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 Table of Contents  
ORIGINAL ARTICLE
Year : 2016  |  Volume : 12  |  Issue : 2  |  Page : 582-589

Neutrophil–lymphocyte ratio and CEA level as prognostic and predictive factors in colorectal cancer: A systematic review and meta-analysis


1 Department of Surgery, Division of Colorectal Surgery, Mackey Memorial Hospital, Zhongshan, Taipei, Taiwan
2 Hospice Palliative Care Center, Mackey Memorial Hospital, Tamshui District, Taipei, Taiwan

Date of Web Publication25-Jul-2016

Correspondence Address:
Chien-Kuo Liu
No. 92, Sector 2, Zhongshan North Road, Taipei - 10449
Taiwan
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.144356

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 > Abstract 


Introduction: There is a growing body of evidence showing the functional relationship between inflammation index like netrophil.lymphocyte ratio. (NLR) and colorectal cancer. (CRC) in both experimental and clinical situations. The serum carcinoembryonic antigen. (CEA) level is the most widely used marker and associate with poor prognosis in most studies. For these factors to be clinically useful, they should be routinely available, well standardized, and validated in different patient cohorts.
Aims: There is a growing body of evidence showing the functional relationship between inflammation index like netrophil-lymphocyte ratio. (NLR) and colorectal cancer. (CRC) in both experimental and clinical situations. The serum carcinoembryonic antigen. (CEA) level is the most widely used marker and associate with poor prognosis in most studies. For these factors to be clinically useful, they should be routinely available, well standardized, and validated in different patient cohorts.
Materials and Methods: We systemically searched PubMed, Embase, and SciVerse Scopus databases, and performed a meta.analysis by Review Manager 5.2 software. (The Cochrane Collaboration, Software Update, Oxford). Two reviewers selected studies, assessed risk of bias, and extracted data independently. Newcastle.Ottawa Scale was applied to assess the quality of included studies.
Results: Fifteen studies involving 7741 patients with CRC were analyzed. Patients with an NLR < 5 before treatment were significantly more likely to have 5-year overall survival (odds ratio [OR] = 2.03; 95% confidence interval [CI] = 1.56-2.63) and 5-year disease-free survival (OR = 1.67; 95% CI = 1.19-2.35). Pretreatment CEA level < 5 were significantly associated with complete tumor response and tumor downstaging after neoadjuvant treatment. The result also showed that patients with NLR > 5 were expected to have a larger tumor, poorer tumor differentiation, and higher CEA level.
Conclusion: NLR and CEA are valuable tools for the prediction of prognosis in CRC and adjusting the treatment strategy.

Keywords: Carcinoembryonic antigen, colorectal cancer, meta-analysis, neutrophil-lymphocyte ratio, prognosis


How to cite this article:
Tsai PL, Su WJ, Leung WH, Lai CT, Liu CK. Neutrophil–lymphocyte ratio and CEA level as prognostic and predictive factors in colorectal cancer: A systematic review and meta-analysis. J Can Res Ther 2016;12:582-9

How to cite this URL:
Tsai PL, Su WJ, Leung WH, Lai CT, Liu CK. Neutrophil–lymphocyte ratio and CEA level as prognostic and predictive factors in colorectal cancer: A systematic review and meta-analysis. J Can Res Ther [serial online] 2016 [cited 2019 Dec 8];12:582-9. Available from: http://www.cancerjournal.net/text.asp?2016/12/2/582/144356

Po-Li Tsai, Wei-Ju Su
contribute equally to this work





 > Introduction Top


The tumor-node-metastasis and Dukes' staging systems are important tools used to estimate prognosis in colorectal cancer (CRC). However, they are not completely effective because of the fact that patients at the same stage of the disease may have various clinical outcomes. Therefore, it is important to identify clinically relevant factors that improve the prediction of survival in patients with CRC. For these factors to be clinically useful, they should be routinely available, well standardized, and validated in different patient cohorts. We chose to conduct a meta-analysis on neutrophil-lymphocyte ratio (NLR) and carcinoembryonic antigen (CEA) level in CRC.

