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Surgical Oncology
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Review
a r t i c l e i n f o a b s t r a c t
Article history: Introduction: There is increasing evidence to suggest that cancer-associated inammation is associated
Accepted 8 December 2013 with poorer long-term outcomes. Various markers have been studied over the past decade in an attempt
to improve selection of patients for surgery. This meta-analysis explored the association between the
Keywords: neutrophil-lymphocyte ratio and prognosis following curative-intent surgery for solid tumours.
Neutrophil lymphocyte ratio Methods: Studies were identied from US National Library of Medicine (Medline) and the Exerpta
Systematic review
Medica database (EBASE) performed in March 2013. A systematic review and meta-analysis were per-
Meta-analysis
formed to generate combined hazard ratios for overall survival (OS) and disease-free survival (DFS).
Resection
Surgery
Results: Forty-nine studies containing 14282 patients were included. Elevated NLR was associated with
Prognosis poorer overall survival [HR: 1.92, 95% CI (1.64e2.24)] (p < 0.001) and disease-free survival [HR: 1.99, 95%
CI (1.80e2.20)] (p < 0.001). Signicant heterogeneity was found with an I2 of 77% and 97% for OS and DFS
respectively. Subgroup analyses demonstrated that gastro-intestinal malignancies; mainly gastric [HR:
1.97, 95% CI (1.41e2.76)], colorectal [HR: 1.65, 95% CI (1.21e2.26)] and oesophageal [HR: 1.48, 95% CI (0.91
e2.42)] cancers were predictive of OS (I2 54.3%). A separate analysis for studies using an NLR cutoff of 5
demonstrated signicantly poorer outcomes [HR: 2.18, 95% CI (1.74e2.73)] (p 0.002) with less het-
erogeneity (I2 58%).
Conclusion: Elevated NLR correlates with poorer prognosis. It potentially represents a simple, robust and
reliable measure that may be useful in identifying high-risk groups who could benet from adjuvant
therapy.
2014 Elsevier Ltd. All rights reserved.
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
Search strategy and inclusion criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
Study characteristics and quality assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
Statistical analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .33
Study demographics and quality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
Meta-analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
Authorship statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
Supplementary data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
0960-7404/$ e see front matter 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.suronc.2013.12.001
32 A. Paramanathan et al. / Surgical Oncology 23 (2014) 31e39
Introduction
Methods
or microwave ablation for the treatment of solid tumours were
Search strategy and inclusion criteria excluded. Haemato-proliferative disorders and haemotological
malignancies were excluded. Studies that looked at surgery as a
An online search was conducted using the US National Library of palliative procedure or without survival data were also excluded. It
Medicine (Medline) and the Exerpta Medica database (EBASE). is acknowledged that all of the studies in this review aimed to
Search terms included (neutrophil lymphocyte ratio or NLR) demonstrate the prognostic inuence of NLR in patients undergo-
and (cancer or malignancy). Fig. 1 outlines the search strategy. ing curative intent surgery. However, some studies included both
Limits included English language and human studies. Appropriate neo-adjuvant and adjuvant treatment protocols to achieve local
references cited by the retrieved studies were also identied. Se- control. It is also emphasized that most studies categorized patients
lection criteria included 1) NLR as a prognostic indicator of overall, according to different NLR ranges.
disease-free and disease specic survival in patients undergoing
curative surgery and patients with solid tumours only.
Experimental and observational studies that included NLR as a Study characteristics and quality assessment
prognostic indicator of overall survival were included. All studies,
which qualied for inclusion, were level III observational studies, as The two primary investigators (A.P and A.S) independently
described by the US Preventative Services Task Force. There were extracted data from each study. Information extracted included
no prospective or randomized controlled trials. Specic inclusion author, publication year, histology, stage, NLR cutoff values prior to
criteria were studies published after the year 1990, with >10 pa- surgical intervention, adjuvant therapy, resection characteristics,
tients, human articles and papers published in the English lan- overall survival, disease-free survival and hazard ratios from
guage. Abstracts, letters, editorials and expert opinions were respective multivariate analyses. The study design, procedural de-
excluded. Conference abstracts were excluded due to a lack of detail tails and patient characteristics were evaluated to determine clin-
regarding the methodology. Studies reporting the use of ablative ical heterogeneity. Study design was evaluated according to
techniques in isolation, be it cryosurgery, radiofrequency ablation whether patient data was collected retrospectively or
A. Paramanathan et al. / Surgical Oncology 23 (2014) 31e39 33
prospectively. The quality of the articles was assessed and pre- studies that reported the median was 64.5 (range 55e75), obtained
sented using criteria validated for assessing retrospective studies from 20 studies (40.8%). Males formed the majority of patients with
[60,61]. a weighted average of 56.9%. 25.7% of patients were in the higher
NLR cohort.
