Prognostic Role of Neutrophil-Lymphocyte Ratio
Prognostic Role of Neutrophil-Lymphocyte Ratio
Many recent studies have suggested that an elevated NLR is associated with poor survival of subjects with cancer. Here we undertook meta-analysis of 100 studies comprising 40559 patients with solid tumors to assess the prognostic effect of NLR. We found a consistent effect of an elevated NLR on survival (HR = 1.81) among various disease subgroups and across disease stages. Inflammation has been reported to contribute to the development of many cancers and is now included as a hallmark of cancer. The magnitude of effect on OS was highest in mesothelioma, where chronic inflammation plays a key role in the pathogenesis as a result of asbestos exposure. In addition, there was a trend for the association of high NLR with worse OS to be greater for metastatic than nonmetastatic disease and may reflect either greater tumor burden or a more prolonged chronic inflammatory process. The prognostic impact of NLR on CSS, PFS, and DFS (or RFS) was retained across disease sites and stages. Of interest, different cutoffs of NLR for different disease sites were reported in the included studies, and although some papers reported that cutoffs were determined using receiver operating characteristic curves (C-index), the method of selecting NLR cutoffs remained unclear in many studies. Although there was an association between NLR cutoff and reported hazard ratio for OS, the magnitude of this association was very small and unlikely to influence the interpretation of our results in view of the relatively narrow range of NLR cutoffs in the included studies.
The mechanisms underlying the association of high NLR and poor outcome of cancer patients are poorly understood. One potential mechanism underlying the prognostic impact of NLR may be an association of high NLR with inflammation. Neutrophilia as an inflammatory response inhibits the immune system by suppressing the cytolytic activity of immune cells such as lymphocytes, activated T cells, and natural killer cells. The importance of lymphocytes has been highlighted in several studies in which increasing infiltration of tumors with lymphocytes has been associated with better response to cytotoxic treatment and prognosis in cancer patients. Inflammatory cytokines and chemokines can be produced by both the tumor and associated host cells such as leukocytes and contribute to malignant progression. An elevated NLR has been associated with an increase in the peritumoral infiltration of macrophages and an increase in interleukin (IL) 17. Others have reported an association between elevated markers of a systemic inflammatory response with elevated circulating concentrations of several cytokines (IL-1ra, IL-6, IL-7, IL-8, IL-9, IL-12, interferon γ, interferon γ–induced protein 10kDa, monocyte chemotactic protein 1, macrophage inflammatory protein 1β, and platelet-derived growth factor, subtype BB). Neutrophils and other cells such as macrophages have been reported to secrete tumor growth promoting factors, including vascular endothelial growth factor, hepatocyte growth factor, IL-6, IL-8, matrix metalloproteinases, and elastases, and thus likely contribute to a stimulating tumor microenvironment. Although a variety of cytokines are implicated in the systemic inflammatory response, IL-6 in particular acts to increase the synthesis of acute-phase proteins, including C-reactive protein, and to decrease albumin production in the liver, the two elements encompassed by the Glasgow Prognostic Score, which have been shown to be prognostic in several solid tumors. Serum concentrations of IL-6 have been shown to be increased in 13 different cancer types and have been associated with tumor stage and adverse prognosis.
Clinicians use prognostic information when speaking to patients. Because NLR provides independent prognostic information, we incorporated NLR in a simple score for men with metastatic castration-resistant prostate cancer. In recent years, effort and resources have been invested in the development of biomarkers, which help to tailor therapy for cancer patients. Small studies with cancer patients showed that chemotherapy can normalize elevated NLR early after the introduction of treatment and that patients with normalized NLR may have improved outcome. Early discontinuation of ineffective treatment and introduction of effective treatment spares unnecessary toxicity and may improve the quality of life of cancer patients. Changes in blood NLR might be useful for tailoring of therapy in patients with advanced cancer where there is a lack of reliable biomarkers. Although the prognostic effect of NLR is smaller in early-stage cancer as compared with advanced cancer, its role might still be relevant for evaluating the early effects of systemic therapy.
This study had some limitations. Only summarized data rather than individual patient data could be used. Second, we found evidence of publication bias, with fewer small studies reporting negative results than would be expected (Figure 4). Furthermore, we only included studies reporting hazard ratios, and consequently 78 publications reporting on the prognostic value of NLR were excluded (eg, because only odds ratios for death, recurrence, or progression were reported, possibly introducing further selection bias). Among the included studies, nine only reported univariate hazard ratios, which could introduce a bias toward overestimation of the prognostic role of NLR. In some studies, hazard ratios from multivariable analysis may not have been statistically significant: this might be because of inclusion in the multivariable model of other markers of systemic inflammation such as C-reactive protein, hypoalbuminemia, Glasgow prognostic score, or platelet-to-lymphocyte ratio, which may provide similar information to NLR and thus lead to a non-statistically significant outcome in multivariable analysis. We aimed to address such confounding by performing sensitivity analyses and did not find a statistically significant difference among subgroups. Finally, neutrophil and lymphocyte counts are nonspecific parameters, which may be influenced by concurrent conditions such as infections, inflammation, and medications. NLR also appears prognostic in noncancer conditions [e.g., acute pancreatitis or cardiac events]. Most of the included studies did not explicitly control for such concurrent conditions, and these may confound the measurement of NLR. However, most studies reported NLR before surgery or before start of systemic therapy. It is common for surgery or cytotoxic therapy to be delayed in the setting of active infection; therefore, it is unlikely that NLR would have been influenced by infection in many cases. Despite this, the confounding effect of concurrent inflammatory conditions cannot be completely excluded.
In summary, a high NLR is associated with adverse survival in many solid tumors, and NLR may serve as a cost-effective prognostic biomarker. The evaluation of the utility of NLR measurement for therapeutic decision making is also warranted.
