DOI:10.1111/hpb.

12355 HPB

REVIEW ARTICLE

Prognostic significance of pre-operative C-reactive protein and

the neutrophillymphocyte ratio in resectable pancreatic cancer:
a systematic review
Lewis Stevens1, Samir Pathak1, Quentin M. Nunes2, Sanjay Pandanaboyana1, Christian Macutkiewicz1, Neil Smart3 &
Andrew M. Smith1
1
Department of Surgery, St James' University Hospital, Leeds, 2Royal Liverpool University Hospital, Liverpool, Merseyside, and 3Exeter Surgical Health
Services Research Unit (HESRU), Royal Devon and Exeter NHS Foundation Trust, Exeter, UK

Abstract
Background: Better pre-operative risk stratification may improve patient selection for pancreatic resec-
tion in pancreatic cancer. C-reactive protein (CRP) and the neutrophillymphocyte ratio (NLR) have
demonstrated prognostic value in some cancers. The role of CRP and NLR in predicting outcome in
pancreatic cancer after curative resection is not well established.
Methods: An electronic search of MEDLINE, EMBASE and CINAHL was performed to identify studies
assessing survival in patients after pancreatic cancer resection with high or low pre-operative CRP or
NLR. Systematic review was undertaken using the PRISMA protocol.
Results: In total, 327 studies were identified with 10 reporting on survival outcomes after a pancreatic
resection in patients with high or low CRP, NLR or both. All but one paper showed a trend of lower
inflammatory markers in patients with longer survival. Three studies from six showed low CRP to be
independently associated with increased survival and two studies of eight showed the same for NLR. All
studies were retrospective cohort studies of low to moderate quality.
Discussion: Inflammatory markers might prove useful guides to the management of resectable pan-
creatic cancer but, given the poor quality of evidence, further longitudinal studies are required before
incorporating pre-operative inflammatory markers into clinical decision making.

Received 25 July 2014; accepted 22 September 2014

Correspondence
Andrew Smith, St James' University Hospital, Beckett Street, Leeds LS9 7TF, UK. Tel:
+44 0113 243 3144. Fax: 01132448182. E-mail: andrewm.smith@leedsth.nhs.uk

Introduction approximately 20% of patients alive at 5 years.6,7 This poor sur-

In spite of the relatively low incidence of around 11 per 100 000
person-years, pancreatic cancer is the 5th highest cause of cancer-
related mortality with all stage, 5-year survival remaining poor at
less than 5%. Advances in staging and adjuvant chemotherapy
regimens1 has resulted in little improvement in the past 30 years.2
Surgical resection is considered for all patients with Stage I or II3,4
disease but these patients comprise only around 20% of all new
diagnoses.5 Even in this group, survival remains poor with
Previously presented as poster at annual meeting of Association of Surgeons
of Great Britain & Ireland, April 2014.
Accepted for presentation as poster at annual congress of European Society
of Surgical Oncology, October 2014.
vival is likely in part as a result of unrecognized stage-specific
heterogeneity of tumour characteristics.
Better risk stratification may improve patient selection for pan-
creatic resection and therefore optimize patient outcomes. The
role of inflammation in cancer is widely recognized8 with inflam-
matory and immune mediators known to modulate
carcinogenesis, tumour invasion and metastasis.912 A number of
markers of inflammation have been investigated in various
cancers with a view to use in risk stratification.13
Inflammatory burden can be measured using a variety of
parameters, with some markers being easily accessible and rela-
tively inexpensive. C-reactive protein (CRP), which is released by
the liver as an acute phase protein in response to raised interleukin
(IL)-6 released by activated macrophages, is used to define the