In addition to the high-risk factors associated with different tumor characteristics, the host's immune system also plays a role in the invasion or metastasis of colon cancer.[1] The host inflammatory response to cancer cells is also associated with tumor progression.[2] Over the last 10-year, laboratory markers of systemic inflammatory response, including plasma C-reactive protein (CRP) concentration,[3] hypoalbuminemia, Glasgow prognostic score (which combines CRP and albumin),[4] absolute white cell count or its components, NLR [5] and platelet-lymphocyte ratios [6] have been investigated as prognostic and predictive markers in patients with different types of cancer, with the best evidence for their effectiveness demonstrated in surgical patients with CRC.[7] However, serum CRP levels and GPS are not routinely examined as part of the preoperative assessment of CRC patients.

White blood cell count plays an important role in the systemic inflammatory response to severe infection. NLR has been used not only as a marker of inflammation [8] but also as a prognostic index for malignancies. NLR can be easily determined in patients who have undergone surgery for colon cancer [9] and has been suggested as a simple index of systemic inflammatory response in critically ill patients and a strong prognostic factor for CRC.[5] However, in some studies, NLR was not an independent prognostic factor [6] and was not associated with cancer-specific survival.[10] Therefore, the predictable and prognostic role of NLR in CRC is still unclear and various in different researches.

Serum CEA level is the most widely used tumor marker for CRC and is associated with an increased risk of relapse and poor patient outcome.[11],[12] The factors that predict response to preoperative chemoradiotherapy (CRT) in CRC have not been well characterized, and the optimal cut-off value of CEA has not been clearly defined. A clear understanding of factors that predict pathologic tumor response is important because it may provide additional information needed to create tailored treatment options according to individual prognosis.[13]

Therefore, the aim of the present study was to explore the emerging role of NLR in predicting the prognosis and clinical outcomes in CRC. We also investigate the relationship between NLR and high-risk factors related to poor prognosis (e.g. tumor size, tumor differentiation, high CEA level). The predictable value of serum CEA levels before treatment was also determined.


 > Materials and Methods Top


This meta-analysis focused on studies that evaluated NLR and CEA as predictive factors for tumor response or prognosis in CRC. We included studies in which patients were diagnosed with surgically and pathologically proven primary CRC.

Comprehensive searches on PubMed, Embase, and SciVerse Scopus were conducted for papers published between January 1980 and February 2013. The following search terms were used: “CRC or colon cancer or rectal cancer,” “neutrophil to lymphocyte ratio or NLR,” and “prognosis or tumor response.” We reviewed the references and performed manual searches and limited retrieval to English language citations.

Inclusion and exclusion criteria

Two investigators (Tsai PL and Liu CK) independently selected articles according to inclusion criteria. Disagreements were discussed with a third reviewer (Leung WH). Studies were included if they met all of the following criteria: (1) Patients were diagnosed with surgically and pathologically proven primary CRC, (2) contained an evaluation of pretreatment NLR or CEA with cut-off value of five for predicting clinical response in CRC; (3) contained a description of tumor response (e.g. completed response (CR), partial response, tumor downstaging) or prognosis (e.g. overall survival [OS], disease-free survival [DFS], progression-free survival [PFS]). The exclusion criteria were as follows: (1) Animal studies, review articles, letters, editorials, communications, and case report with no original data were similarly excluded; (2) studies that were not directly reporting hazard ratios or odds ratios (ORs) which we could not reconstruct them and get exact patient number; (3) studies with insufficient data for estimating.

Data extraction

After assessment for eligibility, two investigators (Tsai and Liu) independently extracted the following data according to a prespecified protocol:First author, year of publication, country of origin, number of patients, study design, disease type of patients, predictive factors before treatment and type of outcomes measured.

