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Neutrophil-to-lymphocyte ratio for the prognostic assessment of hepatocellular carcinoma: A systematic review and meta-analysis of observational studies

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Oncotarget. 2016; 7:45283-45301. https://doi.org/10.18632/oncotarget.9942

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Xingshun Qi, Jianjun Li, Han Deng, Hongyu Li, Chunping Su and Xiaozhong Guo _

Abstract

Xingshun Qi1,*,#, Jianjun Li2,*,#, Han Deng1, Hongyu Li1, Chunping Su3, Xiaozhong Guo1,#

1Department of Gastroenterology, General Hospital of Shenyang Military Area, Shenyang, Liaoning 110840, China

2Department of Radiotherapy, The First Affiliated Hospital, China Medical University, Shenyang, Liaoning 110001, China

3Library of Fourth Military Medical University, Xi’an, Shaanxi 710032 China

*These authors have contributed equally

#Joint senior authors

Correspondence to:

Xingshun Qi, email: xingshunqi@126.com

Jianjun Li, email: 13309883641@163.com

Xiaozhong Guo, email: guo_xiao_zhong@126.com

Keywords: hepatocellular carcinoma, inflammatory, neutrophil, lymphocyte, prognosis

Received: March 26, 2016     Accepted: May 16, 2016     Published: June 10, 2016

ABSTRACT

Background and aims: Neutrophil to lymphocyte ratio (NLR) is an inflammatory-based marker. A systematic review and meta-analysis was performed to explore the prognostic role of NLR in patients with hepatocellular carcinoma (HCC).

Results: Overall, 598 papers were identified, of which 90 papers including 20,475 HCC patients were finally included. Low baseline NLR was significantly associated with better overall survival (HR = 1.80, 95% CI: 1.59–2.04, p < 0.00001) and recurrence-free or disease-free survival (HR = 2.23, 95% CI: 1.80–2.76, p < 0.00001). Low post- treatment NLR was significantly associated with better overall survival (HR = 1.90, 95% CI: 1.22–2.94, p = 0.004). Decreased NLR was significantly associated with overall survival (HR = 2.23, 95%CI: 1.83–2.72, p < 0.00001) and recurrence-free or disease-free survival (HR = 2.23, 95% CI: 1.83–2.72, p < 0.00001). The findings from most of subgroup meta-analyses were consistent with those from the overall meta-analyses.

Materials and Methods: All relevant literatures were identified via PubMed, EMBASE, and Cochrane library databases. Hazard ratio (HR) with 95% confidence interval (95%CI) was calculated. Subgroup meta-analyses were performed according to the treatment options, NLR cut-off value ranges, and regions.

Conclusions: NLR should be a major prognostic factor for HCC patients. NLR might be further incorporated into the prognostic model of HCC.


INTRODUCTION

Prognostic assessment of hepatocellular carcinoma (HCC) is very important for clinicians and patients. The relevant knowledge is being rapidly accumulated. Traditional prognostic variables mainly include portal vein thrombosis, tumor size, and alpha-fetoprotein, etc. [1]. As for the prognostic staging of HCC, the Barcelona Clinic Liver Cancer (BCLC) system is the most frequently used tool with 5 major parameters, such as tumor size, tumor number, Child-Pugh class, physical status, and tumor metastasis [2]. Several alternative staging systems include the Cancer of the Liver Italian Program (CLIP) system [3], the Hong Kong Liver Cancer (HKLC) system [4], and the Japan Integrated Scoring (JIS) system [5]. As for the liver function assessment of HCC, Child-Pugh class is the most frequently used tool with 5 variables, such as bilirubin, albumin, international normalized ratio, ascites, and hepatic encephalopathy [6]. Albumin-bilirubin score is a recently developed and more convenient tool [7]. More recently, the associations of inflammation-based markers with the prognosis of HCC have been actively explored. Neutrophil to lymphocyte ratio (NLR), which refers to the ratio of neutrophil to lymphocyte count, is a readily available marker for assessing the systemic inflammatory changes. NLR reflects the potential balance between neutrophil-associated pro-tumor inflammation and lymphocyte-dependent anti-tumor immune function [811]. An elevated NLR may represent a trend towards increased pro-tumor inflammation and decreased anti-tumor immune function. Herein, we have conducted a systematic review and meta-analysis to analyze the prognostic role of NLR in HCC patients treated with different treatment options. This work was registered at PROSPERO database (registration number: CRD CRD42016033409).