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286
level of inflammatory response.14 The neutrophillymphocyte
ratio (NLR) is readily derived from standard pre-operative blood
tests by dividing the absolute circulating neutrophil concentration
by the absolute circulating lymphocyte population. NLR is raised
in cancer as the disease process produces a cytokine milieu of
raised myeloid growth factors, tumour necrosis factor-, IL-10
and transforming growth factor- leading to neutrophilia with
relative lymphocytopaenia.15,16
Both CRP1719 and NLR2023 have been demonstrated to be
inversely proportional to survival in a number of malignancies.
Indeed, CRP has been incorporated in to clinical scoring systems
to predict outcome in both resectable oesophageal24 and colorectal
cancer.25
The aim of this study was to systematically review the existing
literature and consolidate current knowledge on the prognostic
significance of pre-operative CRP and NLR in patients undergo-
ing pancreatic resection for pancreatic cancer.
Methods
Search strategy and study selection
An electronic search of Medline (1946present), EMBASE (1974
present) and CINAHL (1981present) was performed indepen-
dently by L.S. and S.P. Search terms used were Pancreas,
Pancreatic, Peri-ampullary, Neoplasia, Cancer, Carcinoma, study quality including risk of bias. A pro forma was used to
Adenocarcinoma, Tumour, Outcome, Survival, Prognosis, extract study author and date, number of patients, age, gender,
NeutrophilLymphocyte Ratio, NLR, C-reactive protein and tumour stage, use of adjuvant therapy and primary outcome data,
CRP. Bibliographic references of search results were reviewed to
identify relevant studies not produced by the electronic search.
The final search was undertaken on 24 December 2013.
All citations identified by our search strategy were reviewed
independently by L.S. and S.P., by sequential review of title,
abstract and finally full text to establish inclusion or exclusion as
per Preferred Reporting Items for Systematic Reviews and Meta-
Analyses guidance.26
Inclusion criteria
Included studies analysed the effect of raised pre-operative CRP
or NLR on survival after pancreatic resection for pancreatic
cancer. Given that different centres used various assays and
laboratory techniques, coupled with a lack of agreed definition of
what constitutes an elevated CRP or NLR, only studies which
dichotomized patients to high or low inflammatory markers as
determined by the study authors were included. Some studies
analysed the effect of the Glasgow Prognostic Score (GPS) or the
modified Glasgow Prognostic Score (mGPS) on survival. GPS
assigns a score of 0 to patients with CRP < 10 mg/l and albumin
35 g/l, a score of 1 to those with CRP >10 mg/l or albumin
<35 g/l and a score of 2 for patients with CRP >10 mg/l and
albumin <35 g/l. The mGPS score is identical to GPS except that a
score of 1 is assigned only when CRP is greater than 10 mg/l
whereas an isolated fall in albumin is scored as 0. Only studies that
published patient numbers with each GPS/mGPS score were
included. Patients with a GPS or mGPS score of 0 were analysed as
HPB 2015, 17, 285291
HPB
having low CRP whereas those with a GPS of 2 or a mGPS of 1 or
2 were grouped as having a high CRP. Patients with a GPS of 1
were excluded as it was not possible to ascertain whether the CRP
or the albumin level was raised. Only published, English-language
studies reporting survival outcomes for resectable pancreatic
cancer were included.
Exclusion criteria
Search results were carefully reviewed to exclude duplicate studies
or a second study using the same data set. Studies not reporting
survival data for high or low inflammatory markers indepen-
dently were also excluded, as were studies in which data sets
included unresectable disease. Epidemiological studies, case
reports and conference presentations were excluded.
Quality assessment and data extraction
There is no internationally recognized tool for grading quality of
prognostic factor studies. Huguet et al. suggest a modification of
the Grading of Recommendations Assessment, Development and
Evaluation (GRADE) system to quality assess prognostic factor
studies.27 The modified GRADE system was used in conjunction
with the Quality in Prognosis Studies (QUIPS) tool28 to assess
all as defined by the authors of each study.
Results
The search strategy identified 325 articles for initial review with a
further 2 identified by review of bibliographies of search results.
Ninety-two papers were excluded as duplicates while title review
excluded a further 210 studies as either case reports, abstracts,
letters, reviews or reporting inappropriate outcome measures.
Twenty-five articles underwent abstract review with a further 10
papers excluded as epidemiological studies or not reporting
primary outcomes. After full text review of the remaining 15
papers, 5 were excluded owing to inclusion of unresectable disease
in the final analysis, failure to dichotomize an inflammatory
marker to high or low or inability to extract outcome data from
the published text. Ten studies underwent data extraction (Fig. 1).
Six of the final 10 papers analysed survival related to high or low
CRP and 8 studies investigated NLR, whereas 4 studies investi-
gated both CRP and NLR (Table 1).
The prognostic significance of CRP was analysed in 485
patients with 233 patients (48%) defined as having high CRP. The
cut-off value for a high CRP varied from 3 to 10 mg/l. Four of the
6 studies reported a significantly decreased median survival in
patients with a higher pre-operative CRP on univariate analysis,
with only 1 study not demonstrating such a correlation. Three
studies found CRP to be an independently significant prognosti-
cator on multivariate analysis (Table 2).
2014 International Hepato-Pancreato-Biliary Association
HPB 287

