Prognostic Value of Neutrophil-to-Lymphocyte Ratio in Localized and Advanced Prostate Cancer: A Systematic Review and Meta-Analysis
Prognostic Value of Neutrophil-to- Lymphocyte Ratio in Localized and Advanced Prostate Cancer: A Systematic Review and Meta-Analysis
Lu Tang☯ 0
Xintao Li☯ 0
Baojun Wang☯ 0
Guoxiong Luo 0
Liangyou Gu 0
Luyao Chen 0
Kan Liu 0
Yu Gao 0
Xu Zhang 0
Beicheng Sun, The First Affiliated Hospital of
Nanjing Medical University, CHINA
0 State Key Laboratory of Kidney Disease, Department of Urology, Chinese PLA Medical Academy, Chinese People's Liberation Army General Hospital , Beijing, 100853 , China
Objective and Background Increasing evidence suggests that inflammation plays an essential role in cancer development and progression. The inflammation marker neutrophil-lymphocyte ratio (NLR) is correlated with prognosis across a wide variety of tumor types, but its prognostic value in prostate cancer (PCa) remains controversial. In the present meta-analysis, the prognostic value of NLR in PCa patients is investigated.
Data Availability Statement: All relevant data are
within the paper and its Supporting Information files.
Funding: The authors received funding from the
National Natural Science Foundation of China
Competing Interests: The authors have declared
that no competing interests exist.
We performed a meta-analysis to determine the predictive value of NLR for overall survival (OS), recurrence-free survival (RFS), and clinical features in patients with PCa. We systematically searched PubMed, ISI Web of Science, and Embase for relevant studies published up to October 2015.
A total of 9418 patients from 18 studies were included in the meta-analysis. Elevated pre
treatment NLR predicted poor OS (HR 1.628, 95% CI 1.410–1.879) and RFS (HR 1.357,
95% CI 1.126–1.636) in all patients with PCa. However, NLR was insignificantly associated
with OS in the subgroup of patients with localized PCa (HR 1.439, 95% CI 0.753–2.75).
Increased NLR was also significantly correlated with lymph node involvement (OR 1.616,
95% CI 1.167–2.239) but not with pathological stage (OR 0.827, 95% CI 0.637–1.074) or
Gleason score (OR 0.761, 95% CI 0.555–1.044).
The present meta-analysis indicated that NLR could predict the prognosis for patients with locally advanced or castration-resistant PCa. Patients with higher NLR are more likely to have poorer prognosis than those with lower NLR.
Prostate cancer (PCa) is the most common malignancy in men and a leading cause of
cancerrelated death [
]. The incidence of PCa has increased markedly in recent years. Despite
significant improvements in diagnostic and therapeutic strategies, the prognosis of PCa remains
poor, especially in patients with metastatic castration-resistant PCa (mCRPC) [
finding prognostic markers for PCa is urgently needed to help deliver personalized measures and
thus prevent and treat the disease at an early stage.
Increasing evidence suggests that inflammation plays an essential role in cancer
development and progression [
] and that systemic inflammation is associated with poor prognosis
in a number of cancers [
]. Increased levels of pro-inflammatory cytokines in cancer patients
may reflect both disease activity and the innate response of the host to the tumor [
Cancerrelated inflammation affects the tumor microenvironment [
]. Moreover, inflammatory cells
have significant effects on tumor development; thus, systemic inflammation markers may
represent useful prognostic biomarkers [
]. Neutrophil–lymphocyte ratio (NLR) is an
indicator of general immune response to various stress stimuli, and it is correlated with prognosis
across a wide variety of tumor types. High NLR is associated with adverse outcomes in a variety
of malignancies [
Several retrospective studies have evaluated the prognostic significance of baseline NLR in
patients with PCa. Several studies demonstrated that NLR had prognostic value in localized
and advanced PCa [
]; on the contrary, other studies reported that high serum NLR had
no prognostic value in patients with PCa [
]. Thus, the prognostic value of NLR in PCa
remains controversial. A previous meta-analysis on NLR in patients with urologic tumors
found that NLR could predict overall survival (OS) and recurrence-free survival (RFS) in PCa
. However, this meta-analysis included only six original studies, all of which involved
patients with CRPC. Increasing studies on NLR and PCa have been reported recently. Thus, we
performed a systematic review and meta-analysis of published studies to determine the
predictive value of NLR for PCa prognosis and clinical features.
A systematic literature search was performed using the electronic databases PubMed, ISI Web
of Science, and Embase up to October 2015. Search terms included “NLR,” “neutrophil to
lymphocyte ratio,” “prostate,” and “tumor, cancer, neoplasm or carcinoma.” The titles and
abstracts of potential references were scanned carefully to exclude irrelevant articles. The
remaining articles were evaluated to identify research that contained the topic of interest, and
full texts were then reviewed comprehensively.
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The studies included in this meta-analysis were randomized controlled studies or observational
studies (case–control or cohort) that evaluated the association between pretreatment NLR and
PCa prognosis. Studies were included if they (1) included patients histopathologically
diagnosed with PCa, (2) provided pretreatment NLR and reported cut-off values, (3) focused on
the prognosis of PCa, and (4) analyzed the associations between pretreatment NLR and
survival outcomes (clinical RFS [CRFS], biochemical RFS [BRFS], and OS). Exclusion criteria
were (1) non-English papers; (2) review articles, editorial comments, letters, expert opinion,
conference abstracts, or case reports; (3) overlapping or duplicate data; (4) focus on animal
models or cancer cells; (5) insufficient data for estimating hazard ratios (HRs) and 95%
confidence intervals (CIs); or (6) full text unavailable.
All evaluations were performed independently by two reviewers to assure accurate inclusion
of studies. When several studies contained overlapping data, the study with the largest data set
was used. Multivariate outcomes were preferred to univariate outcomes if both were provided.
However, univariate outcomes were acceptable if no multivariate results were presented. The
given survival or mortality curves were used to calculate the values. If insufficient data were
provided in the text, then we would contact the authors for the additional necessary data.
All data were extracted by two independent reviewers. Disagreements in data extraction were
resolved through consensus. The qualities of the included studies were assessed according to
the Newcastle–Ottawa Quality Assessment Scale. This scale evaluates three aspects, namely,
selection, comparability, and outcomes in the case and control groups. Studies with scores 6
were defined as high-quality studies [
]. The following relevant data were extracted in a
predefined table: author, year, country, age, patient sample, follow-up duration, cut-off score, NLR
(high/low), treatment, and endpoint (OS, CRFS, and BRFS).
Some studies presented survival data using the Kaplan–Meier curves, whereas we used
GetData Graph Digitizer 2.26 (http://getdata-graph-digitizer.com/) to digitize and extract the
relevant survival data.
The cut-off value for NLR varied among the included studies. Thus, we defined the NLR
standard in accordance with the standards indicated in the original article. Several studies
followed up patients for either CRFS or BRFS, and we analyzed these outcomes separately first
and then together in the subgroup analysis.
This meta-analysis was performed using Stata version 12.0 (StataCorp LP, TX, USA), and the
statistical analysis was conducted according to the guidelines proposed by the Meta-analysis of
Observational Studies in Epidemiology group. Associations between NLR and outcomes were
reported as HRs and 95% CIs, either obtained directly from individual articles or calculated
from indirect data. For the analysis of the relationship between NLR and clinicopathological
features, odd ratios (ORs) and 95% CIs were synthesized as the effective value. Heterogeneity
among studies was measured using Q and I2 tests. A fixed-effect model was used in the absence
of significant heterogeneity; otherwise, a random-effect model was used. Potential publication
bias was identified by Begg’s and Egger’s tests. The influence of publication bias on the overall
effect was assessed by the “trim and fill” method described by Duval et al. [
]. P < 0.05 was
considered statistically significant. All P values were two tailed.
Subgroup analyses were performed to investigate the associations of NLR with clinical
features and prognosis in relation to geographic area, statistical methods, patient conditions,
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sample size, NLR cut-off value (3< and 3), follow-up duration, and recurrence type. The
prognostic value of NLR value in terms of pathological stage, Gleason score, and lymph node
involvement was only investigated in three, four, and two studies, respectively. Accordingly, we
only performed pooled analysis on these factors. Furthermore, a sensitivity analysis was
performed to examine the robustness of the pooled results. The meta-analysis followed the
standard PRISMA checklist (S1 Table).