RESULTS

Study selection and characteristics

A total of 598 papers were identified. Among them, 90 papers with 20,475 HCC patients were included in the systematic review (Figure 1) [12101]. Study characteristics were summarized in Table 1. According to the publication type, 21 and 69 papers were published in abstract and full-text forms, respectively. According to the study design, 60 and 5 papers were retrospective and prospective, respectively; 2 papers were both retrospective and prospective; and the study design was not available in 23 papers. According to the regions, 63, 14, and 13 studies were conducted by Asian, European, and American researchers, respectively.

Flowchart of study inclusion.

Figure 1: Flowchart of study inclusion.

Table 1: Study characteristics

First author

Journal (Year)

Type of publication

Study design

Regions

Enrollment period

Study population

No. Pts

Abdelmessih RM

Hepatology (2011)

Abstract

Retrospective

NY, US

1999.3– 2010.4

HCC patients who were downstaged with TACE prior to LT

200

Afshar M

Journal of Hepatology (2015)

Abstract

Retrospective

Birmingham, UK

2009.4– 2014.3

HCC patients treated with sorafenib

217

Agopian VG

Journal of the American College of Surgeons (2015)

Full-text

Retrospective

CA, US

1984– 2013

HCC patients treated with LT

865

Aino H

Molecular and Clinical Oncology (2014)

Full-text

NA

Fukuoka, Japan

1998.4– 2012.4

Advanced HCC patients with extrahepatic metastasis

419

Bertuzzo VR

Transplantation (2011)

Full-text

Retrospective

Bologna, Italy

1997– 2009

HCC patients treated with LT

219

Bodzin A

American Journal of Transplantation (2015)

Abstract

Retrospective

CA, US

1984– 2014

Recurrent HCC after LT

106

Bronson N

HPB (2012)

Abstract

Retrospective

PA, US

2002.6– 2011.7

HCC patients treated with resection

68

Bruixola G

Journal of Clinical Oncology (2015)

Abstract

Retrospective

Valencia, Spain

2008– 2014

HCC patients treated with sorafenib

145

Chan AW

Annals of Surgical Oncology (2011)

Full-text

Retrospective

Hong Kong, China

2001.1– 2011.12

BCLC stage 0/A primary HCC patients treated with surgical resection

597

Chang JX

Annals of Oncology (2014)

Abstract

Retrospective

Beijing, China

2008– 2009

Advanced HCC patients treated with cryoablation

150

Chen TM

Journal of Gastroenterology and Hepatology (2012)

Full-text

Retrospective

Taiwan, China

2003.7– 2010.12

Early HCC patients treated with RFA

158

Chen X

British Journal of Surgery (2012)

Full-text

Prospective

Hong Kong, China

2009.4– 2011.5

HCC patients with Child-Pugh grade A who underwent partial hepatectomy

190

Chen Z

Supportive Care in Cancer (2014)

Abstract

NA

Guangzhou, China

2008.9– 2010.6

Advanced HCC patients without fever or signs of infection

219

da Fonseca LG

Medical Oncology (2014)

Full-text

Retrospective

Sao Paulo, Brazil

2009.7– 2013.11

HCC patients who received sorafenib as initial systemic treatment

120

Dan J

PLoS ONE (2013)

Full-text

Retrospective

Guangzhou, China

2005.5– 2008.8

Small HCC patients treated with RFA

178

Facciorusso A

Journal of Gastroenterology and Hepatology (2014)

