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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-operativeneutrophil lymphocyte ratio on long term outcomes after curativeintent resection of solid tumours

Ashvin Paramanathan a, Akshat Saxena b, David Lawson Morris b,*

aDepartment of Surgery, Western Health, Footscray, Victoria, AustraliabUNSW Department of Surgery, St. George Hospital, Kogarah, Sydney, New South Wales 2217, Australia

a r t i c l e i n f o

Article history:Accepted 8 December 2013

Keywords:Neutrophil lymphocyte ratioSystematic reviewMeta-analysisResectionSurgeryPrognosis

* Corresponding author. Tel.: þ61 2 9113 2070; faxE-mail addresses: david.morris@unsw.edu.au, aksh

0960-7404/$ e see front matter � 2014 Elsevier Ltd.http://dx.doi.org/10.1016/j.suronc.2013.12.001

a b s t r a c t

Introduction: There is increasing evidence to suggest that cancer-associated inflammation is associatedwith poorer long-term outcomes. Various markers have been studied over the past decade in an attemptto improve selection of patients for surgery. This meta-analysis explored the association between theneutrophil-lymphocyte ratio and prognosis following curative-intent surgery for solid tumours.Methods: Studies were identified from US National Library of Medicine (Medline) and the ExerptaMedica database (EBASE) performed in March 2013. A systematic review and meta-analysis were per-formed to generate combined hazard ratios for overall survival (OS) and disease-free survival (DFS).Results: Forty-nine studies containing 14282 patients were included. Elevated NLR was associated withpoorer 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). Significant heterogeneity was found with an I2 of 77% and 97% for OS and DFSrespectively. 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 (0.91e2.42)] cancers were predictive of OS (I2 ¼ 54.3%). A separate analysis for studies using an NLR cutoff of 5demonstrated significantly poorer outcomes [HR: 2.18, 95% CI (1.74e2.73)] (p ¼ 0.002) with less het-erogeneity (I2 ¼ 58%).Conclusion: Elevated NLR correlates with poorer prognosis. It potentially represents a simple, robust andreliable measure that may be useful in identifying high-risk groups who could benefit from adjuvanttherapy.

� 2014 Elsevier Ltd. All rights reserved.

Contents

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32

Search strategy and inclusion criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32Study characteristics and quality assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32Statistical analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33

Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .33Study demographics and quality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33Meta-analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33

Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38Authorship statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38Supplementary data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38

: þ61 3 9113 3997.at16187@gmail.com (D.L. Morris).

All rights reserved.

A. Paramanathan et al. / Surgical Oncology 23 (2014) 31e3932

Introduction

Cancer is one of the leading causes of mortality andmorbidity inboth the developing and developed world [1]. Lung, breast, colo-rectal, gastric and pancreatic cancer are associated with the poorestprognosis; complete resection of localized disease represents thebest opportunity for cure [1]. Identifying prognostic indicators ofcancer progression forms a significant part of cancer research, as itallows for risk stratification and subsequent improvement in theselection of patients for potentially curative resection [2,3]. It is wellrecognized that clinical outcomes are not only determined by thebaseline characteristics of the tumour but also the host’s responseto the progressing malignancy [4]. A variety of host-related factorshave been implicated as prognostic indicators of cancer relatedsurvival [5,6]; these include weight loss, performance status andthe systemic inflammatory response.

It has become increasingly evident that cancer progression isinfluenced by the systemic inflammatory response, first describedby Virchow in 1876 by demonstrating the presence of leukocytes inneoplastic tissue [7]. Inflammation in the tumour microenviron-ment plays an important role in the proliferation and survival ofmalignant cells: it promotes angiogenesis, invasion and metastasis,through recruitment of T lymphocytes, chemokines, activated cy-tokines, IL6, TNF alpha, secretion of CRP, neutrophilia, subversion ofthe adaptive immune system, and alteration of response to hor-mones and chemotherapeutic agents [8,9].

Recently, it has been demonstrated that several biomarkers andhaematological indices representative of the inflammatoryresponse, notably C-reactive protein (CRP), neutrophil-lymphocyteratio (NLR) and platelet-lymphocyte ratio (PLR), are associated withworse outcomes [9]. The neutrophil-lymphocyte ratio in particularhas gained notable interest, with several studies over the last fiveyears investigating its role in prognosticating long-term outcomesin patients undergoing loco-regional therapy [8,10e59]. As hae-matological tests are routinely conducted in cancer patients, theneutrophil-lymphocyte ratio represents a simple, robust andconvenient parameter of the inflammatory response. Thus, weinvestigated the prognostic value of NLR, in predicting long termoutcomes 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 ofMedicine (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. Appropriatereferences cited by the retrieved studies were also identified. Se-lection criteria included 1) NLR as a prognostic indicator of overall,disease-free and disease specific survival in patients undergoingcurative surgery and patients with solid tumours only.

Experimental and observational studies that included NLR as aprognostic indicator of overall survival were included. All studies,which qualified for inclusion, were level III observational studies, asdescribed by the US Preventative Services Task Force. There wereno prospective or randomized controlled trials. Specific inclusioncriteria 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 wereexcluded. Conference abstracts were excluded due to a lack of detailregarding the methodology. Studies reporting the use of ablativetechniques in isolation, be it cryosurgery, radiofrequency ablation

or microwave ablation for the treatment of solid tumours wereexcluded. Haemato-proliferative disorders and haemotologicalmalignancies were excluded. Studies that looked at surgery as apalliative procedure or without survival data were also excluded. Itis acknowledged that all of the studies in this review aimed todemonstrate the prognostic influence of NLR in patients undergo-ing curative intent surgery. However, some studies included bothneo-adjuvant and adjuvant treatment protocols to achieve localcontrol. It is also emphasized that most studies categorized patientsaccording to different NLR ranges.

Study characteristics and quality assessment

The two primary investigators (A.P and A.S) independentlyextracted data from each study. Information extracted includedauthor, publication year, histology, stage, NLR cutoff values prior tosurgical intervention, adjuvant therapy, resection characteristics,overall survival, disease-free survival and hazard ratios fromrespective multivariate analyses. The study design, procedural de-tails and patient characteristics were evaluated to determine clin-ical heterogeneity. Study design was evaluated according towhether 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-sented using criteria validated for assessing retrospective studies[60,61].

Statistical analysis

Studies where elevated NLR level was a predictor for overallsurvival were positive. Hazard ratios of NLR predicting overallsurvival were extracted from each study and aggregated to calcu-late the estimated hazard ratio and its variance directly or indirectlywith methods described in Parmar et al. [62] The methods were: 1)observed number of events in the high NLR and lowNLR group, log-rank expected number of events in high NLR and low NLR group, 2)HR and its 95% confidence interval CI, 3) p value of the log rank orMantzeleHaenszel Test, total number of events in the research andcontrol groups.

An overall weighted average was calculated for discrete vari-ables. This was performed by adding the number of patients withthe outcome of interest from each study, and dividing by the totalnumber of patients in all studies where this variable was analysed.For continuous variables, this method was unable to be used, asmedian values were primarily reported.

Random effects analysis of the Mantel Haenszel Model was usedto combine the HR estimate in each study into an aggregated HR.Where available, adjusted hazard ratios were primarily used for themeta-analysis to account for confounding factors such as age, sex,stage, adjuvant therapy, size, resection margin, histology and otherinflammatory markers including but not limited to platelet-lymphocyte ratio and c-reactive protein. These results were thenpresented in forest plot graphs. The Chi-squared test was per-formed to test the assumption of homogeneity [63]. HR greaterthan 1 and 95% CI for the aggregated HR not crossing 1 indicates aprognostic role of high NLR. When comparing survival differencebetween high NLR and low NLR, all statistical analyses withp < 0.05 were considered significant. Statistical analyses wereperformed with RevMan version 5.1 (Copenhagen: The NordicCochrane Centre, The Cochrane Collaboration, 2011). Eggers testwas performed to test for publication bias.

Results

A literature search through MEDLINE and EMBASE yielded 274studies. 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 randomisedcontrolled trials (level one evidence), no phase II studies (level twoevidence) 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 outof 49 studies reported age as median (median 64.5) while 17 out of49 studies reported age as amean (median 62.5). Thirty-five studies(71.4%) concentrated on gastrointestinal malignancies. There were12 (24.5%) studies that studied the prognostic value of NLR incolorectal carcinoma of which, three (6.1%) were on colorectal livermetastases. 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 appendicealtumours (Table 1).

Study demographics and quality

The median value of the reported mean age was 62.5 (range49.6e68.4), obtained from 17 studies (34.7%). Median age for

studies that reported the medianwas 64.5 (range 55e75), obtainedfrom 20 studies (40.8%). Males formed themajority of patients witha weighted average of 56.9%. 25.7% of patients were in the higherNLR cohort.

All articles were retrospective case series with the exception oftwo studies having matched control groups [15]. No prior system-atic review or meta-analysis on this topic was identified at the timeof the search. The inclusion criteria were clearly described in 48studies (98.0%). One study was an institutional review on outcomesfollowing resection for gallbladder cancer over an undeterminedperiod of time. Prognostic factor measurements were described inall studies. Thirty-one studies (63.2%) directly investigated NLR as aprognostic factor in long term survival following curative intentsurgical resection. The remaining studies looked at other prog-nostic factors primarily with NLR being a secondary objective. Infive of those studies, NLR survival data was reported as part of theoverall analysis, and were included in this review. Forty-three out49 studies (83%) demonstrated that blood counts were obtainedprior 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 studyexcluded patients undergoing preoperative therapy from the sur-vival analysis [46]. A proportion of patients from eleven studiesunderwent post-operative adjuvant therapy with one study look-ing at patients who underwent intraoperative HIPEC. Twentystudies (40.8%) had a NLR cutoff of 5; with a NLR > 5 conferringpoorer prognosis. Ten studies (20.4%) used an NLR of between 3 and13 (26.5%) studies used an NLR of between 1 and 3. The remainingsix (12.2%) studies had multiple subsets of NLR cutoffs. Fourteenstudies (28.6%) obtained their NLR cutoff from the previous litera-ture, six (12.2%) used receiver operator curve analysis, five (10.2%)studies arbitrarily assigned their own cutoff and five (10.2%) studiesused 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 themost consistent prognostic factor with 19(38.7%) studies showing that it significantly predicted long termsurvival.

Meta-analysis

The follow up time was not recorded in 13 (26.5%) studies. Themedian follow up time was 39.1 months (20.9e96.2). Overall sur-vival was reported in 19 (38.8%) studies. Median overall survival fora higher NLR was 18.8 months, compared to 44.3 months for lowerNLR for studies that reported themedian OS. Median 1, 3 and 5 yearOS for higher NLR compared to lower NLRwas 79.0% vs 93.2%, 33.7%vs 75.3% and 35.8% vs 70.1%, respectively. Twenty-seven out of 42studies (64.2%) that looked at overall survival showed significanthazard ratios, while 16 out of 22 (72.7%) studies that looked atdisease 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 ofNLR from multivariate analyses of overall survival and wereincluded. Applying Parmar’s methods, estimated hazard ratios andstandard errors were calculated for nine (18.3%) of the remaining 22studies [16,19,20,22,28,36,40,57,73]. Of the nine, four (8.1%) studiesreported hazard ratios from univariate analyses [19,20,36,40] andwere included. One (2.0%) study reported total numbers of patientsthat were alive at the end of follow up which allowed for an esti-mation of the hazard ratio [28]. The remaining four (8.1%) studiesincluded numbers in each NLR subgroup as well as recording thenumber of overall deaths allowing for an estimation of the hazardratios [16,22,57,73]. Thirteen (26.5%) of the excluded studies weremissing one or more of the following; p value, death rate, NLR

Table 1Summary 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 >3.3Krane [34] 2013 North Carolina, US 68 2005e2011 Bladder cancer >2.5Szkandera [54] 2013 Graz, Austria 260 1998e2010 Soft tissue Sarcoma >3.45Perisanidis [47] 2013 Vienna, Austria 97 2001e2009 Oral cancer >1.9Mallappa [37] 2012 Harrow, UK 297 2003e2004 Colorectal cancer >5Carruthers [13] 2012 Glasgow, UK 115 2000e2005 Rectal cancer >5Perez [46] 2012 New York, USA 335 1995e2010 Gastrointestinal stromal tumour >2.7Dutta [19] 2012 Glasgow, UK 120 1996e2009 Gastric cancer Multiple cutoffsSanjay [45] 2012 Dundee, UK 51 2002e2008 Pancreatic adenocarcinoma >5Gondo [24] 2012 Tokyo Japan 189 2000e2009 Bladder cancer >2.5Hashimoto [27] 2012 Tokyo, Japan 84 1997e2010 Upper urinary tract carcinoma Continuous variableChiang [14] 2012 Taiwan 3731 1998e2003 Colorectal cancer >3Kwon [35] 2012 Busan, Korea 200 2005e2008 Colorectal cancer >5Chua [16] 2012 Sydney, Australia 174 NR Appendiceal tumours >2.6Ohno [42] 2012 Tokyo, Japan 250 1990e2008 Clear cell renal cell carcinoma >2.7Hung [29] 2011 Tao-Yuan, Taiwan 1040 1995e2005 Colorectal cancer >5Jung [30] 2011 Gwanju, Korea 293 2004e2007 Gastric cancer >2.0Wang [8] 2011 Guangzhou, China 324 2006e2009 Gastric cancer >5Garcea [21] 2011 Leicester, UK 74 2001e2011 Pancreatic adenocarcinoma >5Azab [10] 2011 Staten Island, NY 316 2004e2006 Breast cancer Multiple cutoffsThavaramara [55] 2011 Bangkok, Thailand 129 2004e2009 Ovarian cancer >2.6Kao [31] 2011 Sydney, Australia 85 1994e2009 Pleural mesothelioma >3.0Sharaiha [52] 2011 New York, New york 295 1996e2009 Oesophageal cancer >5Dutta [20] 2011 Glasgow, UK 112 1996e2008 Oesophageal cancer Multiple cutoffsMiyata [38] 2011 Osaka, Japan 152 2000e2008 Oesophageal cancer >4Bertuzzo [11] 2011 Bologna, Italy 219 1997e2009 Hepatocellular Carcinoma >5Guo [59] 2011 Hong Kong, China 101 2003e2009 Hepatocellular Carcinoma >3Ding [18] 2010 Guandong, PRC 141 2002e2006 Colorectal cancer >4Shimada [53] 2010 Chiba, Japan 1028 2001e2007 Gastric cancer >4Ubukuta [56] 2010 Ibaraki, Japan 157 1996e2003 Gastric cancer >5Kim [32] 2010 Seoul, South Korea 55 2004e2008 Uterine sarcoma >2.12Bhatti [12] 2010 Nottingham, UK 84 1998e2008 Pancreatic adenocarcinoma >4.0Rashid [49] 2010 Nottingham, UK 294 1997e2007 Oesophageal cancer Multiple cutoffsOhno [43] 2010 Tokyo, Japan 192 1986e2000 Renal cell carcinoma >2.7Mohri [39] 2009 Edobashi, Japan 357 1992e2004 Gastric cancer >2.2Halazun [26] 2009 New York, New York 150 2001e2007 Hepatocellular carcinoma >5Neal [40] 2009 Leicester, UK 174 2000e2005 Colorectal liver metastases >5Roxburgh [73] 2009 Glasgow, UK 227 1997e2005 Colon cancer >5Kishi [33] 2009 Texas, US 200 1997e2007 Colorectal liver >5Gomez [22] 2008 Leeds, UK 96 1994e2007 Hepatocellular carcinoma >5Gomez [23] 2008 Leeds UK 27 1996e2006 Cholangiocarcinoma >5Sarraf [51] 2008 London, UK 178 1999e2005 Non-small-cell lung cancer Multiple cutoffsCho [15] 2008 Seoul, South Korea 192 2003e2006 Ovarian cancer >2.60Ong [44] 2008 Leicester, UK 23 1996e2006 Gallbladder cancer >3.75Halazun [25] 2007 Leeds, UK 440 1996e2006 Colorectal Liver Metastases >5Leitch [36] 2007 Glasgow, Uk 149 1998e2006 Colorectal cancer >5Clark [17] 2007 Ediburgh, UK 44 1998e2005 Pancreatic adenocarcinoma >5Walsh [57] 2005 Suffolk, UK 230 2000e2001 Colorectal cancer >5Hirashima [28] 1998 Kumamoto, Japan 55 1989e1992 Gastric cancer >2

NA ¼ not applicable, NR ¼ not recorded.

A. Paramanathan et al. / Surgical Oncology 23 (2014) 31e3934

subgroup numbers, event rate, univariate or multivariate hazardratios 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. Oneof these studies reported thehazardratios fromboth colonand rectal cancer, resulting in 14 total sets of hazard ratios [14]. Datacould not be extracted from the remaining studies to due a lack ofone or more of the following; p value, death rate, NLR subgroupnumbers, event rate, univariate or multivariate hazard ratios.

In analysing the blood values, high NLR was found to besignificantly 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 DFSwas77% and 97% respectively. The studies were therefore stratified bytumour type for OS. In the subgroup analyses, the combined HR forgastric [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)] andovarian [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 significantly 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 gastriccancer, 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 alsoperformed for studies that looked at an NLR of 5 in predicting OS.Sixteen (32.7%) studies were identified, with results demonstratingthat an NLR > 5 was significantly associated with poorer outcomes[HR: 2.18, 95% CI (1.74e2.73)] (p ¼ 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 intimaterelationship between tumour cells, the immune system and the

Figure 2. Meta analysis for overall survival.

A. Paramanathan et al. / Surgical Oncology 23 (2014) 31e39 35

Figure 3. Forest plot of overall survival.

A. Paramanathan et al. / Surgical Oncology 23 (2014) 31e3936

inflammatory response triggered [7]. This inflammatory responsereflects a non-specific response to tumour hypoxia, tissue injuryand necrosis [16,64]. The complex and diverse neuroendocrino-logical and haemopoetic changes that occur during inflammationare thought to be responsible for both the diminishing of the im-mune response and the increase in tumour proliferation [9]. Workhas been undertaken to identify components of this inflammatoryresponse 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 significantlyassociated poorer overall survival with lower heterogeneity (Fig. 6).The association between an elevated NLR and poor prognosis iscomplex. Theories at present centre around a relative neutrophiliaand lymphocytopaenia that occurs as part of the systemic

Figure 4. Meta-analysis of

inflammatory response triggered by cancer [22,29,37,53]. Sug-gested mechanisms to explain neutrophillia include release of G-CSF by tumour cells, and cancer inflammation through release of IL-1 and TNF-alpha [27,65]. Relative neutrophillia increases thenumber of inflammatory markers that include pro-angiogenicfactors (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 increasednumber of neutrophils and lymphocytes are less efficacious [67].The lymphocyte response is a major component of controllingcancer progression. One theory is that the cell-mediated responseto tumour infiltration is lymphocyte dependent; thus, a low lym-phocytic infiltration at tumour margins corresponds with a poorerprognosis [22,57,68]. Several studies have demonstrated thatdecreased intratumoral T cell activity correlates with primarytumour progression [69]. Lymphocytopaenia represents a signifi-cant decline in the cell-mediated immune system, demonstrated bythe marked decrease in T4 helper and T8 suppressor lymphocytes[37]. Systemic inflammation triggered by malignant cells results inthe release of a number of immune modulators such TGF beta, IL10and CRP which impair lymphocyte action [56]. Hirashima also re-ported that natural killer cell activity is repressed when NLR washigh; this would diminish the cell-mediated immune responseeven further [28]. These responses have direct and indirect in-teractions with the primary tumour to stimulate angiogenesis andextracellular matrix remodelling [16].

Thus, a higher NLR favours a pro-tumour inflammatory status,and this correlates with more advanced disease [13,37]. Resultsfrom our study appear to favour this conclusion; patient groupswith a higher NLR tended to have higher staging. Moreover, whenstudies were categorised by NLR, the groups with higher NLR alsotended to have a worse age and stage. This corroborates reportsthat have previously stated that these preoperative characteristicsare associated with vascular invasion and a more aggressivephenotype [68e70]. It has also been shown that stage is directly

disease free survival.