A flowchart for the selection of literature is shown in Fig 1. A total of 144 records were returned
using the search strategy; 96 of these records were retrieved after the exclusion of duplicated
data. About 39 records were excluded after the initial evaluation of the title and abstract.
Among the remaining 57 records, 23 were excluded including 12 that were letters, comments,
editorials, reviews, and conference abstracts; 2 articles not written in English; 5 non-prognostic
studies; and 4 studies unrelated to NLR. The full texts of the remaining 34 articles were
A total of 16 full-text articles were excluded, including 9 without available data, 3 without
NLR category, 2 that enrolled overlapping patients, 1 with endpoints other than OS or RFS,
and 1 with a sample size that was very small. Finally, 18 studies with 9418 patients were
included in the meta-analysis. All the remaining 18 studies evaluated the prognostic value of
pretreatment NLR in PCa and were reported within 5 years.
Characteristics of eligible studies
Detailed information on the 18 studies is listed in S2–S4 Tables. These studies included 3 from
the United States, 2 from Japan, 2 from Canada, 1 from the Netherlands, 1 from Italy, 2 from
Fig 1. Flowchart of selection of studies for inclusion in meta-analysis.
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China, 1 from a European cohort, 1 from Korea, 1 from Turkey, 1 from a multinational cohort,
1 from the United Kingdom, 1 from Australia, and 1 from Switzerland. These studies included
9418 patients, with a median of 389 patients (range 33–1367) per study. Only 1 study included
2 cohorts, both of which focused on the prognostic role of pretreatment NLR in patients with
mCRPC. The 17 other studies were retrospective observational cohort studies. Among all the
included studies, 10 included locally advanced or mCRPC patients, and the remaining 8
included patients with localized PCa. All the NLR values were detected before treatment.
Patients in 9 studies received docetaxel chemotherapy, patients in 4 received radical
prostatectomy, patients in 3 received curative radiotherapy, and patients in 1 received chemotherapy
with cabazitaxel or mitoxantrone. The treatment schedule was unavailable for 1 study. The
median follow-up time was 18 months (range 0–156 months). The relationship between NLR
and OS was investigated in 13 cohorts (11 by multivariate analysis), and 10 studies investigated
the relationship between NLR and RFS (4 by multivariate analysis). Among the 10 studies
analyzing NLR and RFS, 5 investigated BRFS and the 5 other investigated clinical CRFS. A total of
3 studies investigated the associations between NLR and pathological stage and Gleason score,
and 2 investigated the relationship between NLR and lymph node involvement.
Impact of NLR on recurrence in patients with PCa
A total of 10 studies involving 4819 patients investigated the association between NLR and PCa
recurrence. Patients with high pretreatment NLR had a significantly higher recurrence risk
than those with low NLR (HR 1.367, 95% CI 1.126–1.636) (Fig 2 and Table 1). Significant
heterogeneity was found among these studies (I2 = 57.1, P = 0.013), and thus the data were
analyzed using a random-effect model.
Effect of NLR on OS in patients with PCa
The association between NLR and OS was evaluated in 13 cohorts including 6776 patients.
Those with high pretreatment NLR had significantly poorer OS than those with low NLR (HR
1.628, 95% CI 1.41–1.879) (Fig 3 and Table 1). Significant heterogeneity was observed among
these studies (I2 = 68.7%, P < 0.001).
Fig 2. Meta-analysis of NLR value and RFS in PCa patients.
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2. locally advanced or mCRPC
2. > = 800
2. > = 3
2. > = 18
2. clinical recurrence
NLR, neutrophil-to-lymphocyte ratio; mCRPC, metastatic castration-resistant prostate cancer; BCR, biochemical recurrence; LCI, lower confidence
interval; UCI, upper confidence interval; HR, hazard ratio
Fig 3. Meta-analysis of NLR value and OS in PCa patients.
We explored the heterogeneity by conducting subgroup analyses and meta-regression (S5
Table). In the subgroup analysis of RFS, no significant difference was found between high and
low pretreatment NLR values in terms of RFS in sample sizes 800 (HR 1.102, 95% CI 0.944–
1.286) (S1 and S2 Figs). However, the other subgroup analyses demonstrated better RFS in
patients with low NLR. In the subgroup analyses of OS, no significant difference was observed
between the high and low pretreatment NLR groups in patients with localized PCa (HR 1.439,
95% CI 0.753–2.75); however, higher pretreatment NLR indicated a poorer prognosis in
patients with advanced PCa (HR 1.507, 95% CI 1.395–1.627) (S3 and S4 Figs). The predictive
values of NLR were significant in all the other subgroups analyzed (Supplemental data). The
meta-regression analysis suggested that geographic area (P = 0.017), patient type (P = 0.177),
and sample size (P = 0.008) could partially explain the source of the heterogeneity of pooled
OS. However, meta-regression analysis is only suitable for analyzing more than 10 studies, and
we did not apply this method to the RFS pooled analysis.