Full-text

NA

Foggia, Italy

2005.4– 2010.2

HCC patients treated with RFA

103

Fan W

PLoS ONE (2015)

Full-text

Retrospective

Guangzhou, China

2003.1– 2012.12

Recurrent HCC patients treated with TACE

132

Fu SJ

Medical Oncology (2013)

Full-text

NA

Guangzhou, China

2006.1– 2009.4

HBV-associated HCC patients treated with radical hepatectomy

282

Fu YP

Liver Cancer (2015)

Abstract

NA

Guangzhou, China

NA

HCC patients treated with curative resection

772

Gao F

Medicine (2015)

Full-text

Retrospective

Beijing, China

2008.10– 2012.5

Newly diagnosed with HCC

825

Gomez D; Farid S

World Journal of Surgery (2008); HPB (2010, Abstract)

Full-text

NA

Leeds, UK

1994.1– 2007.4

HCC patients treated with curative resection

96

Guo ZX

Chinese Journal of Cancer (2009)

Full-text

Retrospective

Guangzhou, China

2000– 2005

HCC patients treated with curative resection (age <35 years old)

91

Halazun KJ

Annals of Surgery (2009)

Full-text

Retrospective

NY, US

2001– 2007

HCC patients treated with LT

150

Harimoto N

Transplantation (2013)

Full-text

Retrospective

Fukuoka, Japan

1996.10– 2012.8

HCC patients treated with LDLT

167

Higashi T

Annals of Surgical Oncology (2015)

Full-text

Prospective

Kumamoto, Japan

2008– 2012

HCC patients treated with resection

215

Hu B

Clinical Cancer Research (2014)

Full-text

Retrospective/ Prospective

Shanghai, China

2005– 2006/ 2010– 2011

HCC patients treated with curative resection

133/ 123

Huang GQ

Oncotarget (2015)

Full-text

Retrospective

Wenzhou, China

2007.1– 2014.1

HCC patients treated with curative resection

508

Huang J

Medical Oncology (2014)

Full-text

Prospective

Guangzhou, China

2008– 2009

HCC patients treated with hepatectomy as initial treatment

349

Huang ZL

Journal of Vascular and Interventional Radiology (2011)

Full-text

Retrospective

Guangzhou, China

2001– 2004

HCC patients treated with TACE

145

Kanno Y

Clinical Nutrition (2014)

Abstract

NA

Mibu, Japan

2000– 2012

HCC patients treated with curative surgery

418

Kim DG

Hepatology (2013)

Abstract

NA

Seoul, South Korea

2000.10– 2011.11

HCC patients treated with LDLT

224

Kinoshita A

Annals of Surgical Oncology (2015)

Full-text

Prospective; Retrospective

Tokyo, Japan

2005.1– 2012.8

Newly diagnosed HCC

186

Lai Q

Transplantation International (2014)

Full-text

NA

Brussels, Belgium

1994.1– 2012.3

Patients with pre-LT proven diagnosis of HCC who entered the waiting list for LT

181

Li C

Journal of Surgical Research (2015)

Full-text

NA

Chengdu, China

2007– 2014

HBV-associated HCC patients treated with resection

236

Li JP

Chinese Journal of Cancer Prevention and Treatment (2013)

Full-text

Retrospective

Jinan, China

2006.2– 2009.2

Unresectable HCC patients treated with TACE

154

Li X

Tumor Biology (2014)

Full-text

Retrospective

Guangzhou, China

2008.11– 2010.4

Advanced HCC patients (BCLC stages C and D) who did not receive sorafenib

205

Li X

PLoS ONE (2014)

Full-text

Retrospective

Beijing, China

2006.4– 2014.4

Recurrent HCC patients treated with curative thermal ablation

506

Liao R

World Journal of Surgical Oncology (2015)

Full-text

Retrospective

Chongqing, China

2007.1– 2010.12

Single-nodule small HCC patients treated with curative resection

222

Liao W

Translational Oncology (2014)

