|Year : 2019 | Volume
| Issue : 3 | Page : 187-192
Does neutrophil-to-lymphocyte ratio have a role among the other prognostic factors of nonsmall cell lung cancer?
Fatma Yildirim1, Nurgül Sevimli2, Murat Türk3, Nilgün Yılmaz Demirci4, Ahmet Selim Yurdakul4, Can Öztürk4
1 Department of Pulmonary and Critical Care Medicine, University of Health Sciences, Diskapi Yildirim Beyazit Research and Education Hospital, Ankara, Turkey
2 Tunceli State Hospital, Clinic of Pulmonary Medicine, Tunceli, Turkey
3 Department of Pulmonary Medicine, Erciyes University Faculty of Medicine, Division of Allergy and Immunology, Kayseri, Turkey
4 Department of Pulmonary Medicine, Gazi University Faculty of Medicine, Ankara, Turkey
|Date of Submission||14-Jan-2019|
|Date of Decision||09-Apr-2019|
|Date of Acceptance||09-Jun-2019|
|Date of Web Publication||30-Dec-2019|
Dr. Fatma Yildirim
Department of Pulmonary and Critical Care Medicine, University of Health Sciences, Diskapi Yildirim Beyazit Research and Education Hospital, Ankara 06500
Source of Support: None, Conflict of Interest: None
INTRODUCTION: Neutrophil-to-lymphocyte ratio (NLR), an index of systemic inflammation, has been associated with poor survival for many cancers. The aim of this study was to investigate the clinical significance of blood NLR in nonsmall cell lung cancer (NSCLC) as a prognostic factor.
METHODS: We retrospectively reviewed medical records of patients with NSCLC and collected data from December 2009 to September 2013. NLRs were calculated at the time of diagnosis before any type of treatment. Data about NLR, age, sex, smoking, histopathology, Eastern Cooperative Oncology Group (ECOG) performance score, disease stage, serum albumin, and treatment modalities were investigated. These parameters were tested for its association with the 1-year, 2-year, and overall survival (OS); OS was calculated by the Kaplan–Meier analysis.
RESULTS: A total of 121 patients with a median age of 61.9 (range 34–84), 14 (11.6%) female, and 107 (88.4%) males were included in the study. Majority of the patients were at local or advanced stage (Stage IIIA: 14.9%, Stage IIIB 14.9%, and Stage IV: 48.8%). Most common histological tumor type was squamous cell carcinoma (56.2%). Median neutrophil (N) count was 6.400 μl/ml, median lymphocyte (L) count was 1.570 μl/ml, while median NLR was 3.7. In univariate analysis, survival rates of patients did not have any differences according to gender, age, tumor histology, albumin level, and treatment modality (surgery and chemoradiotherapy). 1-year and 2-year survival rates of patients with ECOG 0 were higher than ECOG 1, 2, 3 patients (P = 0.034). Survival rates of Stage 1 patients (P < 0.001) and Stage 2 patients (P = 0.035) were longer, and survival rates of Stage 4 patients were lower than all other stages (P < 0.001). We divided the patients into 2 groups according to median NLR value of study group as NLR ≤3.7 and NLR >3.7. The percentage of patients who survived at the 1-year and 2-year were higher in the NLR <3.7 group (P = 0.043). The results showed that there was no significant difference regarding the patient's age, smoking history, tumor histology between 2 groups of high-level and low-level NLR. However, more male patients had higher NLR level (P = 0.036), and NSCLC patients with ECOG 2–3 (P = 0.002) and advanced disease stages (P< 0.001) were significantly associated with high-level NLR. Kaplan–Meier survival analysis revealed that there was a significant survival difference between NLR ≤3.7 and NLR >3.7 groups (14 vs. 9 months, P = 0.036). The multivariate Cox regression analysis revealed that the independent predictive factors for longer OS were low ECOG performance score (hazard ratio [HR] 0.786, 95% confidence interval [CI]: 0.799–0.931, P = 0.001), early disease stage (HR 1.517, 95% CI: 0.527–0.886, P < 0.001), and low NLR (HR 0.573, 95% CI: 0.440–0.962, P = 0.036).
CONCLUSIONS: In our study, the increased NLR is an estimator of shorter survival in patients with NSCLC. NLR is an easy-to-measure, reproducible test that can be considered as a routine practice in patients with NSCLC.
Keywords: Neutrophil-to-lymphocyte ratio, non-small cell lung cancer, prognosis
|How to cite this article:|
Yildirim F, Sevimli N, Türk M, Demirci NY, Yurdakul AS, Öztürk C. Does neutrophil-to-lymphocyte ratio have a role among the other prognostic factors of nonsmall cell lung cancer?. Eurasian J Pulmonol 2019;21:187-92
|How to cite this URL:|
Yildirim F, Sevimli N, Türk M, Demirci NY, Yurdakul AS, Öztürk C. Does neutrophil-to-lymphocyte ratio have a role among the other prognostic factors of nonsmall cell lung cancer?. Eurasian J Pulmonol [serial online] 2019 [cited 2020 Aug 8];21:187-92. Available from: http://www.eurasianjpulmonol.com/text.asp?2019/21/3/187/274386
| Introduction|| |
Lung cancer is a rapidly spreading, aggressive tumor, and it is still one of the leading causes of death among all cancer types. Approximately 85% of all lung cancer cases are nonsmall cell lung cancer (NSCLC), and the majority of patients with NSCLC have advanced disease stage at the time of diagnosis. Although there have been recent advances in the diagnosis and treatment of NSCLC, their contributions to the early diagnosis and prediction of prognosis of the disease remain unsatisfactory, and the 5-year survival rate of NSCLC could reach to 15-33.9% even after radical resection of cancer., Therefore, it is necessary to determine the prognostic factors to predict the rapid progression of NSCLC. The prognostic markers for lung cancer that have been studied and accepted so far are the patient's age, gender, smoking status, and tumor stage tumor/node/metastasis (TNM). However, even in patients with same TNM stage and same clinical and demographic characteristics, the tumor course could be different.
Prognostic biomarkers such as carcinoembryonic antigen, cytokeratin-19 fragments, squamous cell carcinoma (SCC) antigen, progastrin-secreting peptide, tumor M2-pyruvate kinase, and C-reactive protein  have been investigated so far, but these have not been found to be used in routine practice because of their costs. Hemogram measurement is a cheap and easy method which is used in followed up of almost all patients. Leukocyte, neutrophil, lymphocyte counts, and neutrophil-to-lymphocyte ratio (NLR) are indicators of systemic inflammation, which are known to play a major role in cell-mediated destruction of cancer cells. Studies conducted so far suggest that NLR can be used to predict disease progression and prognosis in different cancer types. It is proposed that patients with higher systemic inflammation at diagnosis might have more aggressive disease and should be treated promptly and potently, while an increasing NLR during treatment might be a precursor of disease progression and treatment failure., In recent studies, NLR has been investigated and proposed to be a promising biomarker in NSCLC patients.,,, The aim of the our study was to evaluate the prognostic significance of pretreatment NLR levels in NSCLC patients among other prognostic factors.
| Methods|| |
Medical records of the NSCLC patients who were diagnosed and treated at the thoracic oncology unit of Gazi University Faculty of Medicine, Department of Pulmonary Medicine between December 2009 and September 2013 were retrospectively reviewed. Clinicopathological information, patient age, gender, smoking habits, performance status (Eastern Cooperative Oncology Group [ECOG]: the scale was developed by the Eastern Cooperative Oncology Group), hemogram parameters (total white blood cell [WBC] count, neutrophil count, lymphocyte count, NLR), serum albumin level at initial diagnosis, the date of diagnosis, pathological diagnosis, tumor stage, treatment, last visit date, and Exitus data were collected from patients' records. 1-year, 2-year, and overall survival (OS) were examined.
TNM stages of the patients were performed radiologically with 18 FDG-PET/BT, cranial magnetic resonance imaging, and clinically according to the 7th American Joint Committee on Cancer classification. Tumor histology was classified as SCC, adenocarcinoma, and undetermined NSCLC.
All early stage patients (Stage IA-2B) were treated with curative surgery. After surgery, patients received platinum-based adjuvant chemotherapy in accordance with their disease stage. Stage IIIA patients did not undergo surgery. All advanced stage (Stage IIIA-IV) patients received first-line platinum-based chemotherapy and received appropriate medical treatment according to their disease situation.
We used statistical software package (SPSS, version 21.0; SPSS, Inc., Chicago, IL, USA) for data analysis. Data were expressed with frequency distribution and percentages. Chi-squared statistics or Fisher's exact test The Mann–Whitney U-tests were used for comparing the differences between the groups. Survival curves were compared with the log-rank test, and Kaplan–Meier survival curves were drawn. To determine risk factors for mortality, multivariate logistic regression analysis was performed using the maximum likelihood method and backward stepwise selection. Odds ratios were calculated from the coefficients in the logistic regression model, and 95% confidence intervals (CIs) were calculated for all variables.
| Results|| |
A total of 121 patients (14 [11.6%] female, 107 [88.4%] male) with a median age of 61.9 (34–84) were included in the study. Majority of the patients were at local or advanced stage (Stage IIIA: 14.9%, Stage IIIB 14.9%, and IV: 48.8%). Most common histological tumor type was SCC (56.2%). Median neutrophil (N) count was 6.400 μl/ml, median lymphocyte (L) count was 1.570 μl/ml, while median NLR was 3.68 (2.63–6.02). The demographics, disease characteristics, and blood biochemical parameters at the time of NSCLC diagnosis of the patients are shown in [Table 1].
We subsequently investigated the association between clinical factors of NSCLC patients and 1-year survival, 2-year survival, and OS in the univariate analysis. In univariate analysis, survival rates of patients did not have any differences according to gender, age, tumor histology, albumin level, and treatment modality (surgery and chemoradiotherapy). 1-year and 2-year survival rates of patients with ECOG 0 were higher than ECOG 1, 2, 3 patients (P = 0.034). Survival rates of Stage 1 patients (P < 0.001) and Stage 2 patients (P = 0.035) were longer, and survival rates of Stage 4 patients were lower than all other stages (P < 0.001). The percentage of patients who survived at the 1-year and 2-year were higher in the NLR <3.7 group (P = 0.043) [Table 2].
We divided the patients into 2 groups according to median NLR value of study group as NLR ≤3.7 and NLR >3.7. The results showed that there was no significant difference regarding the patient's age, smoking history, tumor histology between 2 groups of high-level and low-level NLR. However, more male patients had higher NLR level (P = 0.036), and NSCLC patients with ECOG 2–3 (P = 0.002) and advanced disease stages (p<0.001) were significantly associated with high-level NLR. The baseline characteristics of the NSCLC patients according to the NLR are listed in [Table 3].
|Table 3: The associations between neutrophil/lymphocyte ratio and clinical features|
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Kaplan–Meier survival analysis revealed that there was a significant survival difference between NLR ≤3.7 and NLR >3.7 groups (14 vs. 9 months, P = 0.036) [Figure 1].
|Figure 1: Kaplan–Meier curve of patients according to NLR >3.7 and NLR ≤3.7|
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The multivariate Cox regression analysis revealed that the independent predictive factors for longer OS were low ECOG performance score (hazard ratio [HR] 0.786, 95% CI: 0.799–0.931, P = 0.001), early disease stage (HR 1.517, 95% CI: 0.527–0.886, P < 0.001), and low NLR (HR 0.573, 95% CI: 0.440–0.962, P = 0.036) [Table 4].
|Table 4: Multivariate cox regression analysis to reveal independent risk factors for survival|
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| Discussion|| |
In this retrospective study, we investigated the prognostic values of inflammatory parameters (WBC, neutrophil, lymphocyte, and NLR) from complete blood count and other clinicopathological factors (age, sex, smoking, ECOG performance status, histopathological types, and disease stage) in NSCLC patients. Our results indicate that early disease stage, good ECOG performance status, and low NLR ratio were the independent prognostic factors for OS. Our results demonstrated that decreased NLR was significantly associated with longer survival.
Studies have shown that inflammatory cells, which are the basic components of microenvironment, have an important role in the progression of the tumor. Several recent studies evaluating the relationship between the immune system and tumors showed that the immune system plays important roles in killing tumor cells and preventing tumor growth while is also providing an inflammatory microenvironment that fosters tumor growth via a process called immunoediting., It has been reported that the immune response profile and inflammatory signature in several cancers may provide useful information on patient prognosis and treatment.
It has been shown that the tumor microenvironment (TME) orchestrates tumorigenesis and malignant progression. The TME significantly influences both tumor therapeutic response and its efficacy. In addition, tumor-associated neutrophils, tumor-infiltrating lymphocytes, and tumor-associated macrophages are important components of the TME and regulate the inflammatory response. These cells have also been identified as prognostic factors in malignant tumors including NSCLC.,
For almost half a century, Coussens and Werb  reported that chronic inflammatory response mediated the formation and development of tumors. Inflammatory reactions in the progression of tumors occur with a number of inflammatory cells, including lymphocytes, monocytes, platelets, and various signaling molecules in the cellular immune system.
In the previous study, a high pretreatment NLR was reported to be associated with a poor outcome for various types of cancers. Some thresholds of NLR for patients with NSCLC have been proposed and commonly used one has been 5.,,,
NLR is an inexpensive, reproducible, and widely available blood test. In previous studies, it has been shown that high neutrophil count and NLR in patients before treatment is associated with a poor prognosis. Recently, an increasing neutrophil count has also been identified as an independent predictor of death in patients with lung cancer NSCLC and in advanced NSCLC , been associated with poor prognosis in stage 4 NSCLC patients. In our study, we included both surgically resected early stage patients and advanced stage patients. The advanced stage, we investigated all the patient group according to NLR threshold 3.7.
Yu et al. performed a meta-analysis to evaluate the relationship between NLR and lung cancer outcome, and it was recently published. They evaluated the relationship between NLR and OS and/or progression-free survival (PFS) in 7219 patients with lung cancer in 18 studies. They found that pretreatment high NLR predicts poor OS (HR = 1.46, 95% CI: 1.30–1.64) and poor PFS (HR = 1.42, 95% CI: 1.15461.75). Their subgroup analysis showed that the prognostic value of NLR was higher in patients undergoing surgery (HR = 1.50, 95% CI: 1.21–1.84) or higher in patients with early stage disease (HR = 1.64, 95% CI: 1.37–1.97). If the NLR cutoff value was ≥4, it was significantly predictive of poor OS (HR = 1.56, 95% CI: 1.31–1.1.85) and PFS (HR = 1.54, 95% CI: 1.13–1.82), especially in small cell lung cancer patients. An NLR cutoff value of ≥4 significantly predicted poor OS (HR = 1.56, 95% CI: 1.31–1.85) and PFS (HR = 1.54, 95% CI: 1.13–1.82), particularly in the cases of small-cell lung cancer.
Limitations of this study can be considered to be that it was retrospective, single center, and there was an inequality in the early-stage and advanced-stage patient numbers. Therefore it seems to be difficult to generalize our results to all NSCLC patients.
| Conclusions|| |
Our study revealed that NLR before treatment is an independent prognostic factor of OS in patients with all stage (early and advanced stage) NSCLC. However, NLR can be greatly influenced by patient's condition and treatment. Larger prospective studies are required to confirm our findings.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin 2017;67:7-30.
Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ, et al.
Cancer statistics, 2009. CA Cancer J Clin 2009;59:225-49.
Fan H, Shao ZY, Xiao YY, Xie ZH, Chen W, Xie H, et al.
Incidence and survival of non-small cell lung cancer in Shanghai: A population-based cohort study. BMJ Open 2015;5:e009419.
Coleman MP, Forman D, Bryant H, Butler J, Rachet B, Maringe C, et al.
Cancer survival in Australia, Canada, Denmark, Norway, Sweden, and the UK, 1995-2007 (the international cancer benchmarking partnership): An analysis of population-based cancer registry data. Lancet 2011;377:127-38.
Tas F, Ciftci R, Kilic L, Karabulut S. Age is a prognostic factor affecting survival in lung cancer patients. Oncol Lett 2013;6:1507-13.
Wainer Z, Wright GM, Gough K, Daniels MG, Choong P, Conron M, et al.
Impact of sex on prognostic host factors in surgical patients with lung cancer. ANZ J Surg 2017;87:1015-20.
Yoshino I, Maehara Y. Impact of smoking status on the biological behavior of lung cancer. Surg Today 2007;37:725-34.
Woodard GA, Jones KD, Jablons DM. Lung cancer staging and prognosis. Cancer Treat Res 2016;170:47-75.
Greenberg AK, Lee MS. Biomarkers for lung cancer: Clinical uses. Curr Opin Pulm Med 2007;13:249-55.
Kobayashi T, Teruya M, Kishiki T, Kaneko S, Endo D, Takenaka Y, et al.
Inflammation-based prognostic score and number of lymph node metastases are independent prognostic factors in esophageal squamous cell carcinoma. Dig Surg 2010;27:232-7.
Liu W, Ha M, Yin N. Combination of platelet count and lymphocyte to monocyte ratio is a prognostic factor in patients undergoing surgery for non-small cell lung cancer. Oncotarget 2017;8:73198-207.
Kacan T, Babacan NA, Seker M, Yucel B, Bahceci A, Eren AA, et al.
Could the neutrophil to lymphocyte ratio be a poor prognostic factor for non small cell lung cancers? Asian Pac J Cancer Prev 2014;15:2089-94.
Putila J, Guo NL. Combining COPD with clinical, pathological and demographic information refines prognosis and treatment response prediction of non-small cell lung cancer. PLoS One 2014;9:e100994.
Travis WD, Brambilla E, Müller-Hermelink HK, Harris CC. Pathology and Genetics: Tumours of the Lung, Pleura, Thymus and Heart. Lyon: IARC Press; 2004.
Balkwill F, Mantovani A. Inflammation and cancer: Back to Virchow? Lancet 2001;357:539-45.
Galdiero MR, Garlanda C, Jaillon S, Marone G, Mantovani A. Tumor associated macrophages and neutrophils in tumor progression. J Cell Physiol 2013;228:1404-12.
Diem S, Schmid S, Krapf M, Flatz L, Born D, Jochum W, et al.
Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) as prognostic markers in patients with non-small cell lung cancer (NSCLC) treated with nivolumab. Lung Cancer 2017;111:176-81.
Coussens LM, Werb Z. Inflammation and cancer. Nature 2002;420:860-7.
Guthrie GJ, Charles KA, Roxburgh CS, Horgan PG, McMillan DC, Clarke SJ. The systemic inflammation-based neutrophil-lymphocyte ratio: Experience in patients with cancer. Crit Rev Oncol Hematol 2013;88:218-30.
Bagley SJ, Kothari S, Aggarwal C, Bauml JM, Alley EW, Evans TL, et al.
Pretreatment neutrophil-to-lymphocyte ratio as a marker of outcomes in nivolumab-treated patients with advanced non-small-cell lung cancer. Lung Cancer 2017;106:1-7.
Cedrés S, Torrejon D, Martínez A, Martinez P, Navarro A, Zamora E, et al.
Neutrophil to lymphocyte ratio (NLR) as an indicator of poor prognosis in stage IV non-small cell lung cancer. Clin Transl Oncol 2012;14:864-9.
Kaya V, Yildirim M, Demirpence O, Yildiz M, Yalcin AY. Prognostic significance of basic laboratory methods in non- small-cell-lung cancer. Asian Pac J Cancer Prev 2013;14:5473-6.
Yu Y, Qian L, Cui J. Value of neutrophil-to-lymphocyte ratio for predicting lung cancer prognosis: A meta-analysis of 7,219 patients. Mol Clin Oncol 2017;7:498-506.
Tomita M, Shimizu T, Ayabe T, Yonei A, Onitsuka T. Preoperative neutrophil to lymphocyte ratio as a prognostic predictor after curative resection for non-small cell lung cancer. Anticancer Res 2011;31:2995-8.
Lee Y, Kim SH, Han JY, Kim HT, Yun T, Lee JS, et al.
Early neutrophil-to-lymphocyte ratio reduction as a surrogate marker of prognosis in never smokers with advanced lung adenocarcinoma receiving gefitinib or standard chemotherapy as first-line therapy. J Cancer Res Clin Oncol 2012;138:2009-16.
[Table 1], [Table 2], [Table 3], [Table 4]