Outcomes of interest and definitions

Primary outcomes were tumor response and prognosis, such as OS, DFS. Secondary outcome included other correlations among NLR, CEA, and favorable tumor characteristics that are associated with high risk of poor prognosis.

Sensitivity analysis

Sensitivity analysis of the data was undertaken to account for heterogeneity. Remove one study involved in the meta-analysis to disclose the influence of the individual data set to the pooled ORs, and the corresponding pooled ORs were not materially changed.

Risk of bias assessment

The quality of the nonrandomized studies was assessed by using the Newcastle–Ottawa Scale included three selection criteria: Selection, comparability, and outcome. Included studies were independently assessed by two reviewers (Tsai PL and Liu CK). Studies achieving six or more stars were considered as being of higher quality. Disagreements regarding inclusion were reconciled via consensus. Publication bias was not be evaluated because of the small number of studies analyzed, which would render low power testing.[14]

Statistical analysis

Meta-analysis was performed according to recommendations from the Cochrane Collaboration. The effect outcomes estimated by OR for dichotomous data and reported with 95% confidence intervals (CIs). Analysis was performed using Review Manager 5.2 software (The Cochrane Collaboration, Software Update, Oxford), and we assessed and quantified the statistical heterogeneity for each pooled estimate using the Cochran Q Chi-square test and I2 statistic. A Chi-square value of <0.1 was considered statistically significant. Random effect model analysis was used when items had high levels of heterogeneity (with I2 >75%). In a random effects model, it is assumed that there is variation between studies and thus the calculated OR has a more conservative value.


 > Results Top


Eligible studies

The search resulted in a total of 598 hits. Initial selections based on titles and abstracts identified 55 potentially relevant articles and were retrieved for the full evaluation. Of these, 43 articles were excluded after the examination of inclusion and exclusion criteria. Thus, 15 studies [6],[9],[13],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26] of 7741 patients in total were considered to be eligible for inclusion in this meta-analysis [Figure 1]. The characteristics of the eligible studies are summarized in [Table 1]. A total of ten studies gained a quality score of six stars or more. All the included studies were retrospective. Thirteen studies were conducted in Asia, and two studies were from the UK. The diagnosis in most of the included studies was rectal cancer without any metastasis, while four studies included patients with CRC with metastasis, three studies analyzed colon cancer and two studies analyzed both rectal and colon cancer. The number of patients in the eligible studies ranged from 50 to 3857. Type of clinical outcomes measured was various, and most studies applied a cut-off value of NLR of five as a predictive factor.
Figure 1: Flow diagram

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Table 1: Characteristics of eligible studies

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Correlation of neutrophil-lymphocyte ratio with overall survival and disease-free survival

A meta-analysis could be conducted while there were at least two researches have been done on the same topic and the same comparison. Many included studies presenting the relationship between pretreatment NLR and prognosis, but only four studies applied the same cut-off value of NLR of five to predict 5-year OS were available for this meta-analysis. Patients with NLR < 5 before treatment were significantly more likely to have 5-year OS.[6],[9],[10],[24] The pooled OR was 2.03 (95% CI = 1.56-2.63) without significant heterogeneity (P = 0.09; I2 = 54%) [Figure 2]a. There were only two studies reporting the data of pretreatment NLR (cut-off value of five) and 5-year DFS.[9],[24] Patients with NLR < 5 before treatment were expected to have better 5-year DFS after treatment. The pooled OR was 1.67 (95% CI = 1.19-2.35) without significant heterogeneity (P = 0.31; I2 = 1%) [Figure 2]b.
Figure 2: (a) Forest plots demonstrating association between neutrophil-lymphocyte ratio (NLR) and 5-year overall survival. “Events” reflects patients with NLR<5 (b) Forest plots demonstrating association between neutrophil-lymphocyte ratio and 5-year disease-free survival

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Correlation of neutrophil-lymphocyte ratio with tumor characteristics

