Surgical Oncology 23 (2014) 31e39

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Surgical Oncology
journal homepage: www.elsevier.com/locate/suronc

Review

A systematic review and meta-analysis on the impact of pre-operative

neutrophil lymphocyte ratio on long term outcomes after curative
intent resection of solid tumours
Ashvin Paramanathan a, Akshat Saxena b, David Lawson Morris b, *
a
Department of Surgery, Western Health, Footscray, Victoria, Australia
b
UNSW Department of Surgery, St. George Hospital, Kogarah, Sydney, New South Wales 2217, Australia

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

* Corresponding author. Tel.: 61 2 9113 2070; fax: 61 3 9113 3997.

E-mail addresses: david.morris@unsw.edu.au, akshat16187@gmail.com (D.L. Morris).

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

Cancer is one of the leading causes of mortality and morbidity in

both the developing and developed world [1]. Lung, breast, colo-
rectal, gastric and pancreatic cancer are associated with the poorest
prognosis; complete resection of localized disease represents the
best opportunity for cure [1]. Identifying prognostic indicators of
cancer progression forms a signicant part of cancer research, as it
allows for risk stratication and subsequent improvement in the
selection of patients for potentially curative resection [2,3]. It is well
recognized that clinical outcomes are not only determined by the
baseline characteristics of the tumour but also the hosts response
to the progressing malignancy [4]. A variety of host-related factors
have been implicated as prognostic indicators of cancer related
survival [5,6]; these include weight loss, performance status and
the systemic inammatory response.
It has become increasingly evident that cancer progression is
inuenced by the systemic inammatory response, rst described
by Virchow in 1876 by demonstrating the presence of leukocytes in
neoplastic tissue [7]. Inammation in the tumour microenviron-
ment plays an important role in the proliferation and survival of
malignant cells: it promotes angiogenesis, invasion and metastasis,
through recruitment of T lymphocytes, chemokines, activated cy-
tokines, IL6, TNF alpha, secretion of CRP, neutrophilia, subversion of
the adaptive immune system, and alteration of response to hor-
mones and chemotherapeutic agents [8,9].
Recently, it has been demonstrated that several biomarkers and
haematological indices representative of the inammatory
response, notably C-reactive protein (CRP), neutrophil-lymphocyte
ratio (NLR) and platelet-lymphocyte ratio (PLR), are associated with
worse outcomes [9]. The neutrophil-lymphocyte ratio in particular
has gained notable interest, with several studies over the last ve
years investigating its role in prognosticating long-term outcomes
in patients undergoing loco-regional therapy [8,10e59]. As hae-
matological tests are routinely conducted in cancer patients, the
neutrophil-lymphocyte ratio represents a simple, robust and
convenient parameter of the inammatory response. Thus, we
investigated the prognostic value of NLR, in predicting long term
outcomes following curative-intent surgery for solid tumours.
Figure 1. Search characteristics.

Methods
Search strategy and inclusion criteria
An online search was conducted using the US National Library of
Medicine (Medline) and the Exerpta Medica database (EBASE).
Search terms included (neutrophil lymphocyte ratio or NLR)
and (cancer or malignancy). Fig. 1 outlines the search strategy.
Limits included English language and human studies. Appropriate
references cited by the retrieved studies were also identied. Se-
lection criteria included 1) NLR as a prognostic indicator of overall,
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
prognostic indicator of overall survival were included. All studies,
which qualied for inclusion, were level III observational studies, as
described by the US Preventative Services Task Force. There were
no prospective or randomized controlled trials. Specic inclusion
criteria were studies published after the year 1990, with >10 pa-
tients, human articles and papers published in the English lan-
guage. Abstracts, letters, editorials and expert opinions were
excluded. Conference abstracts were excluded due to a lack of detail
regarding the methodology. Studies reporting the use of ablative
techniques in isolation, be it cryosurgery, radiofrequency ablation
or microwave ablation for the treatment of solid tumours were
excluded. Haemato-proliferative disorders and haemotological
malignancies were excluded. Studies that looked at surgery as a
palliative procedure or without survival data were also excluded. It
is acknowledged that all of the studies in this review aimed to
demonstrate the prognostic inuence of NLR in patients undergo-
ing curative intent surgery. However, some studies included both
neo-adjuvant and adjuvant treatment protocols to achieve local
control. It is also emphasized that most studies categorized patients
according to different NLR ranges.
Study characteristics and quality assessment
The two primary investigators (A.P and A.S) independently
extracted data from each study. Information extracted included
author, publication year, histology, stage, NLR cutoff values prior to
surgical intervention, adjuvant therapy, resection characteristics,
overall survival, disease-free survival and hazard ratios from
respective multivariate analyses. The study design, procedural de-
tails and patient characteristics were evaluated to determine clin-
ical heterogeneity. Study design was evaluated according to
whether patient data was collected retrospectively or
 A. Paramanathan et al. / Surgical Oncology 23 (2014) 31e39
prospectively. The quality of the articles was assessed and pre-
sented using criteria validated for assessing retrospective studies
[60,61].
Statistical analysis
Studies where elevated NLR level was a predictor for overall
survival were positive. Hazard ratios of NLR predicting overall
survival were extracted from each study and aggregated to calcu-
late the estimated hazard ratio and its variance directly or indirectly
with methods described in Parmar et al. [62] The methods were: 1)
observed number of events in the high NLR and low NLR group, log-
rank expected number of events in high NLR and low NLR group, 2)
HR and its 95% condence interval CI, 3) p value of the log rank or
MantzeleHaenszel Test, total number of events in the research and
control groups.
An overall weighted average was calculated for discrete vari-
ables. This was performed by adding the number of patients with
the outcome of interest from each study, and dividing by the total
number of patients in all studies where this variable was analysed.
For continuous variables, this method was unable to be used, as
median values were primarily reported.
Random effects analysis of the Mantel Haenszel Model was used
to combine the HR estimate in each study into an aggregated HR.
Where available, adjusted hazard ratios were primarily used for the
meta-analysis to account for confounding factors such as age, sex,
stage, adjuvant therapy, size, resection margin, histology and other
inammatory markers including but not limited to platelet-
lymphocyte ratio and c-reactive protein. These results were then
presented in forest plot graphs. The Chi-squared test was per-
formed to test the assumption of homogeneity [63]. HR greater
than 1 and 95% CI for the aggregated HR not crossing 1 indicates a
prognostic role of high NLR. When comparing survival difference
between high NLR and low NLR, all statistical analyses with
p < 0.05 were considered signicant. Statistical analyses were
performed with RevMan version 5.1 (Copenhagen: The Nordic
Cochrane Centre, The Cochrane Collaboration, 2011). Eggers test
was performed to test for publication bias.
Results
A literature search through MEDLINE and EMBASE yielded 274
studies. Fig. 1 demonstrates the methodology for study selection.
49 studies comprising 14282 patients were found to meet the se-
lection criteria for this review. There were no phase III randomised
controlled trials (level one evidence), no phase II studies (level two
evidence) and 49 observational studies [8e40,42e49,51e57,59].
The mean number of patients per study was 291 (range 23e3731).
The median number of patients in the studies was 174. Twenty out
of 49 studies reported age as median (median 64.5) while 17 out of
49 studies reported age as a mean (median 62.5). Thirty-ve studies
(71.4%) concentrated on gastrointestinal malignancies. There were
12 (24.5%) studies that studied the prognostic value of NLR in
colorectal carcinoma of which, three (6.1%) were on colorectal liver
metastases. Seven (14.2%) studies were on gastric cancer, four
(8.2%) on oesophageal cancers, four (8.2%) on pancreatic carcinoma,
four (8.2%) on hepatocellular carcinoma, one (2.0%) on gastro-
intestinal stromal tumours, one (2.0%) on cholangiocarcinoma,
one (2.0%) on gallbladder cancer and one (2.0%) on appendiceal
tumours (Table 1).
Study demographics and quality
The median value of the reported mean age was 62.5 (range
49.6e68.4), obtained from 17 studies (34.7%). Median age for
33
studies that reported the median was 64.5 (range 55e75), obtained
from 20 studies (40.8%). Males formed the majority of patients with
a weighted average of 56.9%. 25.7% of patients were in the higher
NLR cohort.
All articles were retrospective case series with the exception of
two studies having matched control groups [15]. No prior system-
atic review or meta-analysis on this topic was identied at the time
of the search. The inclusion criteria were clearly described in 48
studies (98.0%). One study was an institutional review on outcomes
following resection for gallbladder cancer over an undetermined
period of time. Prognostic factor measurements were described in
all studies. Thirty-one studies (63.2%) directly investigated NLR as a
prognostic factor in long term survival following curative intent
surgical resection. The remaining studies looked at other prog-
nostic factors primarily with NLR being a secondary objective. In
ve of those studies, NLR survival data was reported as part of the
overall analysis, and were included in this review. Forty-three out
49 studies (83%) demonstrated that blood counts were obtained
prior to surgery. All patients from three studies underwent neo-
adjuvant therapy. A proportion of patients from 21 (42.8%)
studies underwent preoperative therapy; of those, one study
excluded patients undergoing preoperative therapy from the sur-
vival analysis [46]. A proportion of patients from eleven studies
underwent post-operative adjuvant therapy with one study look-
ing at patients who underwent intraoperative HIPEC. Twenty
studies (40.8%) had a NLR cutoff of 5; with a NLR > 5 conferring
poorer prognosis. Ten studies (20.4%) used an NLR of between 3 and
13 (26.5%) studies used an NLR of between 1 and 3. The remaining
six (12.2%) studies had multiple subsets of NLR cutoffs. Fourteen
studies (28.6%) obtained their NLR cutoff from the previous litera-
ture, six (12.2%) used receiver operator curve analysis, ve (10.2%)
studies arbitrarily assigned their own cutoff and ve (10.2%) studies
used an NLR value that showed the biggest difference in results. 45
(92%) studies described how preoperative bloods were obtained.
Two (4.1%) studies obtained bloods prior to neo-adjuvant therapy.
Stage was found to be the most consistent prognostic factor with 19
(38.7%) studies showing that it signicantly predicted long term
survival.
Meta-analysis
The follow up time was not recorded in 13 (26.5%) studies. The
median follow up time was 39.1 months (20.9e96.2). Overall sur-
vival was reported in 19 (38.8%) studies. Median overall survival for
a higher NLR was 18.8 months, compared to 44.3 months for lower
NLR for studies that reported the median OS. Median 1, 3 and 5 year
OS for higher NLR compared to lower NLR was 79.0% vs 93.2%, 33.7%
vs 75.3% and 35.8% vs 70.1%, respectively. Twenty-seven out of 42
studies (64.2%) that looked at overall survival showed signicant
hazard ratios, while 16 out of 22 (72.7%) studies that looked at
disease free survival showed predictive hazard ratios.
Altogether, 36 (73.4%) studies were included in the meta-
analyses. Twenty-seven (55.1%) studies reported hazard ratios of
NLR from multivariate analyses of overall survival and were
included. Applying Parmars methods, estimated hazard ratios and
standard errors were calculated for nine (18.3%) of the remaining 22
studies [16,19,20,22,28,36,40,57,73]. Of the nine, four (8.1%) studies
reported hazard ratios from univariate analyses [19,20,36,40] and
were included. One (2.0%) study reported total numbers of patients
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
included numbers in each NLR subgroup as well as recording the
number of overall deaths allowing for an estimation of the hazard
ratios [16,22,57,73]. Thirteen (26.5%) of the excluded studies were
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