Full-text

Retrospective

Guilin, China

1999.9– 2007.6

HCC patients treated with curative resection

256

Liese J

Transplantation (2014)

Abstract

Retrospective

Frankfurt, Germany

2007.1– 2012.12

HCC patients treated with LT

92

Limaye AR

Hepatology Research (2013)

Full-text

Retrospective

FL, US

2000– 2008

HCC patients treated with LT

160

Long J

Hepatology International (2016)

Full-text

Prospective

Beijing, China

2010.8– 2014.7

HCC with PVTT patients treated with microwave ablation after TACE

60

Lu D

Transplantation (2015)

Abstract

NA

Hangzhou, China

2002– 2012

Small HCC patients treated with LT

140

Luè A

Journal of Hepatology (2014)

Abstract

NA

4 different hospitals, Spain

2005.8– 2013.10

HCC patients treated with sorafenib

186

Mano Y

Annals of Surgery (2013)

Full-text

Retrospective

3 different hospitals, Japan

1996.1– 20009.12

HCC patients treated with curative resection

958

McNally ME

Annals of Surgical Oncology (2013)

Full-text

Retrospective

OH, US

A 10–year period

HCC patients treated with TACE

104

Mizukoshi E

Hepatology (2015)

Abstract

NA

Kanazawa, Japan

NA

HCC patients treated with hepatic arterial infusion chemotherapy

36

Motomura T

Journal of Hepatology (2013)

Abstract

NA

Fukuoka, Japan

1999.7– 2011.3

HCC patients treated with LT

158

Na GH

World Journal of Gastroenterology (2014)

Full-text

Retrospective

Seoul, South Korea

2000.10– 2011.11

HCC patients treated with LDLT

224

Nagai S

Transplantation (2015)

Abstract

NA

IN, US

2001– 2012

HCC patients treated with LT

268

Ni XC

Medicine (2015)

Full-text

Retrospective

Shanghai, China

2010.12– 2012.1

HCC patients treated with resection (test cohort)

367

Oh BS

BMC Cancer (2013)

Full-text

Retrospective

Seoul, South Korea

2007.1– 2010.12

Newly diagnosed HCC

318

Okamura Y

World Journal of Surgery (2015)

Full-text

Retrospective

Shizuoka, Japan

2002.9– 2012.11

HCC patients treated with resection

256

Parisi I

Liver Transplantation (2014)

Full-text

NA

London, UK

1996– 2010

HCC patients treated with LT

150

Peng W

Journal of Surgical Research (2014)

Full-text

Retrospective

Chengdu, China

2007.2– 2012.3

Small HCC patients treated with curative resection

189

Pinato DJ

Translational Research (2012)

Full-text

Retrospective

London, UK

NA

HCC patients treated with TACE

54

Pinato DJ

Journal of Hepatology (2012)

Full-text

Retrospective

London, UK

1993– 2011

HCC patients (training set)

112

Ruan DY

World Journal of Gastroenterology (2015)

Full-text

Retrospective

Guangzhou, China

2003.9– 2011.6

HCC patients treated with curative resection

200

Shindoh J

Transplant International (2014)

Full-text

Retrospective

Tokyo, Japan

1996.1– 2012.12

HCC patients treated with LDLT

124

Sirin G

Hepatology International (2015)

Abstract

Retrospective

Kocaeli, Japan

2007– mid–2012

HCC patients treated with segmental resection and/or RFA

49

Sukato DC

Journal of Vascular and Interventional Radiology (2015)

Full-text

Retrospective

PA, US

2000.8– 2012.11

Intermediate- or advanced-stage HCC patients treated with radioembolization

176

Sullivan KM

Journal of Surgical Oncology (2014)

Full-text

NA

WI, US

2011.7– 2012.4

HCC patients

75

Sun Q

Biomedical Research (2014)

Full-text

Retrospective

Beijing, China

2003– 2008

HCC patients treated with resection

80

Tajiri K

Journal of Gastroenterology and Hepatology (2016)