Data on tumor differentiation were available from three studies involving 1329 CRC patients.[6],[9],[26] The pooled estimates displayed that pretreatment NLR > 5 tended to be associated with poorer tumor differentiation (OR = 1.56; 95% CI = 0.95-2.56) without significant heterogeneity (P = 0.42; I2 = 0%) [Figure 3]a.
Figure 3: (a) Forest plots demonstrating association between neutrophil-lymphocyte ratio and tumor differentiation (b) Forest plots demonstrating association between neutrophil-lymphocyte ratio and tumor size (c) Forest plots demonstrating association between neutrophil-lymphocyte ratio and T-stage

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There were three studies providing data with reference to NLR (cut-off value of five) and tumor size in CRC patients before receiving anticancer treatment.[6],[9],[26] The pooled analysis showed that patients with NLR > 5 were more likely to have larger tumor (at least 5 cm) (OR = 2.22; 95% CI = 1.61-3.07) with no obvious heterogeneity (P = 0.28; I2 = 22%) [Figure 3]b.

Information on NLR and T-stage in CRC patients could be retrieved from only two studies.[6],[9] There were no evidence of heterogeneity between the enrolled studies (P = 0.89; I2 = 0%). The pooled OR of 1.54 (95% CI = 1.16-2.05) showed that patients with NLR > 5 were expected to have T4 stage [Figure 3]c.

Correlation of neutrophil-lymphocyte ratio with carcinoembryonic antigen level

Three studies presented the relationship between NLR and CEA level before anticancer treatment.[6],[9],[26] The pooled estimates displayed a significant relationship between NLR > 5 and higher CEA level (>5). The pooled OR was 1.59 (95% CI = 1.20-2.10) without significant heterogeneity (P = 0.32; I2 = 11%) [Figure 4].
Figure 4: Forest plots demonstrating association between neutrophil-lymphocyte ratio and carcinoembryonic antigen level

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Correlation of carcinoembryonic antigen with tumor response to treatment

Six studies examined the relationship between CEA and tumor CR.[13],[15],[16],[17],[18],[19] In these studies, CR was defined as no tumor cells being detected at either the primary site or in regional lymph nodes on pathological examination. For those patients who did not undergo surgery, no detectable cancer cells on multiple biopsy specimens or no evidence of recurrence were included as criteria in the CR group. Patients with CEA level <5 before treatment were significantly more likely to have a tumor CR after receiving neoadjuvant combined CRT (CCRT) or radiation therapy (OR = 3.09; 95% CI = 2.12-4.51). The pooled analysis had no significant heterogeneity (P = 0.21; I2 = 29%) [Figure 5]a. We also assessed tumor downstaging, which was defined as pathological stage T2 or lower by comparing pretreatment clinical and postoperative pathologic T classifications.[13],[15],[18] Patients with pretreatment CEA level <5 significantly tended to have better tumor shrinkage. The pooled OR was 1.70 (95% CI = 1.28-2.26), but with significant heterogeneity (P = 0.0003; I2 = 88%) [Figure 5]b.
Figure 5: (a) Forest plots demonstrating association between carcinoembryonic antigen (CEA) and complete response. “Events” reflects patients with CEA ≤5. (b) Forest plots demonstrating association between carcinoembryonic antigen and tumor downstaging

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Sensitivity analysis was performed for the tumor downstaging group in an attempt to reduce heterogeneity. Analyzing studies with >100 patients did not eliminate the heterogeneity (OR = 1.97; 95% CI = 0.58-6.67; I2 = 94%; P < 0.0001).


