Abstract
Background: Previous studies showed the prognostic impact of inflammatory markers such as the neutrophil-to-lymphocyte ratio (NLR) and C-reactive protein (CRP), in resected non-small cell lung cancer (NSCLC). However, there are no studies that examined both of these markers simultaneously. Patients and Methods: Three hundred and one consecutive cases of resected NSCLC with a follow-up period of more than 5 years were reviewed retrospectively. Results: A significant association was only observed between NLR and patients' survival (p<0.0001). High CRP also led to a higher 5-year survival rate than low CRP (38.71% vs. 70.71%, p<0.0001). We evaluated the prognostic significance of the use of NLR and CRP combined. The 5-year survival of patients with both low NLR and low CRP was 74.18%. On the other hand, that of patients with both of these at a low level was significantly poor (20.00%, p<0.0001). Univariate and multivariate analyses of the clinicopathological factors affecting survival revealed that the combined use of preoperative NLR and CRP was an independent prognostic determinant. Conclusion: The combined use of preoperative NLR and CRP might be useful to predict the prognosis of patients with NSCLC.
- Neutrophil-to-lymphocyte ratio
- C-reactive protein
- non-small cell lung cancer
- prognosis
- inflammatory markers
It is widely accepted that inflammation contributes to the initiation and progression of cancer (1). Simple routine biochemical and haematological markers such as the neutrophil-to-lymphocyte ratio (NLR) and C-reactive protein (CRP) might represent host immune responsiveness.
Previous studies showed that a high pretreatment neutrophil count or NLR was associated with poor survival in patients with all stages or advanced lung cancer (2, 3) and resectable non-small cell lung cancer (NSCLC) (4, 5). CRP has been also proposed as a prognostic factor for patients with advanced NSCLC (6, 7) and to a lesser extent for those with resectable disease (8, 9). Both NLR and CRP are markers of inflammation, however, it is not known whether there is a relationship between NLR and CRP or not. Moreover it is unknown in detail whether their combined use is of benefit or not.
Therefore, in the present study, the prognostic impact of NLR and CRP was retrospectively investigated in cases with completely resected NSCLC.
Patients and Methods
The present retrospective study was conducted from 2001 through 2006 and included 301 patients with NSCLC who had underwent complete resection, which consisted of either a lobectomy or a pneumonectomy, together with regional lymph node dissection. Exclusion criteria were any condition that may affect the number of leukocytes or the differential count, such as immediate past, current history and sign or symptoms of infection, bone marrow, hematological or autoimmune disease, recent (14 days or less) steroid or nonsteroidal anti-inflammatory drug intake, smoking, receiving blood transfusion, and those with incomplete clinical data. Moreover, any patients treated with a follow-up period of less than 5 years before the study commenced were also excluded. The overall follow-up periods ranged from 62.7 to 131.7 months.
The NLR was calculated from the full blood count routinely performed before surgery. Based on a previous study, the data were dichotomized using a cut-off value of NLR set at 2.5 (5). The serum levels of CRP were measured by a latex photometric immunoassay (Mitsubishi Kagaku Iatron, Tokyo, Japan). The cut-off value of CRP was set as 0.5 mg/dl according to the manufacturer's instructions and a previous study (8). Pathological (p) TNM staging was recorded in all patients based on the 7th edition of AJCC/UICC TNM classifications. The baseline characteristics are summarized in Table I. Follow-up information, including cause of death, was ascertained through a review of clinic notes and direct or family contact. Comparisons of categorical data between the two groups were made using linear regression analysis. Survival curves were obtained according to the Kaplan–Meier method. Comparison of survival curves was carried out using the log-rank test. Statistical calculations were conducted with JMP (SAS Institute Inc. Cary, NC, USA) and values of p less than 0.05 were accepted as being significant.