Statistical analysis All articles were retrospective case series with the exception of
two studies having matched control groups [15]. No prior system-
Studies where elevated NLR level was a predictor for overall atic review or meta-analysis on this topic was identied at the time
survival were positive. Hazard ratios of NLR predicting overall of the search. The inclusion criteria were clearly described in 48
survival were extracted from each study and aggregated to calcu- studies (98.0%). One study was an institutional review on outcomes
late the estimated hazard ratio and its variance directly or indirectly following resection for gallbladder cancer over an undetermined
with methods described in Parmar et al. [62] The methods were: 1) period of time. Prognostic factor measurements were described in
observed number of events in the high NLR and low NLR group, log- all studies. Thirty-one studies (63.2%) directly investigated NLR as a
rank expected number of events in high NLR and low NLR group, 2) prognostic factor in long term survival following curative intent
HR and its 95% condence interval CI, 3) p value of the log rank or surgical resection. The remaining studies looked at other prog-
MantzeleHaenszel Test, total number of events in the research and nostic factors primarily with NLR being a secondary objective. In
control groups. ve of those studies, NLR survival data was reported as part of the
An overall weighted average was calculated for discrete vari- overall analysis, and were included in this review. Forty-three out
ables. This was performed by adding the number of patients with 49 studies (83%) demonstrated that blood counts were obtained
the outcome of interest from each study, and dividing by the total prior to surgery. All patients from three studies underwent neo-
number of patients in all studies where this variable was analysed. adjuvant therapy. A proportion of patients from 21 (42.8%)
For continuous variables, this method was unable to be used, as studies underwent preoperative therapy; of those, one study
median values were primarily reported. excluded patients undergoing preoperative therapy from the sur-
Random effects analysis of the Mantel Haenszel Model was used vival analysis [46]. A proportion of patients from eleven studies
to combine the HR estimate in each study into an aggregated HR. underwent post-operative adjuvant therapy with one study look-
Where available, adjusted hazard ratios were primarily used for the ing at patients who underwent intraoperative HIPEC. Twenty
meta-analysis to account for confounding factors such as age, sex, studies (40.8%) had a NLR cutoff of 5; with a NLR > 5 conferring
stage, adjuvant therapy, size, resection margin, histology and other poorer prognosis. Ten studies (20.4%) used an NLR of between 3 and
inammatory markers including but not limited to platelet- 13 (26.5%) studies used an NLR of between 1 and 3. The remaining
lymphocyte ratio and c-reactive protein. These results were then six (12.2%) studies had multiple subsets of NLR cutoffs. Fourteen
presented in forest plot graphs. The Chi-squared test was per- studies (28.6%) obtained their NLR cutoff from the previous litera-
formed to test the assumption of homogeneity [63]. HR greater ture, six (12.2%) used receiver operator curve analysis, ve (10.2%)
than 1 and 95% CI for the aggregated HR not crossing 1 indicates a studies arbitrarily assigned their own cutoff and ve (10.2%) studies
prognostic role of high NLR. When comparing survival difference used an NLR value that showed the biggest difference in results. 45
between high NLR and low NLR, all statistical analyses with (92%) studies described how preoperative bloods were obtained.
p < 0.05 were considered signicant. Statistical analyses were Two (4.1%) studies obtained bloods prior to neo-adjuvant therapy.
performed with RevMan version 5.1 (Copenhagen: The Nordic Stage was found to be the most consistent prognostic factor with 19
Cochrane Centre, The Cochrane Collaboration, 2011). Eggers test (38.7%) studies showing that it signicantly predicted long term
was performed to test for publication bias. survival.
Results Meta-analysis
A literature search through MEDLINE and EMBASE yielded 274 The follow up time was not recorded in 13 (26.5%) studies. The
studies. Fig. 1 demonstrates the methodology for study selection. median follow up time was 39.1 months (20.9e96.2). Overall sur-
49 studies comprising 14282 patients were found to meet the se- vival was reported in 19 (38.8%) studies. Median overall survival for
lection criteria for this review. There were no phase III randomised a higher NLR was 18.8 months, compared to 44.3 months for lower
controlled trials (level one evidence), no phase II studies (level two NLR for studies that reported the median OS. Median 1, 3 and 5 year
evidence) and 49 observational studies [8e40,42e49,51e57,59]. OS for higher NLR compared to lower NLR was 79.0% vs 93.2%, 33.7%
The mean number of patients per study was 291 (range 23e3731). vs 75.3% and 35.8% vs 70.1%, respectively. Twenty-seven out of 42
The median number of patients in the studies was 174. Twenty out studies (64.2%) that looked at overall survival showed signicant
of 49 studies reported age as median (median 64.5) while 17 out of hazard ratios, while 16 out of 22 (72.7%) studies that looked at
49 studies reported age as a mean (median 62.5). Thirty-ve studies disease free survival showed predictive hazard ratios.