Correlations between NLR and clinicopathological features
The correlations between NLR and clinical features of PCa are presented in S6 Table. Three,
four, and two studies were available for the pooled analysis with regard to pathological stage,
Gleason score, and lymph node involvement, respectively. NLR was positively related to lymph
node involvement (OR 1.616, 95% CI 1.167–2.139) but showed no significant correlation with
pathological stage (OR 0.827, 95% CI 0.637–1.074) or Gleason score (OR 0.761, 95% CI 0.555–
1.044). The combined OR value was calculated using the random-effect model because of the
heterogeneity among the studies.
Publication bias analysis
The funnel plot was only asymmetrical for OS. The P values of Begg’s and Egger’s tests for
studies indicated the presence of publication bias in terms of OS (P = 0.001 and P < 0.001) but
not RFS (P = 0.210 and P = 0.235) among the included studies (Figs 4 and 5).
Accordingly, we performed a “trim and fill” analysis for studies focusing on OS. Six studies
evaluating the prognostic value of NLR in OS were estimated to be unpublished. The filled
meta-analysis (HR 1.424, 95% CI 1.231–1.647, P < 0.001) was also similar to our pooled
A sensitivity analysis was performed in which one study was deleted at a time (S5 Fig). The
pooled HRs for OS and RFS were insignificantly changed, thereby suggesting the robustness of
The present meta-analysis indicated that the inflammation marker NLR had prognostic values
for OS and RFS in patients with PCa. Although high pretreatment NLR had a significant
prognostic value in patients with advanced PCa, such NLR had no predictive value in terms of OS
in patients with localized PCa. Therefore, higher pretreatment NLR had a stronger predictive
effect in patients with more advanced disease. In terms of RFS, patients with higher
pretreatment NLR had shorter RFS than those with lower NLR in both localized and advanced PCa;
however, the association was more significant in patients with advanced PCa. Two previous
studies in patients with colorectal and lung cancers also concluded that the prognostic value of
NLR was higher in more advanced cancers [
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Fig 4. Begg’s test results of OS and RFS of PCa patients.
According to the subgroup analyses, NLR was significantly correlated with OR and RFS
based on the multivariate analysis. Therefore, NLR was an independent risk factor for the
outcomes. The further subgroup analysis showed that an NLR cut-off value 3 had a more
significant prognostic value than a cut-off value <3 (supplemental data). Thus, a higher NLR cut-off
may increase the specificity for predicting a poor prognosis in patients with PCa.
NLR was also associated with lymph node involvement but not with pathological stage or
Gleason score. This deduction is consistent with the conclusion that NLR is an independent
prognostic marker for PCa. A study that assessed NLR in esophageal cancer also showed that
NLR was associated with tumor invasion and lymph node metastasis but not with tumor
differentiation or vascular invasion [
]. In addition, NLR was associated with vascular invasion but
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Fig 5. Egg’s test results of OS and RFS of PCa patients.
not with tumor differentiation in hepatic cancer [
]. These observations suggest that
inflammation severity may affect metastasis progression in PCa but not intrinsic tumor
characteristics, such as tumor stage and Gleason score. The results of our analysis showed that the
prognostic values of NLR in terms of OS or RFS were more significant in mCRPC, thereby
supporting the association between inflammation and metastatic progression. Given the limited
number of studies enrolled in this meta-analysis, these conclusions require further
Heterogeneity was observed in the included studies. This heterogeneity may be partially
explained by geographic area, patient type, and sample size. Significant heterogeneity in
selection bias is inevitable in studies with smaller sample sizes. Moreover, the treatments adopted in
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the studies also varied. Baseline pretreatment, types and doses of chemotherapy regimens, and
dichotomized cut-off values also differed among the studies. However, the subgroup analysis
showed that the prognostic value of NLR was unaffected by the factors included in the analysis.