Idencaon
Records idened through Addional records idened
database searching through other sources
(n = 325) (n = 2)

Records aer duplicates removed

(n = 235)
Screening

Records screened Records excluded

(n = 235) (n = 220)

Full-text arcles excluded,

Eligibility

Full-text arcles assessed with reasons :

for eligibility Unable to dichotomize or
(n = 15) extract data (n = 3)
Unresectable data included in
analysis (n = 2)

Studies included in
Included

qualitave synthesis
(n = 10)

Figure 1 PRISMA 2009 flow diagram

NLR as a prognostic indicator in resectable pancreatic cancer
was investigated in 685 patients across 8 studies, with 160 patients
(23%) having a high NLR. The cut-off value for a raised NLR was
set at 5 in all but one study, which used an NLR cut-off value of 4
(Bhatti et al.35). All but one of the studies showed a trend of
increased median survival in patients with a low pre-operative
NLR. Three studies demonstrated statistically significant length-
ened survival on univariate analysis whereas two studies showed
NLR to be an independent prognostic indicator on multivariate
analysis (Table 3).
Study quality
All studies were retrospective, cohort studies of low to moderate
quality as per the GRADE classification and are particularly sus-
ceptible to study level selection bias and publication bias.28 All
studies but one included consecutive patients undergoing a pan-
creatic resection whereas Hamed et al.30 excluded 22 patients
owing to incomplete data. In all studies, only patients with histo-
logically confirmed pancreatic cancer were included. There is sig-
nificant population heterogeneity with regard to confounding
factors such as patient age, nature of pancreatic resection per-
formed, tumour stage and co-morbidities such as active infection,
cardiovascular disease, pulmonary disease and obesity which are
all known to be associated with raised inflammatory markers.3941
The distribution of each potential confounder within high and
low inflammatory marker populations is poorly reported across
the studies, making external validation difficult. Furthermore
there was inconsistent inclusion of patients who had biliary inter-
vention such as ERCP and PTC prior to surgery or measurement
of an inflammatory marker. Only in the studies by Pine et al.36 and
Sanjay et al.32 were patients who underwent biliary intervention
pre-operatively, excluded from data analysis. Jamieson et al.33,38
recorded blood measurements at least 1 week after biliary decom-
pression and, along with Bhatti et al.,35 excluded patients with
concurrent inflammatory or infective processes.
Discussion
The 5-year survival for pancreatic cancer, considered curable at
presentation, remains poor in spite of increasingly sophisticated

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Table 1 Demographic data of studies analysing the relationship of CRP or NLR and prognosis after a pancreatic cancer resection
Author Year of Study period CRP or Number Age (years) Male : Stage Staging system Resection Adjuvant Median
publication NLR female performed therapy follow-up &
range (months)

Stotz, M29 2013 20042010 Both 110 <65 = 55 51:59 I2 UICC 7th Edition3 Undefined 88a Undefined
65 = 55 II 99
III 9

Hamed, M30 2013 20002010 NLR 85 Undefined Undefined Undefined N/A PD Undefined 23.5 (IQR =
11.543.5)
La Torre, M31 2012 Apr 2003Nov Both 101 <65 = 39 53:48 I 21* AJCC4 edition PD or PPPD 7a Undefined
2009 65 = 62 II 72* undefined 7b
III 9* 12 c
IV 1*
Sanjay, P32 2012 20022008 Both 51 70 34:17 Undefined N/A PD 18 d Undefined