(71.4%) concentrated on gastrointestinal malignancies. There were Altogether, 36 (73.4%) studies were included in the meta-
12 (24.5%) studies that studied the prognostic value of NLR in analyses. Twenty-seven (55.1%) studies reported hazard ratios of
colorectal carcinoma of which, three (6.1%) were on colorectal liver NLR from multivariate analyses of overall survival and were
metastases. Seven (14.2%) studies were on gastric cancer, four included. Applying Parmars methods, estimated hazard ratios and
(8.2%) on oesophageal cancers, four (8.2%) on pancreatic carcinoma, standard errors were calculated for nine (18.3%) of the remaining 22
four (8.2%) on hepatocellular carcinoma, one (2.0%) on gastro- studies [16,19,20,22,28,36,40,57,73]. Of the nine, four (8.1%) studies
intestinal stromal tumours, one (2.0%) on cholangiocarcinoma, reported hazard ratios from univariate analyses [19,20,36,40] and
one (2.0%) on gallbladder cancer and one (2.0%) on appendiceal were included. One (2.0%) study reported total numbers of patients
tumours (Table 1). that were alive at the end of follow up which allowed for an esti-
mation of the hazard ratio [28]. The remaining four (8.1%) studies
Study demographics and quality included numbers in each NLR subgroup as well as recording the
number of overall deaths allowing for an estimation of the hazard
The median value of the reported mean age was 62.5 (range ratios [16,22,57,73]. Thirteen (26.5%) of the excluded studies were
49.6e68.4), obtained from 17 studies (34.7%). Median age for missing one or more of the following; p value, death rate, NLR
34 A. Paramanathan et al. / Surgical Oncology 23 (2014) 31e39
Table 1
Summary of baseline characteristics.
First author Year Location (city, country) Patients (n) Study period Tumour NLR cut-off
Pichler [48] 2013 Graz, Austria 678 2000e2010 Clear cell renal cell carcinoma >3.3
Krane [34] 2013 North Carolina, US 68 2005e2011 Bladder cancer >2.5
Szkandera [54] 2013 Graz, Austria 260 1998e2010 Soft tissue Sarcoma >3.45
Perisanidis [47] 2013 Vienna, Austria 97 2001e2009 Oral cancer >1.9
Mallappa [37] 2012 Harrow, UK 297 2003e2004 Colorectal cancer >5
Carruthers [13] 2012 Glasgow, UK 115 2000e2005 Rectal cancer >5
Perez [46] 2012 New York, USA 335 1995e2010 Gastrointestinal stromal tumour >2.7
Dutta [19] 2012 Glasgow, UK 120 1996e2009 Gastric cancer Multiple cutoffs
Sanjay [45] 2012 Dundee, UK 51 2002e2008 Pancreatic adenocarcinoma >5
Gondo [24] 2012 Tokyo Japan 189 2000e2009 Bladder cancer >2.5
Hashimoto [27] 2012 Tokyo, Japan 84 1997e2010 Upper urinary tract carcinoma Continuous variable
Chiang [14] 2012 Taiwan 3731 1998e2003 Colorectal cancer >3
Kwon [35] 2012 Busan, Korea 200 2005e2008 Colorectal cancer >5
Chua [16] 2012 Sydney, Australia 174 NR Appendiceal tumours >2.6
Ohno [42] 2012 Tokyo, Japan 250 1990e2008 Clear cell renal cell carcinoma >2.7
Hung [29] 2011 Tao-Yuan, Taiwan 1040 1995e2005 Colorectal cancer >5
Jung [30] 2011 Gwanju, Korea 293 2004e2007 Gastric cancer >2.0
Wang [8] 2011 Guangzhou, China 324 2006e2009 Gastric cancer >5
Garcea [21] 2011 Leicester, UK 74 2001e2011 Pancreatic adenocarcinoma >5
Azab [10] 2011 Staten Island, NY 316 2004e2006 Breast cancer Multiple cutoffs
Thavaramara [55] 2011 Bangkok, Thailand 129 2004e2009 Ovarian cancer >2.6
Kao [31] 2011 Sydney, Australia 85 1994e2009 Pleural mesothelioma >3.0
Sharaiha [52] 2011 New York, New york 295 1996e2009 Oesophageal cancer >5
Dutta [20] 2011 Glasgow, UK 112 1996e2008 Oesophageal cancer Multiple cutoffs
Miyata [38] 2011 Osaka, Japan 152 2000e2008 Oesophageal cancer >4
Bertuzzo [11] 2011 Bologna, Italy 219 1997e2009 Hepatocellular Carcinoma >5
Guo [59] 2011 Hong Kong, China 101 2003e2009 Hepatocellular Carcinoma >3