Results
The survival curve based on NLR is shown in Figure 1A. The 5-year survival of the patients with high NLR and low NLR was 45.98% or 71.50%, respectively (p<0.0001). Similarly, as shown in Figure 1B, the 5-year survival rate was 38.71% among patients with high CRP, and 70.71% among patients with low CRP (p<0.0001). Linear regression analysis revealed a significant relationship between NLR and CRP (r2=0.1895, p<0.0001). However, patients with high NLR did not always have a high CRP value. In our series, 89/301 (29.57%) patients had either high NLR or high CRP. Therefore, we evaluated the prognostic significance of the use of NLR and CRP combined. As shown in Figure 2, the 5-year survival of patients with both high NLR and high CRP was 20.00%, which was significantly poor compared with that of patients with low value of both (74.18%, p<0.0001). The 5-year survival of patients with low NLR/high CRP and high NLR/low CRP was 56.25% and 59.65%, respectively. The survival rate of patients with either of these at a high value exhibited an intermediate value. Univariate Cox proportional hazard regression analysis revealed that the gender (male vs. female), the histological subtype (adenocarcinoma vs. others), pT status (pT1 vs. pT2-3), pN status (pN0 vs. pN1-2), serum CEA level (normal vs. high) and the combined use of NLR and CRP were related to patients' prognoses (Table II). The parameters that were significant in univariate analysis were further examined in multivariate analysis (Table III). After multivariate adjustment, pT status, pN status and the combined use of NLR and CRP were independent prognostic determinants.
Discussion
Previous studies reported reduced survival associated with NLR (4, 5) and CRP (8, 9) in resectable NSCLC. Our study also showed similar results. Both high NLR as well as high CRP may reflect an inflammatory response to the tumor. It is now well known that inflammatory processes almost always accompany cancer, and persistence of inflammation-like processes within cancer tissue causes suppression of antitumor immunity by several mechanisms, such as activation of type 2 T-helper responses, recruitment of regulatory T-cells and activation of the chemokine system, and results in promotion of cancer growth and metastasis (1, 10). Thus, inflammation may result in the aggressive growth of a tumor, and it is considered that high NLR and CRP could be a marker of production of acute inflammatory cytokines by the tumor. The cytokines interleukin-6 and tumor necrosis factor-alpha, which are implicated in the pathogenesis of cancer-related inflammation, as well as of acute inflammatory processes, are also known to induce a high NLR (11-13). CRP is produced by hepatocytes which are also regulated by interleukin-6 (14, 15). Taken together, the mechanisms for high NLR and that for high CRP might be similar. In fact, our results also highlighted a significant relationship between NLR and CRP. However patients with high NLR did not always have high CRP. In our series, 89/301 (29.57%) patients had either high NLR or high CRP, thereby suggesting the existence of other mechanisms. Furthermore, high NLR or high CRP in NSCLC patients is not always a marker of tumor production of some inflammatory cytokines. For example, a higher CRP level was reported in chronic obstructive pulmonary disease patients compared with healthy individuals (16). Thus, we suggested that the combined analysis of NLR and CRP might be a more accurate marker of cancer-related inflammation. Therefore, we evaluated the prognostic significance of the combined use of preoperative NLR and CRP and found it might be useful in predicting the prognosis of patients with NSCLC. The association between the use of NLR and CRP combined and poor prognosis is probably complex and largely unclear. There are still insufficient data linking systemic inflammation and pathogenesis of NSCLC. It is now becoming clear that the tumor microenvironment, which is largely orchestrated by inflammatory cells, is a major participant in the neoplastic process (1, 10). This environment promotes proliferation, survival, and migration of tumor cells and results in increased tumor aggressiveness. Since high NLR and high CRP may reflect an inflammatory response to the tumor, the combined use of these markers reflects the ability of tumors to maintain a microenvironment suitable for the survival of remnant cells through the up-regulation of some inflammatory cytokines (1, 10). From our results, these markers might be used to stratify patients in the context of chemotherapy trials, in addition to more traditional means such as radiological staging. They might also have a role in measuring response to treatment. Pro-inflammatory markers could also be used as a target for intervention rather than just a monitoring tool. Modulation of the inflammatory cascade could improve outcome or improve palliation. Therefore, the subgroup of NSCLC patients with high NLR and CRP could represent a reasonable study population for an adjuvant therapy trial. Further prospective studies in this area are warranted.
Since NLR and CRP are quick and easy assays to perform, their measurement may be useful as a clinical biological marker to predict prognosis of patients with resected NSCLC.
- Received March 19, 2012.
- Revision received April 19, 2012.
- Accepted April 20, 2012.
- Copyright© 2012 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved