Abstract
Recently, a series of studies explored the correlation between the neutrophil to lymphocyte ratio and the prognosis of lung cancer. However, the current opinion regarding the prognostic role of the neutrophil to lymphocyte ratio in lung cancer is inconsistent.
We performed a meta-analysis of published articles to investigate the prognostic value of the neutrophil to lymphocyte ratio in lung cancer. The hazard ratio (HR) and its 95% confidence interval (CI) were calculated.
An elevated neutrophil to lymphocyte ratio predicted worse overall survival, with a pooled HR of 1.243 (95%CI: 1.106-1.397; Pheterogeneity=0.001) from multivariate studies and 1.867 (95%CI: 1.487-2.344; Pheterogeneity=0.047) from univariate studies. Subgroup analysis showed that a high neutrophil to lymphocyte ratio yielded worse overall survival in non-small cell lung cancer (NSCLC) (HR=1.192, 95%CI: 1.061-1.399; Pheterogeneity=0.003) as well as small cell lung cancer (SCLC) (HR=1.550, 95% CI: 1.156-2.077; Pheterogeneity=0.625) in multivariate studies.
The synthesized evidence from this meta-analysis of published articles demonstrated that an elevated neutrophil to lymphocyte ratio was a predictor of poor overall survival in patients with lung cancer.
NLR; Lung Cancer; Overall Survival; Meta-Analysis
INTRODUCTION
Lung cancer is one of the leading causes of cancer-related deaths (11. Siegel R, Naishadham D, Jemal A. Cancer statistics. CA Cancer J
Clin. 2013;63(1): 11-30, 10.3322/caac.v63.1
10.3322/caac.v63.1...
,22. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global
cancer statistics. CA Cancer J Clin. 2011;61(2):69-90,
10.3322/caac.v61:2
10.3322/caac.v61:2...
).
Non-small cell lung cancer (NSCLC) accounts for approximately 85% of lung cancer
cases, and small-cell lung cancer (SCLC) accounts for nearly 13% of overall lung
cancer cases. Despite continue efforts and progress in diagnosis and treatment, the
overall survival (OS) for lung cancer patients remains poor (11. Siegel R, Naishadham D, Jemal A. Cancer statistics. CA Cancer J
Clin. 2013;63(1): 11-30, 10.3322/caac.v63.1
10.3322/caac.v63.1...
,22. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global
cancer statistics. CA Cancer J Clin. 2011;61(2):69-90,
10.3322/caac.v61:2
10.3322/caac.v61:2...
). Prognostic factors
influencing survival have been previously identified, including tumor stage,
performance status, weight loss, age, sex, histopathology, and plasma lactate
dehydrogenase (LDH) and carcinoembryonic antigen (CEA) levels (33. Gail MH, Eagan RT, Feld R, Ginsberg R, Goodell B, Hill L, et al.
Prognostic factors in patients with resected stage I non-small cell lung cancer.
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Lancet. 2009;374(9687):379-86, 10.1016/S0140-6736(09)60737-6
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). Although novel immunological and histological biomarkers
such as intercellular adhesion molecule-1 (IDM-1) and epidermal growth factor
receptor (EGFR) have been identified (88. Gu X, Ma C, Yuan D, Song Y. Circulating soluble intercellular
adhesion molecule-1 in lung cancer: a systematic review. Transl Lung Cancer Res.
2012;1(1):36-44.,99. Tanner NT, Sherman CA, Silvestri GA. Biomarkers in the selection
of maintenance therapy in non-small cell lung cancer. Transl Lung Cancer Res.
2012;1(2):96-8.), these marks are expensive and often
time-consuming to measure. Thus, there remains no promising prognostic factor that
can be easily detected and closely linked to clinical outcomes for lung cancer
patients (1010. Donnem T, Bremnes RM, Busund LT, Andersen S, Pezzella F. Gene
expression assays as prognostic and predictive markers in early stage non-small
cell lung cancer. J Thorac Dis. 2012;4(2):212-3.).
The tumor immune environment plays an important role in tumor progression by
promoting tumor angiogenesis, tumor metastasis, and cancer cell proliferation and by
interfering with the response to systemic treatment (1111. Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related
inflammation. Nature. 2008;454(7203):436-44,
10.1038/nature07205
10.1038/nature07205...
,1212. Hanahan D, Weinberg RA. Hallmarks of cancer: the next
generation. Cell. 2011;144(5):646-74,
10.1016/j.cell.2011.02.013
10.1016/j.cell.2011.02.013...
). Neutrophils and T and B
lymphocytes have been suggested to play vital roles in tumor inflammation (1313. Lin X, Li W, Lai J, Okazaki M, Sugimoto S, Yamamoto S, et al.
Five-year update on the mouse model of orthotopic lung transplantation:
scientific uses, tricks of the trade, and tips for success. J Thorac Dis.
2012;4(3):247-58.,1414. Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting:
integrating immunity’s roles in cancer suppression and promotion.
Science. 2011;331(6024):1565-70, 10.1126/science.1203486
10.1126/science.1203486...
),
and the imbalance between neutrophils and lymphocytes is thought to be secondary to
tumor hypoxia or necrosis and associated with anti-apoptotic effects (1515. Roxburgh CS, McMillan DC. Role of systemic inflammatory response
in predicting survival in patients with primary operable cancer. Future Oncol.
2010;6(1):149-63, 10.2217/fon.09.136
10.2217/fon.09.136...
). The neutrophil to lymphocyte ratio (NLR),
representing a combination of circulating neutrophil and lymphocyte counts, can
reflect the imbalance between neutrophils and lymphocytes in patients with tumors
and serves as a representative index of systemic inflammation.
Recently, an elevated preoperative or pretreatment NLR, calculated from peripheral
blood tests, was identified as an independent and readily available prognostic
biomarker related to poor survival in numerous cancers, including colorectal cancer,
breast cancer, gastric cancer and esophageal cancer (1616. Walsh SR, Cook EJ, Goulder F, Justin TA, Keeling NJ.
Neutrophil-lymphocyte ratio as a prognostic factor in colorectal cancer. J Surg
Oncol. 2005;91(3):181-4, 10.1002/(ISSN)1096-9098
10.1002/(ISSN)1096-9098...
1717. Azab B, Bhatt VR, Phookan J, Murukutla S, Kohn N, et al.
Usefulness of the neutrophil-to -lymphocyte ratio in predicting short- and
long-term mortality in breast cancer patients. Ann Surg Oncol.
2012;19(1):217-24, 10.1245/s10434-011-1814-0
10.1245/s10434-011-1814-0...
1818. Gwak MS, Choi SJ, Kim JA, Ko JS, Kim TH, Lee SM, et al. Effects
of gender on white blood cell populations and neutrophil-lymphocyte ratio
following gastrectomy in patients with stomach cancer. J Korean Med Sci.
2007;22(Suppl):S104-8, 10.3346/jkms.2007.22.S.S104
10.3346/jkms.2007.22.S.S104...
1919. Sharaiha RZ, Halazun KJ, Mirza F, Port JL, Lee PC, Neugut AI et
al. Elevated preoperative neutrophil: lymphocyte ratio as a predictor of
postoperative disease recurrence in esophageal cancer. Ann Surg Oncol.
2011;18(12):3362-9, 10.1245/s10434-011-1754-8
10.1245/s10434-011-1754-8...
). Additionally, a
series of studies have explored the correlation between the NLR and the prognosis of
lung cancer. However, according to their results, the current opinion on the
prognostic role of the NLR in lung cancer is inconsistent and inconclusive. Thus, we
performed this meta-analysis, which is the first systematic study on the subject, to
investigate the prognostic value of the NLR in lung cancer.
MATERIALS AND METHODS
Search strategy and study selection
To identify eligible studies regarding the NLR for predicting the prognosis of lung cancer, a systematic review was conducted. Relevant studies were identified by searching the PubMed and Web of Science databases using the following search terms: NLR, neutrophil-to-lymphocyte ratio, neutrophil lymphocyte ratio or neutrophil-lymphocyte ratio with lung cancer, carcinoma of the lung, pulmonary carcinoma and prognosis, prognostic, survival or outcome. The last search was updated on October 31, 2014. Both Medical subheadings (MeSH) and free text terms were used as keywords. The reference lists of papers of interest and published review articles were also explored to potentially retrieve additional studies. The inclusion criteria for the studies were as follows: (a) provided clear information on lung cancer confirmation and the included patients; (b) investigated the association of the pre-treatment NLR with OS; and (c) full text articles in English. The exclusion criteria were as follows: (a) letters, reviews, expert opinions, case reports or laboratory studies; (b) studies with overlapping or duplicate data; and (c) a lack of key information for evaluating the hazard ratio (HR) for further analysis.
Data extraction
All searches were conducted independently by two investigators. The same two authors independently extracted data on the name of the first author, the year of publication, the country of origin, ethnicity, the total number of cases, cancer types, stages, cut-off values, follow ups and HRs of the NLR for OS with 95% confidence intervals (CIs). Any discrepancy was resolved by consensus and, if needed, by consultation with the third author.
Statistical analysis
OS results were evaluated as HRs for each included study. HRs and 95% CIs were
obtained directly from each publication. If not available, the necessary data
were extracted to calculate the HR using the method reported by Tierney et al.
(2020. Tierney JF, Stewart LA, Ghersi D, Burdett S, Sydes MR. Practical
methods for incorporating summary time-to-event data into meta-analysis. Trials.
2007;7(8):16, 10.1186/1745-6215-8-16
10.1186/1745-6215-8-16...
). The heterogeneity of pooled
results was estimated using Cochran’s Q test and Higgins’
I-squared statistic. A p-value <0.10 for the Q-test indicated significant
heterogeneity, and a random-effects model (DerSimonian-Laird method) was used to
calculate the pooled HRs (2121. DerSimonian R, Laird N. Meta-analysis in clinical trials.
Control Clin Trials. 1986;7(3): 177-88,
10.1016/0197-2456(86)90046-2
10.1016/0197-2456(86)90046-2...
). Otherwise,
a fixed-effects model (Mantel-Haenszel method) was applied (2222. Mantel N, Haenszel W. Statistical aspects of the analysis of
data from retrospective studies of disease. J Natl Cancer Inst. 1959;22(4):
719-48.). Egger’s linear regression and
Begg’s funnel plot test were applied to evaluate publication bias in the
literature, and a p-value <0.05 was considered significant. A trim and fill
method was performed to estimate asymmetry in the funnel plot. Meta-regression
was performed to explore the potential source of heterogeneity using variables
such as the year of publication, ethnicity, cancer type, cutoff value and sample
size. To validate the credibility of outcomes in this meta-analysis, sensitivity
analysis was performed by sequential omission of each individual study using the
‘‘metainf’’ STATA command. All statistical analyses
were conducted with STATA software version 12.0 (STATA Corporation, College
Station, TX, USA), and all p-values were two-sided.
RESULTS
Study characteristics
We identified fourteen studies according to the inclusion and exclusion criteria
(2323. Teramukai S, Kitano T, Kishida Y, Kawahara M, Kubota K, Komuta
K, et al. Pretreatment neutrophil counts as an independent prognostic factor in
advanced non-small cell lung cancer-an analysis of Japan multinational trial
organization LC00-03. Eur J Cancer. 2009; 45(11):1950-8,
10.1016/j.ejca.2009.01.023
10.1016/j.ejca.2009.01.023...
2424. 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(5):2089-94,
10.7314/APJCP.2014.15.5.2089
10.7314/APJCP.2014.15.5.2089...
2525. Yao Y, Yuan D, Liu H, Gu X, Song Y. Pretreatment neutrophil to
lymphocyte ratios associated with response to therapy and prognosis of advanced
non-small cell lung cancer patients treated with first-line platinum-based
chemotherapy. Cancer Immunol Immunother. 2013; 62(3):471-9,
10.1007/s00262-012-1347-9
10.1007/s00262-012-1347-9...
2626. Lee Y, Kim SH, Han JY, Kim HT, Yun T, Soo LJ. Early
neutrophil-to-lymphocyte ratio reduction as a surrogate marker of prognosis in
never smokers with advanced lung adenocarcinoma receiving gefitinib or standard
chemotherapyas first-line therapy. J Cancer Res Clin Oncol.
2012;138(12):2009-16, 10.1007/s00432-012-1281-4
10.1007/s00432-012-1281-4...
2727. Wang X, Jiang R, Li K. Prognostic significance of pretreatment
laboratory parameters in Combined Small-Cell Lung Cancer. Cell Biochem Biophys.
2014;69(3):633-40, 10.1007/s12013-014-9845-3
10.1007/s12013-014-9845-3...
2828. 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(11):864-9, 10.1007/s12094-012-0872-5
10.1007/s12094-012-0872-5...
2929. Unal D, Eroglu C, Kurtul N, Oguz A, Tasdemir A. Are
neutrophil/lymphocyte and platelet/lymphocyte rates in patients with non-small
cell lung cancer associated with treatment response and prognosis? Asian
Pac J Cancer Prev. 2013;14(9):5237-42,
10.7314/APJCP.2013.14.9.5237
10.7314/APJCP.2013.14.9.5237...
3030. Pinato DJ, Shiner RJ, Seckl MJ, Stebbing J, Sharma R, Mauri FA.
Prognostic performance of inflammation based prognostic indices in primary
operable non-small cell lung cancer. Br J Cancer. 2014;110(8):1930-5,
10.1038/bjc.2014.145
10.1038/bjc.2014.145...
3131. Kang MH, Go SI, Song HN, Lee A, Kim SH, Kang JH, et al. The
prognostic impact of the neutrophil-to lymphocyte ratio in patients with
small-cell lung cancer. Br J Cancer. 2014;111(3):452-460,
10.1038/bjc.2014.317
10.1038/bjc.2014.317...
3232. Cannon NA, Meyer J, Iyengar P, Ahn C, Westover KD, Choy H, et
al. T Neutrophil-lymphocyte and platelet-lymphocyte ratios as prognostic factors
following stereotactic radiation therapy for early-stage non-small cell lung
cancer. J Thorac Oncol 2015; 10(2):280-285,
10.1097/JTO.0000000000000399
10.1097/JTO.0000000000000399...
3333. 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(9):2995-8.3434. Sarraf KM, Belcher E, Raevsky E, Nicholson AG, Goldstraw P, Lim
E. Neutrophil/lymphocyte ratio and its association with survival after complete
resection in non-small cell lung cancer. J Thorac Cardiovasc. Surg
2009;137(2):425-8.3535. Liao Y, Ni Y, He R, Liu W, Du J. Clinical implications of
fibroblast activation protein-a in non-small cell lung cancer after curative
resection: a new predictor for prognosis. J Cancer Res Clin Oncol.
2013;139(9):1523-8, 10.1007/s00432-013-1471-8
10.1007/s00432-013-1471-8...
3636. Tomita M, Shimizu T, Ayabe T, Nakamura K, Onitsuka T. Elevated
preoperative inflammatory markers based on neutrophil-to-lymphocyte ratio and
C-reactive protein predict poor survival in resected non-small cell lung cancer.
Anticancer Res. 2012; 32(8):3535-8.). The detailed screening process is shown in Figure 1. All of these articles were
published in English. The characteristics of the included studies are shown in
Table 1. Three studies were
performed in China and Japan, whereas two each were performed in the USA, UK and
Turkey and one each in Spain and Korea. Among the included studies, participants
were Asian in seven studies and Caucasian in the other seven studies. A total of
twelve studies explored the NLR in the prognosis of NSCLC, and two studies
explored the NLR in SCLC. The cut-off value used in each study was not
consistent, ranging from 2.5 to 5.0. The number of patients in each study ranged
from 59 to 388. Six studies calculated HRs by multivariate analysis, five
studies calculated HRs by univariate analysis, and the other three studies
calculated HRs by both multivariate and univariate analyses. In total, nine
studies contained HRs calculated from multivariate analysis, and eight studies
contained HRs calculated from univariate analysis.
Outcome from eligible studies
As shown in Table 2, fourteen studies evaluating OS were classified into two groups: nine multivariate studies with HRs and 95% CIs acquired from multivariate analysis, and eight univariate studies with data from univariate analysis. In both the multivariate and univariate analysis groups, an elevated NLR predicted a worse outcome of OS, with a pooled HR of 1.243 (95%CI: 1.106-1.397; Pheterogeneity=0.001) and 1.867 (95%CI: 1.487-2.344; Pheterogeneity=0.047), respectively (Figure 2).
Subgroup analysis by cancer type in the multivariate studies showed that a high NLR yielded worse OS in NSCLC (HR=1.192, 95%CI: 1.061-1.399; Pheterogeneity=0.003) and SCLC (HR=1.550, 95%CI: 1.156-2.077; Pheterogeneity=0.625). The cancer type in the univariate studies was NSCLC only.
In the subgroup analysis by ethnicity, regardless of whether the patients were Asian or Caucasian, an elevated NLR remained a poor predictor of OS in multivariate studies (Caucasian: HR=1.545, 95%CI: 1.052-2.269; Pheterogeneity=0.005; Asian: HR=1.261, 95%CI: 1.092-1.547; Pheterogeneity=0.021) and univariate studies (Caucasian: HR=1.722, 95%CI: 1.360-2.179; Pheterogeneity=0.133; Asian: HR=1.661, 95%CI: 1.419-1.945; Pheterogeneity=0.036).
Considering different cut-off values, these studies used two subsets of NLR cut-offs and revealed similar results. The NLR was found to be a negative prognostic marker for the outcome of OS in multivariate studies (NLR≥4: HR=1.646, 95%CI: 1.319-2.053; Pheterogeneity=0.247; NLR<4: HR=1.221, 95%CI: 1.016-1.468; Pheterogeneity=0.082) and univariate studies (NLR≥4: HR=1.500, 95%CI: 1.111-2.025; Pheterogeneity=0.262; NLR<4: HR=2.043, 95%CI: 1.497-2.789; Pheterogeneity=0.017).
Further analysis of studies evaluating OS by sample size (studies with more than 200 cases were classified as ‘‘large’’, and studies with less than 200 cases were classified as ‘‘small’’) also revealed that a high NLR remained a worse prognostic marker regardless of the sample size (large: HR=1.608, 95%CI: 1.186-2.179; Pheterogeneity=0.082; small: HR=1.090, 95%CI: 1.034-1.131; Pheterogeneity=0.103) in multivariate studies and (large: HR=2.018, 95%CI: 1.229-3.315; Pheterogeneity=0.016; small: HR=1.736, 95%CI: 1.403-2.148; Pheterogeneity=0.211) in univariate studies.
Heterogeneity
Meta-regression analysis was performed to explore the potential source of heterogeneity among multivariate and univariate studies for OS using variables such as the year of publication, ethnicity, cancer type, cut-off value and sample size. In multivariate studies, the results showed that year of publication (p=0.193), ethnicity (p=0.573), cancer type (p=0.407), cut-off value (0.116) and sample size (p=0.183) did not contribute to the source of heterogeneity. The same results were shown in the univariate studies; the year of publication (p=0.146), ethnicity (p=0.963), cut-off (0.457) and sample size (p=0.795) also did not contribute to the source of heterogeneity.
