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: [email protected]
Jianjun Li, email: [email protected]
Xiaozhong Guo, email: [email protected]
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 [8–11]. 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) [12–101]. 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.
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).
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).
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).
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).
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).
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 [102–103]. 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 [106–108]. 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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