In addition, the sensitivity analysis indicated that our results were relatively conclusive. The
results of the random-effect model were similar to those of the fixed-effect model, thus
indicating that the pooled results were robust.
Therefore, NLR could serve as a prognostic marker because of the following reasons. First,
inflammation is theoretically a critical component in the pathogenesis and progression of
]. Inflammatory mediators and pro-inflammatory cytokines are systemically elevated in
patients with advanced cancer and contribute to the development of the acute phase response.
NLR is an indicator of systemic inflammation and general immune response of the host [
]. It is also correlated with prognosis across a wide variety of tumor types [
NLR can be available from blood routine test in daily clinical practice, an approach that is low
cost, convenient, and reproducible. Finally, as shown in the present meta-analysis, NLR is
closely associated with the progress and prognosis of advanced PCa patients. Therefore, NLR
can better serve as a marker for advanced PCa patients.
NLR has other predictive values in PCa. Higher NLR was associated with lower
prostatespecific antigen response to abiraterone or docetaxel chemotherapy [
]. Thus, NLR could
be used to estimate the probability of response to adjuvant therapy. In addition, NLR could
also act as a biomarker to predict PCa in men undergoing prostate needle biopsy  and to
predict the progression of benign prostatic hyperplasia [
]. However, NLR prior to prostate
biopsy was higher in patients with prostatitis than in those with PCa or benign prostate
]. Therefore, patients with prostatitis must be excluded when employing NLR as a
biomarker for PCa.
This study has several limitations. First, most of the included studies were retrospective and
thus more susceptible to bias in data selection and analysis. Second, the NLR cut-off values in
the included studies ranged from 2 to 5, and this heterogeneity could hinder the application of
these ratios in the clinical setting. Therefore, more original research is required to determine
the most suitable NLR cut-off value. Third, one study investigating OS did not include NLR in
the multivariate analysis because it failed to gain statistical significance in the univariate
analysis. Thus, the corresponding HR and 95% CI could only be retrieved from univariate analysis.
For BRFS and CRFS, similar conditions were observed in two and four studies, which may
have impaired the accuracy of the pooled analysis. Fourth, the included studies did not report
cancer-specific survival, an outcome important for cancer survival analysis. Fifth, NLR could
be affected by other conditions, such as acute coronary syndromes, valvular heart diseases,
renal diseases, liver diseases, hypertension, inflammatory diseases, infection, and some
]. However, the inaccessibility of these clinical data means that we were unable to
include these factors in the pooled analysis.
Despite the above limitations, our meta-analysis supports the values of pretreatment NLR
for predicting recurrence and survival outcome in patients with locally advanced or metastatic
PCa. Notably, NLR can only predict the recurrence of localized PCa. NLR can be easily
obtained from routine blood tests and thus may supplement prostate-specific antigen, Gleason
score, and magnetic resonance imaging for evaluating the condition of patients.
NLR is a useful predictive marker in the progress and prognosis of patients with locally
advanced or metastatic PCa. Patients with higher NLR are more likely to have poorer prognosis
than those with lower NLR.
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S1 Fig. Meta-analysis of the NLR value and OS in the subgroup of PCa patients according
to NLR value.
to NLR value.
to patient type.
to patient type.
S2 Fig. Meta-analysis of the NLR value and RFS in the subgroup of PCa patients according
S3 Fig. Meta-analysis of the NLR value and OS in the subgroup of PCa patients according
S4 Fig. Meta-analysis of the NLR value and RFS in the subgroup of PCa patients according
S5 Fig. Sensitivity analysis for the pooled analysis of OS and RFS.
S1 Table. Checklist of items to include when reporting a systematic review or meta-analysis.
S2 Table. Characteristics of included studies.
S3 Table. Results of the association between NLR and overall survival.
S4 Table. Results of the association between NLR and recurrence-free survival.
S5 Table. Heterogeneity test and publication bias analyses among included studies.
S6 Table. Results of the meta-analysis on the association between NLR and clinical features
Wrote the paper: BJW LYC KL YG.
Conceived and designed the experiments: LT XTL XZ. Performed the experiments: XTL BJW.
Analyzed the data: BJW GXL LYC LYG. Contributed reagents/materials/analysis tools: KL YG.
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