironment resulting in the release of MMP family members, which act on pro-inflammatory cytokines, chemokines and other proteins to regulate diverse aspects of inflammation. This plays an active role in maintaining tumour-promoting inflammation [
32]. In addition, neutrophil-derived reactive oxygen species further decrease the adhesion-promoting properties of the extracellular matrix and, via activation of nuclear factor (NF)-kB and STAT3, inhibit apoptosis of the tumour cells. These events result in accelerated tumour progression, invasion of the surrounding tissues, angiogenesis and often metastasis [
33-
35]. Finally, T lymphocyte cells are the primary cells responsible for direct recognition and killing of tumour cells. The long life of memory T cells (Tm) determines their crucial role in carcinogenesis and carcinogenic progression. Tm in peripheral blood from GC patients was statistically lower than those of healthy donors. The gastric cancer patients in stages III to IV had significantly lower levels of Tm compared to patients in stages I to II. Therefore, reduction of Tm may be related to immunodeficiency of gastric cancer [
36].
There are a number of limitations of our study, many of which also apply to meta-analysis research in general. This study was limited to analysing studies published in English, so publication bias cannot be excluded. Heterogeneity among these studies was also relatively large; this might be caused by the fact that they were conducted in different countries or used patients with different histological types of cancer among other factors. Randomised controlled trial research is not appropriate in this setting, but research with larger patient groups is required so that a more robust subgroup analysis can be performed.
Body composition changes especially muscle-mass depletion have been associated with the systemic inflammatory response (SIR) in GC patients, and this relationship might indicate the mechanism by which reduced muscle mass is associated with worse outcomes. Inflammation generates not only a cancer-promoting microenvironment but also systemic changes in the host that favour cancer progression. We believe that this meta-analysis provides good evidence for an altered SIR, expressed as NLR, acting as a promoter in the fatal progression of GC. Modifying a patient’s SIR may become as important a therapeutic target as the tumour itself. Whether preoperative NLR can be altered before intervention and thereby influence long-term outcomes remains to be established. Preoperative administration of corticosteroids in patients undergoing surgery for cancer is associated with a reduction in post-operative morbidity [
37]. This observation may be due to the alteration of the inflammatory response to surgery [
37-
39]. Also, studies suggest that non-steroidal anti-inflammatory drugs (NSAIDs) have a preventative effect against the development and progression of GC [
40].
NLR is an easily measurable inflammatory biomarker. Our results demonstrate that an elevated NLR is associated with worse OS and a lower disease-free interval in patients with GC. Our study therefore highlights the importance of NLR as a predictor of survival during post-therapy follow-up. To date, no specific therapies or interventions to modify a high NLR exist. Interventions to modify pre- and post-operative inflammatory responses and to modulate the immune response may prove beneficial in improving long-term cancer outcomes. The ability of NLR to predict transition to and toxicity from therapies is of particular interest, and future studies should aim to address these possibilities.
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Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
CJ was involved in the design of the study and acquisition, analysis and interpretation of data and drafted the manuscript. HD and ZY participated in the design of the study and performed the statistical analysis. SP conceived of the study and helped to draft the manuscript. All authors read and approved the final manuscript.