Ding [18] 2010 Guandong, PRC 141 2002e2006 Colorectal cancer >4
Shimada [53] 2010 Chiba, Japan 1028 2001e2007 Gastric cancer >4
Ubukuta [56] 2010 Ibaraki, Japan 157 1996e2003 Gastric cancer >5
Kim [32] 2010 Seoul, South Korea 55 2004e2008 Uterine sarcoma >2.12
Bhatti [12] 2010 Nottingham, UK 84 1998e2008 Pancreatic adenocarcinoma >4.0
Rashid [49] 2010 Nottingham, UK 294 1997e2007 Oesophageal cancer Multiple cutoffs
Ohno [43] 2010 Tokyo, Japan 192 1986e2000 Renal cell carcinoma >2.7
Mohri [39] 2009 Edobashi, Japan 357 1992e2004 Gastric cancer >2.2
Halazun [26] 2009 New York, New York 150 2001e2007 Hepatocellular carcinoma >5
Neal [40] 2009 Leicester, UK 174 2000e2005 Colorectal liver metastases >5
Roxburgh [73] 2009 Glasgow, UK 227 1997e2005 Colon cancer >5
Kishi [33] 2009 Texas, US 200 1997e2007 Colorectal liver >5
Gomez [22] 2008 Leeds, UK 96 1994e2007 Hepatocellular carcinoma >5
Gomez [23] 2008 Leeds UK 27 1996e2006 Cholangiocarcinoma >5
Sarraf [51] 2008 London, UK 178 1999e2005 Non-small-cell lung cancer Multiple cutoffs
Cho [15] 2008 Seoul, South Korea 192 2003e2006 Ovarian cancer >2.60
Ong [44] 2008 Leicester, UK 23 1996e2006 Gallbladder cancer >3.75
Halazun [25] 2007 Leeds, UK 440 1996e2006 Colorectal Liver Metastases >5
Leitch [36] 2007 Glasgow, Uk 149 1998e2006 Colorectal cancer >5
Clark [17] 2007 Ediburgh, UK 44 1998e2005 Pancreatic adenocarcinoma >5
Walsh [57] 2005 Suffolk, UK 230 2000e2001 Colorectal cancer >5
Hirashima [28] 1998 Kumamoto, Japan 55 1989e1992 Gastric cancer >2
subgroup numbers, event rate, univariate or multivariate hazard predictive of overall survival. Hepatocellular carcinoma [HR: 3.52,
ratios resulting in a failure to estimate hazard ratios 95% CI (2.34e5.28)] and colorectal liver metastases [HR: 2.29, 95%
[14,17,18,21,27,32,37,42e44,46,49]. Thirteen studies (26.5%) re- CI (1.74e3.02)] were not signicantly associated with overall sur-
ported hazard ratios from multivariate analysis of disease-free sur- vival. The subgroup I2 test for OS was 54.3%. There was still het-
vival. One of these studies reported the hazard ratios from both colon erogeneity amongst the different subgroups; I2 values of gastric
and rectal cancer, resulting in 14 total sets of hazard ratios [14]. Data cancer, colorectal cancer, oesophageal cancer, hepatocellular car-
could not be extracted from the remaining studies to due a lack of cinoma, colorectal liver metastases and ovarian cancer were 60%,
one or more of the following; p value, death rate, NLR subgroup 54%, 74%, 19%, 0%, and 79% respectively. A separate analysis was also
numbers, event rate, univariate or multivariate hazard ratios. performed for studies that looked at an NLR of 5 in predicting OS.
In analysing the blood values, high NLR was found to be Sixteen (32.7%) studies were identied, with results demonstrating
signicantly associated with poor overall survival [HR: 1.92, 95% CI that an NLR > 5 was signicantly associated with poorer outcomes
(1.64e2.24)] (p < 0.001) and disease free survival [HR: 1.99, 95% CI [HR: 2.18, 95% CI (1.74e2.73)] (p 0.002). There was less hetero-
(1.80e2.20)] (p < 0.001) (Figs. 2e5). The I2 value for OS and DFS was geneity with an I2 of 58% (Figs. 6 and 7).
77% and 97% respectively. The studies were therefore stratied by
tumour type for OS. In the subgroup analyses, the combined HR for Discussion
gastric [HR: 1.97, 95% CI (1.41e2.76)], colorectal [HR: 1.65, 95% CI
(1.21e2.26)], oesophageal [HR: 1.48, 95% CI (0.91e2.42)] and It is well established and accepted that there is an intimate
ovarian [HR: 2.02, 95% CI (0.18e22.57)] cancer were found to be relationship between tumour cells, the immune system and the
A. Paramanathan et al. / Surgical Oncology 23 (2014) 31e39 35
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