Jamieson, NB 33
2011 Jan 2006Apr Both 135 <65 = 73 78:57 Undefined N/A PD or PPPD 74 d Undefined
2009 65 = 62
Garcea, G34 2011 20012011 NLR 74 66 46:28 Undefined N/A Undefined 53 a 1125.8
35
Bhatti, I 2010 Jun 1998Jun NLR 84 65 48:36 Undefined N/A PD 30 a Undefined
2008
Pine, JK36 2009 20012006 CRP 58 68 29:29 Undefined N/A PD Undefined Undefined

Clark, E37 2007 19982005 NLR 44 65 Undefined Undefined N/A PD Undefined Undefined

Jamieson, NB38 2005 Jan 1993Jul CRP 65 <65 = 37 33:32 I 17 UICC edition PD or PPPD 0 20 (Minimum 15)
2001 >65 = 28 II 2 undefined
III 46

NLR, neutrophillymphocyte ratio; CRP, C-reactive protein; UICC, International Union against Cancer; AJCC, American Joint Committee on Cancer; PD, pancreaticoduedenectomy/
Whipple's procedure; PPPD, pylorus-preserving pancreaticoduodenectomy.
*Numbers reported at stage breakdown exceeds participants. aChemotherapy, bradiotherapy, cchemoradiotherapy, dundefined.

Table 2 Results of analysis of papers studying the prognostic value of CRP in resected pancreatic cancer
Author Year CRP Cut off Number Median survival & Univariate analysis Multivariate analysis
value (mg) range (months)
Stotz, M29 2013 Low 10 mGPS of 0 = 73 20 HR 1.095 (P = 0.585) Not performed
High >10 mGPS of 1 = 21 20
mGPS of 2 = 16 13
La Torre, M31 2012 Low 10 GPS of 0 = 32 37.2 P = 0.0001 HR 1.7745 (P = 0.005)
High >10 GPS of 2 = 34 7.3
Sanjay, P32 2012 Low 3 13 21 (636) P = 0.015 HR 3.969 (P = 0.011)
High >3 38 13 (370)
Jamieson, NB33 2011 Low 10 mGPS of 0 = 74 26.7 (19.134.3a) P < 0.001 HR 2.26 (P = 0.0001)
High >10 mGPS of 1 = 31 16.5 (9.922.2 ) a

mGPS of 2 = 30 13.1 (6.719.4a)

Pine, JK 36
2009 Low 5 28 16.9b HR 1.14 (P = 0.69) Not performed
High >5 30 16.6b
Jamieson, NB38 2005 Low 10 32 18.2 (14.921.4) HR 2.56 (P = <0.001) P > 0.05
High >10 33 8.3 (6.610.0)

CRP, C-reactive protein.

a
95% confidence interval,
b
extrapolated from KaplanMeier survival curves.

staging techniques.6,7 Better patient stratification is needed to
optimize management planning and patient outcomes. Correla-
tion between raised inflammatory markers, such as CRP and full
blood count, and prognosis has been reported in various malig-
nancies.13 This probably represents a modulated inflammatory
response as a result of tumour burden and the tumour micro-
environment. The aim of this study was to review the evidence
for CRP and NLR as prognostic indicators in resectable pancreatic
cancer to determine their usefulness in refining patient
management.
The majority of studies reviewed demonstrated that an elevated
CRP or NLR is associated with a decreased median survival be it
overall, cancer-specific or disease-free. Two studies demonstrated
NLR to be an independent prognostic indicator whereas three