Figure 5. Funnel plot of disease free survival.

A. Paramanathan et al. / Surgical Oncology 23 (2014) 31e39 37

representative of tumour progression and is subsequently reflectiveof the immune response (neutrophillia and lymphocytopaenia),and it is not surprising that higher stages correspond with higherNLR and therefore worse survival [57].

These results provide evidence to support the hypothesis thatthe magnitude of the inflammatory response to cancer is directlyprognostic of long-term outcomes in patients undergoing curativeintent surgery for solid tumours. Subsequently, the NLR potentiallyrepresents a convenient, inexpensive, reproducible and robustmeasurement of the balance between the pro-tumour inflamma-tory status and the anti-tumour immune status in the tumourmicroenvironment [16,18,30,51]. With further prospective work,the NLR may allow better risk stratification amongst patientseligible for curative surgery and may facilitate administration ofneo-adjuvant and adjuvant therapy in higher risk candidates. Im-mune modulators have previously been trialled in other cancers,and given the findings, there may be provision for its use bothpreoperatively and postoperatively. It has been shown that COX-2inhibitors suppress angiogenic markers such as VEGF, and mayprevent proliferation and further growth of tumours [25]. Thiscould allow both preoperative and post-operative treatment inselected patients to enhance outcomes [25].

However, the NLR represents only one aspect of the inflamma-tory response, and it is thought that scoring systems such as theGlasgow Prognostic Scale and mGPS that incorporate several

Figure 6. NLR > 5 predi

markers of the immune system are more representative of the in-flammatory response [64,71]. The Glasgow prognostic scale rep-resented multiple aspects of the inflammatory system includingNLR, PLR, CRP, albumin and HB and was derived from a study of alarge cancer registry [71]. Although seemingly more representative,it has been suggested that single continuous variables such as theNLR may be more accurate in measuring dynamic changes to animmune system, compared to scoring tables which apply differentweightings to different inflammatory markers and is a static cate-gorical measure [35]. Given that most of the evidence is retro-spective, it is difficult to determine whether single continuousmeasures or scoring tables have greater prognostic value e predi-cating the need for future prospective studies to validate thesefindings.

There were limitations to the results of this study. Firstly,there was significant heterogeneity between studies with an I-squared value of 77% for OS and 97% for DFS respectively. Twoobvious explanations for the heterogeneity were the histologyand difference in NLR cutoffs e however, subgroup analysesproduced similarly high I-squared values. Perhaps the greatestlimitation in this review was the discordance of NLR cutoffs usedin 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 atan increased risk e in fact, several other studies demonstratedNLR ranges of 4 and below (even as low as 2.6), having prognosticsignificance in overall survival (Fig. 2). Most of the studies in thisreview used an NLR of 5 as the cutoff based purely on previouswork. Only four studies used ROC sensitivity and specificity an-alyses to determine an NLR cutoff. The result was a significantdiscordance in numbers between groups e more than half thestudies had very small numbers of patients who were classified inthe higher NLR group. Given the retrospective nature of all of thestudies, the magnitude of any confounding factors would havebeen further amplified. Most studies had cohorts of patients thathad undergone adjuvant therapy and were not excluded from theanalyses. Consequently, the results from the HCC group are alsodifficult to interpret, as the vast majority of their patients hadhepatitis B or C, which would have affected the immune systemand hence the NLR. The NLR is also influenced by multiple otherfactors. Age, for example, is known to be associated withdecreasing absolute lymphocyte counts [10]. Given that mostcancer surgery is undertaken on the elderly, a surveillance toolsuch as the NLR may not adequately prognosticate survival.

cts overall survival.

Figure 7. Funnel Plot of overall survival for NLR > 5.

A. Paramanathan et al. / Surgical Oncology 23 (2014) 31e3938

Likewise, other factors such as critically ill patients and medicalcomorbidities affect the NLR [72].

In conclusion, this systematic review demonstrates an associa-tion between a high NLR and worse long-term outcomes followingcurative intent surgery. The NLR potentially represents a simple androbust measurement of prognosis; however, it needs to be vali-dated in larger prospective studies for it to be useful in riskstratification.

Conflict of interest statement

The authors have no conflicts 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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