Publication bias and sensitivity analysis
We conducted leave-one-out sensitivity analysis by removing one study per time to check if any individual study affected the results. The result patterns were not obviously affected by any single study in either the univariate or multivariate group (Figures 3, 4). Begg’s funnel plot and Egger’s linear regression tests were used to evaluate publication bias. In the univariate studies, the results did not show any evidence of publication bias (p=0.711 for Begg’s test, and p=0.141 for Egger’s test). However, publication bias was found in the multivariate studies (p=0.002 for Egger’s test and p=0.251 for Begg’s test and). Therefore, a trim and fill method was used to evaluate the asymmetry in the funnel plot. The recalculated pooled HRs with presumed missing studies did not significantly change for multivariate studies (HR=1.118, 95%CI: 1.002-1.233; Pheterogeneity=0.026; Figure 5), indicating the stability of the results.
Funnel plots adjusted with the trim and fill method for OS. Circles: included studies. Diamonds: presumed missing studies.
DISCUSSION
Systemic inflammation appears to play a pivotal role in the progression of numerous
cancers by promoting tumor angiogenesis, tumor metastasis and cancer cell
proliferation and by affecting the tumor response to systemic treatment (1111. Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related
inflammation. Nature. 2008;454(7203):436-44,
10.1038/nature07205
10.1038/nature07205...
). The NLR, a combination of circulating
neutrophil and lymphocyte counts, serves as a representative index of systemic
inflammation. Moreover, because it is calculated from peripheral blood test results,
the NLR is a readily available biomarker of systemic inflammation that may predict
the prognostic outcome of patients. Indeed, recent studies have evaluated the
predictive value of the NLR in various types of cancers (1616. Walsh SR, Cook EJ, Goulder F, Justin TA, Keeling NJ.
Neutrophil-lymphocyte ratio as a prognostic factor in colorectal cancer. J Surg
Oncol. 2005;91(3):181-4, 10.1002/(ISSN)1096-9098
10.1002/(ISSN)1096-9098...
1717. Azab B, Bhatt VR, Phookan J, Murukutla S, Kohn N, et al.
Usefulness of the neutrophil-to -lymphocyte ratio in predicting short- and
long-term mortality in breast cancer patients. Ann Surg Oncol.
2012;19(1):217-24, 10.1245/s10434-011-1814-0
10.1245/s10434-011-1814-0...
1818. Gwak MS, Choi SJ, Kim JA, Ko JS, Kim TH, Lee SM, et al. Effects
of gender on white blood cell populations and neutrophil-lymphocyte ratio
following gastrectomy in patients with stomach cancer. J Korean Med Sci.
2007;22(Suppl):S104-8, 10.3346/jkms.2007.22.S.S104
10.3346/jkms.2007.22.S.S104...
1919. Sharaiha RZ, Halazun KJ, Mirza F, Port JL, Lee PC, Neugut AI et
al. Elevated preoperative neutrophil: lymphocyte ratio as a predictor of
postoperative disease recurrence in esophageal cancer. Ann Surg Oncol.
2011;18(12):3362-9, 10.1245/s10434-011-1754-8
10.1245/s10434-011-1754-8...
).
Our current study aimed to evaluate the role of the NLR in lung cancer, and to the
best of our knowledge, it is the first meta-analysis to investigate the prognostic
role of the NLR in lung cancer.
This meta-analysis, including 14 studies with 2,734 lung cancer cases, showed that an elevated NLR indeed predicted worse OS, regardless of whether the HRs were calculated from multivariate or univariate analysis. Subgroup analysis showed that a high NLR yielded a worse OS in NSCLC and SCLC based on multivariate analysis. The cancer type of the studies using univariate analysis was NSCLC only. In the subgroup analyses by ethnicity, we found that regardless of whether patients were Asian or Caucasian, an elevated NLR was still a poor predictor of OS in both multivariate and univariate analyses. Considering different cut-off values, these studies using two subsets of NLR cut-offs revealed similar results, showing that the NLR was a negative prognostic marker for the outcome of OS regardless of the analysis method. Further analysis by sample size also revealed the same results. Meta-regression analysis was performed using variables such as the year of publication, ethnicity, cancer type, cut-off value and sample size; however, none of these variables contributed to heterogeneity.
The NLR has been related to patient prognosis in numerous cancers, although the
specific mechanism for this relationship remains incompletely understood. Myeloid
cells are known to play a critical role in tumor pathogenesis by promoting cancer
cell proliferation, tumor angiogenesis, cell invasion, and metastasis (3737. Diakos CI, Charles KA, McMillan DC, Clarke SJ. Cancer-related
inflammation and treatment effectiveness. Lancet Oncol. 2014; 15(11):e493-503,
10.1016/S1470-2045(14)70263-3
10.1016/S1470-2045(14)70263-3...
). In particular, tumor-derived inflammation
can increase myelopoiesis with defective myeloid cell differentiation and
proliferation by regulating the bone marrow and spleen, leading to the accumulation
of immature myeloid cells in the peripheral circulation (3838. Gabrilovich DI, Ostrand-Rosenberg S, Bronte V. Coordinated
regulation of myeloid cells by tumours. Nat Rev Immunol. 2012; 12(4):253-68,
10.1038/nri3175
10.1038/nri3175...
). In the context of cancer-mediated myelopoiesis, the
neutrophil precursors myelocytes and promyelocytes proliferate and are released into
the peripheral blood. Neutrophils are the most abundant granulocytes, which account
for most peripheral white blood cells (3737. Diakos CI, Charles KA, McMillan DC, Clarke SJ. Cancer-related
inflammation and treatment effectiveness. Lancet Oncol. 2014; 15(11):e493-503,
10.1016/S1470-2045(14)70263-3
10.1016/S1470-2045(14)70263-3...
).
Thus, the prognostic and predictive value of peripheral neutrophils as an
independent index or as part of the NLR in cancers is apparent, and enhanced
neutrophil responses and/or lymphocyte suppression, leading to a high NLR, might
promote tumor progression and inhibit the antitumor immune response.
Our study has several limitations that should be carefully considered. First, the studies included in the analysis were full texts in English and were identified by searching the PubMed and Web of Science databases. Thus, publication bias cannot be excluded, although it did not affect the results according to the trim and fill method. In addition, marked heterogeneity of the studies was found; this may have been caused by the year of publication, ethnicity, cancer type, cut-off value and sample size. However, no variables listed above that were analyzed in the meta-regression analysis contributed to the observed heterogeneity. In fact, the existence of heterogeneity may have resulted from a variety of other factors. Due to the lack of detailed data, we could not use other clinical parameters in the meta-regression analysis. Additionally, the number of included studies was not large enough for part of the subgroup analysis; for example, only two studies investigated the NLR for OS in SCLC, and only two univariate studies with a small sample size (less than 100 cases was classified as “small”) yielded a trend of a poor prognostic role of the NLR for OS. In the future, more well-designed studies are needed to present more reliable results.
In conclusion, despite the limitations listed above, the synthesized evidence from published articles revealed that elevated NLR was a poor predictor of survival in patients with lung cancer. The NLR is an easily available blood test and may serve as a useful prognostic biomarker in lung cancer that does not require any additional resources for routine use. Nevertheless, the clinical utility of the NLR must still be confirmed in future analyses.
The authors thank all of the patients and clinical investigators who were involved in the studies included in this meta-analysis.
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Publication Dates
-
Publication in this collection
July 2015
History
-
Received
27 Jan 2015 -
Reviewed
18 Mar 2015 -
Accepted
30 Apr 2015