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Table 3 Results of analysis of papers studying the prognostic value of NLR in resected pancreatic cancer
Author Year NLR Cut off Number Median survival Disease free Univariate analysis Multivariate analysis
value & range (months) survival (months)
Stotz, M29 2013 Low <5 73 21.25b HR 1.852 (P = 0.006) HR 1.611 (P = 0.039)
High 5 37 11.2b
Hamed, M30 2013 Low <5 67 20.6 (1136.6) 0.153 Not performed
High 5 18 11.3 (8.126.3)
La Torre, M31 2012 Low <5 81 21 0.13 Not performed
High 5 21 17
Sanjay, P32 2012 Low 5 38 16.2 (363) P = 0.272 Not performed
High >5 13 9.18 (370)
Jamieson, NB33 2011 Low <5 105 20.9 (15.526.3a) P = 0.51 Not performed
High 5 30 25.7 (16.235.1a)
Garcea, G34 2011 Low <5 50 52 P = 0.0057 Not performed
High >5 24 12
Bhatti, I35 2010 Low 4 71 14 (13.015.8) HR 1.784 (P = 0.023) HR 1.21 (P = 0.039)
High >4 13 7.1 (1.412.9)
Clark, E37 2007 Low <5 40 10.5 (7.121.2) P = 0.16 Not performed
High 5 4 8.9 (5.313.3)

NLR, neutrophillymphocyte ratio.

a
95% confidence interval,
b
extrapolated from KaplanMeier survival curves.

studies showed CRP to be an independent prognostic indicator in
resectable pancreatic cancer.
The evidence base does have significant limitations with all
studies being retrospective and of low quality. Population groups
are heterogeneous with regard to cut-off between high or low
inflammatory marker, timing of sample, presence of associated
inflammatory condition, use of anti-inflammatory medications
and tumour stage. There is inconsistent reporting of data with
regard to range of survival for patients with high and low inflam-
matory markers making meaningful pooling of data for meta-
analysis impossible.
Accepting these limitations, the available studies do suggest a
correlation between pre-operative inflammatory markers and
post-operative survival. These easily measured parameters may
therefore help decision making in the management of pancreatic
cancer. This may include improved staging, selection of patients
for neoadjuvant and adjuvant therapies and help in determining
follow-up arrangements. Before this is possible, however, high-
quality longitudinal studies are required to establish their inde-
pendent prognostic value.
Most recurrence and cancer-related mortality in patients after
resection of pancreatic cancer is observed in later stage disease or
with positive resection margins.42 Given the significantly better
prognosis for patients achieving full tumour clearance with nega-
tive margins,43 differentiation between tumour stage IIB (border-
line resectable) and stage III (unresectable) is paramount to allow
more tailored management plans. Pine et al.36 showed the CRP
level to be associated with tumour resectability whereas Ong et al.44
found NLR to be significantly higher in patients found to have
unresectable disease at laparotomy. Further research is warranted
to determine if pre-operative inflammatory markers may help
define resectable stage IIB disease and reduce futile surgical inter-
vention.
Neoadjuvant chemotherapy and radiotherapy are not routinely
used for pancreatic cancer although recent trials to investigate its
usefulness, particularly in borderline resectable disease, have had
promising results.45 CRP has been shown to predict a response to
palliative chemotherapy in pancreatic cancer46 whereas NLR has
been shown to predict a complete pathological response to
neoadjuvant chemoradiotherapy in locally advanced colorectal
cancer.47 Research into inflammatory markers as predictors
of effectiveness of neoadjuvant therapy in pancreatic cancer is
therefore justified.
Garcea et al.34 showed that pre-operative NLR value correlates
with disease recurrence. Patients without recurrence had a mean
NLR of 3.1 compared with 4.7 in those with recurrence (P = 0.02).
There may therefore be a role for pre-operative inflammatory
markers being used to guide follow-up, with patients defined as
higher risk being followed up more closely or with a lower thresh-
old for further cross-sectional imaging post-operatively.
Conclusion
The evidence suggests an association between CRP and NLR and
survival after a pancreatic resection. However, there is insufficient
high-quality data available to justify the use of either CRP or NLR

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in clinical decision-making for the management of resectable pan-
creatic cancer at present. There is a need for high-quality longitu-
dinal studies, which should be prospective in design to allow for
adequate data collection, particularly potential confounders such
as inflammatory disease and tumour stage. To have a maximal
impact, any study should be robustly reported to allow external
validation.
Conflict of interest
None declared.
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2014 International Hepato-Pancreato-Biliary Association