Full-text

Retrospective

Toyama, Japan

2003– 2014

HCC patients treated with RFA

163

Tajiri K

Hepatology Research (2015)

Full-text

Retrospective

Toyama, Japan

2010– 2013

Advanced HCC patients treated with hepatic arterial infusion chemotherapy

26

Terashima T

Hepatology Research (2015)

Full-text

Retrospective

Ishikawa, Japan

2003.3– 2012.12

Advanced HCC patients treated with hepatic arterial infusion chemotherapy

266

Uchida K

American Journal of Transplantation (2012)

Abstract

NA

FL, US

2002.3– 2010.12

HCC patients treated with DDLT

275

Wang GY

PLoS ONE (2011)

Full-text

Retrospective

Guangzhou, China

2003.10– 2009.6

HBV-associated HCC patients treated with LT

101

Wang K

Liver Transplantation (2013)

Abstract

Retrospective

Hangzhou, China

NA

HCC patients treated with LT

235

Wang Q

Annals of Surgical Oncology (2015)

Full-text

NA

NY, US

1983– 2013

HBV-associated HCC patients treated with resection

234

Wang W

Hepatology Research (2015)

Full-text

Retrospective

Hangzhou, China

2002.1– 2012.12

Male HCC patients treated with LT

248

Wei K

Medical Oncology (2014)

Full-text

Retrospective

Tianjin, China

2010.1.1– 2013.5.31

Intermediate-advanced HCC patients treated with concurrent TAE in combination with sorafenib

40

Weinmann AJ

Hepatology (2015)

Abstract

Retrospective

Mainz, Germany

2007– 2013

HCC patients treated with sorafenib

148

Xiao GQ

Hepatobiliary and Pancreatic Diseases International (2015);

Full-text

Retrospective

Chengdu, China

1999.2– 2012.9

HCC patients treated with LT

305

Xu X

Chinese Medical Journal (2014)

Full-text

Retrospective

Xi’an, China

2003.7– 2012.9

HCC patients treated with TACE

178

Xue TC

Tumor Biology (2015)

Full-text

Retrospective

Shanghai, China

2008.1– 2011.3

Huge HCC patients treated with TACE

165

Yamamura K

Journal of Hepato-Biliary-Pancreatic Sciences (2014)

Full-text

Prospective

Aichi, Japan

2003.1– 2012.12

HCC patients treated with resection

113

Yang X

Chinese Journal of Radiology (2015)

Full-text

Retrospective

Chengdu, China

2000– 2010

HBV-associated HCC patients treated with TACE

546

Yang Z

Oncotarget (2015)

Full-text

Retrospective

Shanghai, China

2009.9– 2015.5

HBV-associated HCC patients treated with TACE

189

Yip V

HPB (2011)

Abstract

NA

Liverpool, UK

1997– 2008

HCC patients treated with resection

47

Yoshizumi T

Anticancer Research (2016)

Full-text

NA

Fukuoka, Japan

1999.4– 2015.3

HCC patients within Milan criteria treated with LDLT

129

Yoshizumi T

Transplantation Proceedings (2013)

Full-text

NA

Fukuoka, Japan

1999.4– 2011.12

HCC patients within Kyushu University criteria treated with LDLT

152

Yoshizumi T

Hepatology Research (2013)

Full-text

NA

Fukuoka, Japan

1999.4– 2012.8

Recurrent HCC adult patients treated with LDLT

104

Young AL

Journal of American College of Surgeons (2012)

Full-text

Retrospective

Leeds, UK

1994.1.1– 2008.12.31

HCC patients treated with resecction

142

Zhang J

Oncology Letters (2014)

Full-text

Retrospective

Wuhan, China

2002.3– 2012.8

Non-viral HCC patients treated with TACE

138

Zhang W

Medical Oncology (2015)

Full-text

Retrospective

Tianjin, China

2009.8.1– 2012.3.28

HCC patients who received sorafenib after resection

38

Zheng YB

Asian Pacific Journal of Cancer Prevention (2013)

Full-text

Retrospective

Guangzhou, China

2011.1– 2012.12

HCC patients treated with sorafenib monotherapy

65

Zheng YB

Chinese Journal of Interventional Imaging and Therapy (2013)

Full-text

Retrospective

Guangzhou, China

2008.1– 2012.12

HCC patients treated with TACE

77

Zhou D

Scientific Reports (2015)

Full-text

Retrospective

Guangzhou, China

2007– 2009

HCC patients treated with surgical resection, ablative therapy, and TACE

1061

Zhou DS

World Journal of Gastroenterology (2015)

Full-text

Retrospective

Guangzhou, China

2009.9– 2011.11

HBV–related HCC patients treated with TACE

224

Abbreviations:

DDLT, deceased donor liver transplantation; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; LDLT, living donor liver transplantation; LT, liver transplantation; RFA, radiofrequency ablation; TACE, transarterial chemoembolization.

Notes:

Some data from Kinoshita A, Annals of Surgical Oncology (2015) is also published by the same authors in British Journal of Cancer (2012).

Some data from Wang GY, PLoS ONE (2011) is also published by the same authors in National Medical Journal of China (2011).

Some data from Xiao GQ, Hepatobiliary and Pancreatic Diseases International (2015) is also published by the same authors in World Journal of Gastroenterology (2013) and Hepato-gastroenterology (2014).

Study quality

Quality of included studies was summarized in Supplementary Table 1. Three, 18, 12, 30, and 27 studies had 7, 6, 5, 4, and ≤ 3 points, respectively.

Meta analyses

Association of baseline NLR with overall survival

There were 39 groups of individual data regarding the association of baseline NLR with overall survival. They were extracted from 38 papers. HR was 1.80 (95% CI: 1.59–2.04, p < 0.00001), suggesting that low baseline NLR group had a significantly better overall survival than high baseline NLR group (Figure 2). Heterogeneity among studies was statistically significant (I2 = 86%, p < 0.00001). Funnel plot suggested a potential publication bias (Supplementary Figure 1).

Forest plot evaluating the association between baseline NLR and overall survival in HCC patients.

Figure 2: Forest plot evaluating the association between baseline NLR and overall survival in HCC patients.

Association of post-treatment NLR with overall survival

There were 4 groups of individual data regarding the association of post-treatment NLR with overall survival. They were extracted from 3 papers. HR was 1.90 (95% CI: 1.22–2.94, p = 0.004), suggesting that low post-treatment NLR group had a significantly better overall survival than high post-treatment NLR group (Figure 3). Heterogeneity among studies was statistically significant (I2 = 89%, p < 0.00001).

Forest plot evaluating the association between post-treatment NLR and overall survival in HCC patients.

Figure 3: Forest plot evaluating the association between post-treatment NLR and overall survival in HCC patients.

Association of NLR change with overall survival

There were 7 groups of individual data regarding the association of NLR change with overall survival. They were extracted from 7 papers. HR was 2.23 (95% CI: 1.83–2.72, p < 0.00001), suggesting that decreased NLR group had a significantly better overall survival than increased NLR group (Figure 4). Heterogeneity among studies was not statistically significant (I2 = 0%, p = 0.95).

Forest plot evaluating the association between NLR change and overall survival in HCC patients.

Figure 4: Forest plot evaluating the association between NLR change and overall survival in HCC patients.

Association of baseline NLR with recurrence-free or disease-free survival

There were 20 groups of individual data regarding the association of baseline NLR with recurrence-free or disease-free survival. They were extracted from 20 papers. HR was 2.23 (95% CI: 1.80–2.76, p < 0.00001), suggesting that low baseline NLR group had a significantly better recurrence-free or disease-free survival than high baseline NLR group (Figure 5). Heterogeneity among studies was statistically significant (I2 = 88%, p < 0.00001). Funnel plot suggested a potential publication bias (Supplementary Figure 2).

Forest plot evaluating the association between baseline NLR and recurrence-free or disease-free survival in HCC patients.

Figure 5: Forest plot evaluating the association between baseline NLR and recurrence-free or disease-free survival in HCC patients.

Association of NLR change with recurrence-free or disease-free survival

There were 4 groups of individual data regarding the association of NLR change with recurrence-free or disease-free survival. They were extracted from 4 papers. HR was 2.23 (95% CI: 1.83–2.72, p < 0.00001), suggesting that decreased NLR group had a significantly better overall survival than increased NLR group (Figure 6). Heterogeneity among studies was not statistically significant (I2 = 0%, p = 0.52).

Forest plot evaluating the association between NLR change and recurrence-free or disease-free survival in HCC patients.

Figure 6: Forest plot evaluating the association between NLR change and recurrence-free or disease-free survival in HCC patients.

Subgroup meta-analyses

Results of subgroup meta-analyses were summarized in Table 2.

Table 2: Results of subgroup meta-analyses

DISCUSSION

The present study systematically reviewed the role of NLR in the assessment of prognosis of HCC patients. To our knowledge, two previous meta-analyses also explored the association of NLR with prognosis of HCC [102103]. Both of them were published in 2014. In the first meta-analysis, Xiao et al. searched the relevant literatures in August 2013 and identified 15 studies with 3,094 patients [102]. In the second meta-analysis, Xue et al. searched the relevant literatures in October 2013 and identified 26 studies with 4,461 patients [103]. Several advantages and features of our work should be acknowledged: 1) the relevant literatures were identified more recently (January 2016), and a larger number of relevant studies were included (90 papers with 20,475 patients); 2) according to the different time points when NLR values were obtained, we divided into baseline NLR, post-treatment NLR, and NLR change; 3) overall survival and recurrence-free or disease-free survival were selected as the primary outcomes; and 4) according to the treatment options, NLR cut-off values, and regions, we performed subgroup meta-analyses.

The major finding of our study was that low baseline NLR was significantly associated with better overall survival and recurrence-free or disease-free survival of HCC patients. This was based on a relatively large number of relevant data (38 papers for overall survival and 20 papers for recurrence-free or disease-free survival). Therefore, in our opinion, the relationship of baseline NLR with survival of HCC patients should be stable. This consideration was also confirmed by the subgroup meta-analyses: 1) except for one subgroup meta-analysis in patients undergoing radiofrequency ablation, other subgroup meta-analyses in patients undergoing different treatment modalities supported such an inverse association between them; 2) except for one subgroup meta-analysis with a NLR cut-off value of ≥ 1 and < 2, other subgroup meta-analyses with other NLR cut-off value ranges supported such an inverse association between them; and 3) regardless of regions, subgroup meta-analyses supported such an inverse association between them. Certainly, two following issues should be acknowledged. First, only one study focused on the patients undergoing radiofrequency ablation. Thus, more data might be necessary for the validation of our findings. Second, only two studies employed a NLR cut-off value of ≥ 1 and < 2. Given such a small NLR cut-off value, the survival difference between high and low NLR groups might be hardly achieved.

Another finding was that low post-treatment NLR was significantly associated with better overall survival of HCC patients. However, due to a small number of included studies, the subgroup meta-analyses were performed in patients undergoing transarterial chemoembolization and hepatic arterial infusion chemotherapy, studies with a NLR cut-off value of ≥ 2 and < 3 and NLR cut-off value of 4, and Asian studies. Except for one subgroup meta-analysis in HCC patients undergoing hepatic arterial infusion chemotherapy, other subgroup meta-analyses supported statistically significant associations. Similarly, we also found that decreased NLR after treatment was significantly associated with better recurrence-free or disease-free survival of HCC patients. Notably, such an inverse association was maintained regardless of treatment modalities.