NA not applicable, NR not recorded.

subgroup numbers, event rate, univariate or multivariate hazard
ratios resulting in a failure to estimate hazard ratios
[14,17,18,21,27,32,37,42e44,46,49]. Thirteen studies (26.5%) re-
ported hazard ratios from multivariate analysis of disease-free sur-
vival. One of these studies reported the hazard ratios from both colon
and rectal cancer, resulting in 14 total sets of hazard ratios [14]. Data
could not be extracted from the remaining studies to due a lack of
one or more of the following; p value, death rate, NLR subgroup
numbers, event rate, univariate or multivariate hazard ratios.
In analysing the blood values, high NLR was found to be
signicantly associated with poor 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) (Figs. 2e5). The I2 value for OS and DFS was
77% and 97% respectively. The studies were therefore stratied by
tumour type for OS. In the subgroup analyses, the combined HR for
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
ovarian [HR: 2.02, 95% CI (0.18e22.57)] cancer were found to be
predictive of overall survival. Hepatocellular carcinoma [HR: 3.52,
95% CI (2.34e5.28)] and colorectal liver metastases [HR: 2.29, 95%
CI (1.74e3.02)] were not signicantly associated with overall sur-
vival. The subgroup I2 test for OS was 54.3%. There was still het-
erogeneity amongst the different subgroups; I2 values of gastric
cancer, colorectal cancer, oesophageal cancer, hepatocellular car-
cinoma, colorectal liver metastases and ovarian cancer were 60%,
54%, 74%, 19%, 0%, and 79% respectively. A separate analysis was also
performed for studies that looked at an NLR of 5 in predicting OS.
Sixteen (32.7%) studies were identied, with results demonstrating
that an NLR > 5 was signicantly associated with poorer outcomes
[HR: 2.18, 95% CI (1.74e2.73)] (p 0.002). There was less hetero-
geneity with an I2 of 58% (Figs. 6 and 7).
Discussion
It is well established and accepted that there is an intimate
relationship between tumour cells, the immune system and the
A. Paramanathan et al. / Surgical Oncology 23 (2014) 31e39 35