Discussion
Many recent studies have suggested that an elevated NLR is associated with poor survival of subjects with cancer. Here we undertook meta-analysis of 100 studies comprising 40559 patients with solid tumors to assess the prognostic effect of NLR. We found a consistent effect of an elevated NLR on survival (HR = 1.81) among various disease subgroups and across disease stages. Inflammation has been reported to contribute to the development of many cancers and is now included as a hallmark of cancer. The magnitude of effect on OS was highest in mesothelioma, where chronic inflammation plays a key role in the pathogenesis as a result of asbestos exposure. In addition, there was a trend for the association of high NLR with worse OS to be greater for metastatic than nonmetastatic disease and may reflect either greater tumor burden or a more prolonged chronic inflammatory process. The prognostic impact of NLR on CSS, PFS, and DFS (or RFS) was retained across disease sites and stages. Of interest, different cutoffs of NLR for different disease sites were reported in the included studies, and although some papers reported that cutoffs were determined using receiver operating characteristic curves (C-index), the method of selecting NLR cutoffs remained unclear in many studies. Although there was an association between NLR cutoff and reported hazard ratio for OS, the magnitude of this association was very small and unlikely to influence the interpretation of our results in view of the relatively narrow range of NLR cutoffs in the included studies.
The mechanisms underlying the association of high NLR and poor outcome of cancer patients are poorly understood. One potential mechanism underlying the prognostic impact of NLR may be an association of high NLR with inflammation. Neutrophilia as an inflammatory response inhibits the immune system by suppressing the cytolytic activity of immune cells such as lymphocytes, activated T cells, and natural killer cells. The importance of lymphocytes has been highlighted in several studies in which increasing infiltration of tumors with lymphocytes has been associated with better response to cytotoxic treatment and prognosis in cancer patients. Inflammatory cytokines and chemokines can be produced by both the tumor and associated host cells such as leukocytes and contribute to malignant progression. An elevated NLR has been associated with an increase in the peritumoral infiltration of macrophages and an increase in interleukin (IL) 17. Others have reported an association between elevated markers of a systemic inflammatory response with elevated circulating concentrations of several cytokines (IL-1ra, IL-6, IL-7, IL-8, IL-9, IL-12, interferon γ, interferon γ–induced protein 10kDa, monocyte chemotactic protein 1, macrophage inflammatory protein 1β, and platelet-derived growth factor, subtype BB). Neutrophils and other cells such as macrophages have been reported to secrete tumor growth promoting factors, including vascular endothelial growth factor, hepatocyte growth factor, IL-6, IL-8, matrix metalloproteinases, and elastases, and thus likely contribute to a stimulating tumor microenvironment. Although a variety of cytokines are implicated in the systemic inflammatory response, IL-6 in particular acts to increase the synthesis of acute-phase proteins, including C-reactive protein, and to decrease albumin production in the liver, the two elements encompassed by the Glasgow Prognostic Score, which have been shown to be prognostic in several solid tumors. Serum concentrations of IL-6 have been shown to be increased in 13 different cancer types and have been associated with tumor stage and adverse prognosis.
Clinicians use prognostic information when speaking to patients. Because NLR provides independent prognostic information, we incorporated NLR in a simple score for men with metastatic castration-resistant prostate cancer. In recent years, effort and resources have been invested in the development of biomarkers, which help to tailor therapy for cancer patients. Small studies with cancer patients showed that chemotherapy can normalize elevated NLR early after the introduction of treatment and that patients with normalized NLR may have improved outcome. Early discontinuation of ineffective treatment and introduction of effective treatment spares unnecessary toxicity and may improve the quality of life of cancer patients. Changes in blood NLR might be useful for tailoring of therapy in patients with advanced cancer where there is a lack of reliable biomarkers. Although the prognostic effect of NLR is smaller in early-stage cancer as compared with advanced cancer, its role might still be relevant for evaluating the early effects of systemic therapy.
This study had some limitations. Only summarized data rather than individual patient data could be used. Second, we found evidence of publication bias, with fewer small studies reporting negative results than would be expected (Figure 4). Furthermore, we only included studies reporting hazard ratios, and consequently 78 publications reporting on the prognostic value of NLR were excluded (eg, because only odds ratios for death, recurrence, or progression were reported, possibly introducing further selection bias). Among the included studies, nine only reported univariate hazard ratios, which could introduce a bias toward overestimation of the prognostic role of NLR. In some studies, hazard ratios from multivariable analysis may not have been statistically significant: this might be because of inclusion in the multivariable model of other markers of systemic inflammation such as C-reactive protein, hypoalbuminemia, Glasgow prognostic score, or platelet-to-lymphocyte ratio, which may provide similar information to NLR and thus lead to a non-statistically significant outcome in multivariable analysis. We aimed to address such confounding by performing sensitivity analyses and did not find a statistically significant difference among subgroups. Finally, neutrophil and lymphocyte counts are nonspecific parameters, which may be influenced by concurrent conditions such as infections, inflammation, and medications. NLR also appears prognostic in noncancer conditions [e.g., acute pancreatitis or cardiac events]. Most of the included studies did not explicitly control for such concurrent conditions, and these may confound the measurement of NLR. However, most studies reported NLR before surgery or before start of systemic therapy. It is common for surgery or cytotoxic therapy to be delayed in the setting of active infection; therefore, it is unlikely that NLR would have been influenced by infection in many cases. Despite this, the confounding effect of concurrent inflammatory conditions cannot be completely excluded.
In summary, a high NLR is associated with adverse survival in many solid tumors, and NLR may serve as a cost-effective prognostic biomarker. The evaluation of the utility of NLR measurement for therapeutic decision making is also warranted.
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