Several limitations should be clarified. First, HR value for the association of NLR with overall survival was relatively small. Thus, their relationship might be weak. Whether the prognostic assessment of HCC can be guided by baseline NLR value should be further explored. Second, all included studies were observational, and most of them were retrospective. The quality of included studies was relatively low according to the NEWCASTLE-OTTAWA quality assessment scale. A major concern was a low comparability of patient characteristics between low and high NLR groups. This was primarily because all included studies were observational and NLR was only one of many variables included in univariate or multivariate analyses in a majority of original studies. Third, the heterogeneity was statistically significant in several meta-analyses. Random-effect model was employed to produce more conservative results. Fourth, because the researchers paid close attention on the prognostic role of NLR, some relevant paper has been published after this paper was finished [104].

In conclusion, the importance of NLR for assessing the overall survival and recurrence-free or disease-free survival should be acknowledged. Thus, we would like to suggest that NLR may be incorporated into the algorithm regarding the prognostic assessment of HCC. Further studies should confirm the prognostic ability of NLR in different specific settings according to the stage of HCC and treatment options and explore the superiority of NLR over other traditional prognostic scores or models. Additionally, considering that NLR change was associated with prognosis of HCC patients, future studies should explore how to prolong the survival of HCC patients by improving the inflammatory conditions.

MATERIALS AND METHODS

We searched 3 major databases, including PubMed, EMBASE, and Cochrane library databases from the inception of databases. Search items were as follows: ((hepatocellular carcinoma) OR (liver cancer)) AND ((NLR) OR ((neutrophil) AND lymphocyte)). The last search was performed on January 20, 2016. All relevant literatures regarding the prognostic role of NLR in HCC patients were identified. Exclusion criteria were as follows: 1) duplicates; 2) comments; 3) erratum; 4) reviews; 5) case reports; 6) experimental studies; and 7) original studies did not evaluate the prognostic role of NLR in HCC patients. Publication language was not restricted.

We extracted the following data from the included studies: first author, journal, publication year, publication type, study design, regions, enrollment period, study population, number of patients, NLR cut-off values, and overall survival and recurrence-free or disease-free survival data according to the NLR value. In cases of uncertainty, we communicated with the authors and/or journal editors to validate the accuracy of data.

Given the nature of included studies, the study quality was assessed according to the NEWCASTLE-OTTAWA quality assessment scale for cohort studies [105]. This scale consisted of 8 questions with a maximum of 9 points. A study with more points would be of higher quality.

Data analysis was described as previously [106108]. Briefly, only random-effects models were employed. Hazard ratios (HRs) were calculated because the overall survival and recurrence-free or disease-free survival were time-dependent data. I2 statistic and the Chi-square test were used to evaluate the heterogeneity among studies. Funnel plots were performed to evaluate the publication bias, if there were ≥ 10 groups of individual data included in the meta-analysis.

Notably, the meta-analyses were performed according to the times when NLR values were obtained (i.e. baseline NLR, post-treatment NLR, and NLR change). As for the baseline and post-treatment NLR, the patients were divided into two groups (i.e., low and high NLR group) according to the definitions of original studies. If the patients were divided into ≥ 3 groups in the original studies, the relevant data would not be included in the meta-analyses. Additionally, subgroup meta-analyses were performed according to the treatment options (i.e., liver transplantation, surgical resection, radiofrequency ablation, transarterial chemoembolization, radioembolization, hepatic arterial infusion chemotherapy, transarterial embolization plus sorafenib, sorafenib, and mixed treatments), NLR cut-off value ranges, and regions (i.e., America, Asia, and Europe).

CONFLICTS OF INTERESTS

None.

Authors’ contributions

XQ: designed the study, performed the literature search and selection, data extraction, quality assessment, and statistical analysis, and drafted the manuscript; JL and HD: performed the literature selection, data extraction, and quality assessment; CS: performed the literature search; HL and XG: gave critical comments and revised the manuscript. All authors have made an intellectual contribution to the manuscript and approved the submission.

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