Figure 2. Meta analysis for overall survival.

36 A. Paramanathan et al. / Surgical Oncology 23 (2014) 31e39
Figure 3. Forest plot of overall survival.
inammatory response triggered [7]. This inammatory response
reects a non-specic response to tumour hypoxia, tissue injury
and necrosis [16,64]. The complex and diverse neuroendocrino-
logical and haemopoetic changes that occur during inammation
are thought to be responsible for both the diminishing of the im-
mune response and the increase in tumour proliferation [9]. Work
has been undertaken to identify components of this inammatory
response that can identify patients at risk of poorer outcomes.
The results demonstrate clearly that an elevated NLR is associ-
ated with worse overall survival and disease free interval. A sub-
sequent analysis demonstrated that an NLR of 5 was signicantly
associated poorer overall survival with lower heterogeneity (Fig. 6).
The association between an elevated NLR and poor prognosis is
complex. Theories at present centre around a relative neutrophilia
and lymphocytopaenia that occurs as part of the systemic
Figure 4. Meta-analysis of disease free survival.
inammatory response triggered by cancer [22,29,37,53]. Sug-
gested mechanisms to explain neutrophillia include release of G-
CSF by tumour cells, and cancer inammation through release of IL-
1 and TNF-alpha [27,65]. Relative neutrophillia increases the
number of inammatory markers that include pro-angiogenic
factors (VEGF), growth factors (CXCL8), proteases (tissue in-
hibitors of metalloproteinase) and anti-apoptotic markers (NF-kB)
that support tumour growth and progression [10,26,30,66].
Although neutrophils have anti-tumour effects, the increased
number of neutrophils and lymphocytes are less efcacious [67].
The lymphocyte response is a major component of controlling
cancer progression. One theory is that the cell-mediated response
to tumour inltration is lymphocyte dependent; thus, a low lym-
phocytic inltration at tumour margins corresponds with a poorer
prognosis [22,57,68]. Several studies have demonstrated that
decreased intratumoral T cell activity correlates with primary
tumour progression [69]. Lymphocytopaenia represents a signi-
cant decline in the cell-mediated immune system, demonstrated by
the marked decrease in T4 helper and T8 suppressor lymphocytes
[37]. Systemic inammation triggered by malignant cells results in
the release of a number of immune modulators such TGF beta, IL10
and CRP which impair lymphocyte action [56]. Hirashima also re-
ported that natural killer cell activity is repressed when NLR was
high; this would diminish the cell-mediated immune response
even further [28]. These responses have direct and indirect in-
teractions with the primary tumour to stimulate angiogenesis and
extracellular matrix remodelling [16].
Thus, a higher NLR favours a pro-tumour inammatory status,
and this correlates with more advanced disease [13,37]. Results
from our study appear to favour this conclusion; patient groups
with a higher NLR tended to have higher staging. Moreover, when
studies were categorised by NLR, the groups with higher NLR also
tended to have a worse age and stage. This corroborates reports
that have previously stated that these preoperative characteristics
are associated with vascular invasion and a more aggressive
phenotype [68e70]. It has also been shown that stage is directly
 A. Paramanathan et al. / Surgical Oncology 23 (2014) 31e39
Figure 5. Funnel plot of disease free survival.
representative of tumour progression and is subsequently reective
of the immune response (neutrophillia and lymphocytopaenia),
and it is not surprising that higher stages correspond with higher
NLR and therefore worse survival [57].
These results provide evidence to support the hypothesis that
the magnitude of the inammatory response to cancer is directly
prognostic of long-term outcomes in patients undergoing curative
intent surgery for solid tumours. Subsequently, the NLR potentially
represents a convenient, inexpensive, reproducible and robust
measurement of the balance between the pro-tumour inamma-
tory status and the anti-tumour immune status in the tumour
microenvironment [16,18,30,51]. With further prospective work,
the NLR may allow better risk stratication amongst patients
eligible for curative surgery and may facilitate administration of
neo-adjuvant and adjuvant therapy in higher risk candidates. Im-
mune modulators have previously been trialled in other cancers,
and given the ndings, there may be provision for its use both
preoperatively and postoperatively. It has been shown that COX-2
inhibitors suppress angiogenic markers such as VEGF, and may
prevent proliferation and further growth of tumours [25]. This
could allow both preoperative and post-operative treatment in
selected patients to enhance outcomes [25].
However, the NLR represents only one aspect of the inamma-
tory response, and it is thought that scoring systems such as the
Glasgow Prognostic Scale and mGPS that incorporate several
Figure 6. NLR > 5 predicts overall survival.
37
markers of the immune system are more representative of the in-
ammatory response [64,71]. The Glasgow prognostic scale rep-
resented multiple aspects of the inammatory system including
NLR, PLR, CRP, albumin and HB and was derived from a study of a
large cancer registry [71]. Although seemingly more representative,
it has been suggested that single continuous variables such as the
NLR may be more accurate in measuring dynamic changes to an
immune system, compared to scoring tables which apply different
weightings to different inammatory markers and is a static cate-
gorical measure [35]. Given that most of the evidence is retro-
spective, it is difcult to determine whether single continuous
measures or scoring tables have greater prognostic value e predi-
cating the need for future prospective studies to validate these
ndings.
There were limitations to the results of this study. Firstly,
there was signicant heterogeneity between studies with an I-
squared value of 77% for OS and 97% for DFS respectively. Two
obvious explanations for the heterogeneity were the histology
and difference in NLR cutoffs e however, subgroup analyses
produced similarly high I-squared values. Perhaps the greatest
limitation in this review was the discordance of NLR cutoffs used
in most of the studies. Most studies used NLR > 5 as the cutoff,
but this did not imply that patients with an NLR < 5 were not at
an increased risk e in fact, several other studies demonstrated
NLR ranges of 4 and below (even as low as 2.6), having prognostic
signicance in overall survival (Fig. 2). Most of the studies in this
review used an NLR of 5 as the cutoff based purely on previous
work. Only four studies used ROC sensitivity and specicity an-
alyses to determine an NLR cutoff. The result was a signicant
discordance in numbers between groups e more than half the
studies had very small numbers of patients who were classied in
the higher NLR group. Given the retrospective nature of all of the
studies, the magnitude of any confounding factors would have
been further amplied. Most studies had cohorts of patients that
had undergone adjuvant therapy and were not excluded from the
analyses. Consequently, the results from the HCC group are also
difcult to interpret, as the vast majority of their patients had
hepatitis B or C, which would have affected the immune system
and hence the NLR. The NLR is also inuenced by multiple other
factors. Age, for example, is known to be associated with
decreasing absolute lymphocyte counts [10]. Given that most
cancer surgery is undertaken on the elderly, a surveillance tool
such as the NLR may not adequately prognosticate survival.
38 A. Paramanathan et al. / Surgical Oncology 23 (2014) 31e39
Figure 7. Funnel Plot of overall survival for NLR > 5.
Likewise, other factors such as critically ill patients and medical
comorbidities affect the NLR [72].
In conclusion, this systematic review demonstrates an associa-
tion between a high NLR and worse long-term outcomes following
curative intent surgery. The NLR potentially represents a simple and
robust measurement of prognosis; however, it needs to be vali-
dated in larger prospective studies for it to be useful in risk
stratication.
Conict of interest statement
The authors have no conicts of interest to declare.
Authorship statement
Guarantor of the integrity of the study: Ashvin Paramanathan,
Akshat Saxena and David Lawson Morris.
Appendix A. Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.suronc.2013.12.001.
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