 > Discussion Top


To the best of our knowledge, this is the first meta-analysis to investigate the potential usefulness of NLR and CEA levels as prognostic and predictive factors in CRC. It is important to identify prognostic and predictive factors of CRC because it may help determine the most effective treatment. However, there are still pending satisfactory detecting markers of prognosis. Previous investigators have explored the role of serum CRP, albumin,[20] absolute neutrophil counts,[27] CEA,[28] and NLR [5] in predicting the clinical outcomes of patients with CRC. In the present study, we investigated the impact of neutrophil/lymphocyte counts and CEA levels on CRC prognosis. We chose NLR and CEA because they are inexpensive, reproducible, and widely available blood tests and have been found to be important indicators of adverse prognoses in CRC.[29]

Netrophil-lymphocyte ratio has been suggested as a simple index of systemic inflammatory response. Neutrophilia occurs during systemic inflammation and lymphopenia is a marker of depressed cell-medicated immunity.[8] Increases in NLR may suppress lymphokine-activated killer cells, thereby increasing the possibility of tumor metastasis.[30] Inflammatory cells in the tumor microenvironment have significant effects on tumor development. The prognostic NLR in malignancy may be due to the high tumor angiogenesis activity of tumor-induced neutrophils contributing to tumor progression, lymphocyte count associated with disease severity, and immune escape of tumor cells from tumor-infiltrating lymphocytes.[31] Walsh et al. were the first to report that preoperative elevated NLR was correlated with overall and cancer-specific survival in CRC.[5] Furthermore, elevated NLR has been repeatedly reported to be a prognostic factor for some types of cancer.[32],[33],[34],[35],[36]

Elevated pretreatment NLR is not only associated with poor prognosis in CRC, but also with CRC recurrence in patients who undergo elective, potentially curative resection for CRC.[37] Although there are different cut-off points for NLR, many studies have demonstrated similar findings that patients with elevated NLR have worse prognoses for outcomes such as DFS,[21],[38] PFS,[22],[39] time to recurrence,[38] and recurrence-free survival.[23]

In the current review, we have demonstrated that pretreatment NLR is a factor that predicts all stages of CRC prognosis. Elevated NLR is a significant prognostic factor for 5-year OS. Furthermore, we found that elevated NLR was associated with T4-stage cancer, a CEA >5 mg/mL, and tumor size >5 cm, but was not related to tumor differentiation. A cut-off score of 5 was chosen in accordance with previous studies.[5],[24],[40] Because it is an easy measure to use in clinical practice. However, other cut-off scores have been previously chosen.[21],[41]

Carcinoembryonic antigen level is widely used to monitor recurrence during postoperative follow-up. CEA exists in the embryonic and fetal gut, liver, and some adult organs and was first described in 1965.[42] High preoperative serum CEA levels are associated with advanced tumor stage, poor prognosis, and reduced survival periods.

The response of rectal cancer to radiotherapy varies, with complete pathological response in 4-30% patients and downstaging in 30-60% patients.[43] The determination of factors predicting pathologic tumor response is important because it may provide additional information to allow treatment to be tailored according to individual prognosis.[13]

Some studies have revealed that prognostic factors such as tumor volume, CEA level, distance from the anal verge,[27] fatigue during CRT,[44] and treatment interval between radiation and surgical resection [45] correlate with clinical response. Although many studies have shown the biological properties of tumors with molecular markers to predict the tumor's response to preoperative radiotherapy in patients with rectal cancer, neither molecular marker nor gene expression profiling data have identified definitive predictors of preoperative CRT tumor response.[43]

Serum CEA levels are usually measured for patients with rectal cancer. Measurement of serum CEA levels is standardized for normal limit, easily performed, and widely used.[46] In some studies, pre-CRT CEA levels have been shown to be a common predictor of pathological CR (pCR), downstaging, and tumor response in multivariate analyses.[13],[43] In contrast, Das et al.[28] found that CEA levels were not specified, pretreatment CEA was only significantly associated with pCR in univariate analysis but not in multivariate analysis. Therefore, there is some controversy surrounding the role of pre-CRT CEA in patients with rectal cancer.

In terms of prognostic values, some previous studies have reported that CEA response was shown to be a prognostic factor after preoperative CCRT or CRT and surgical resection; however, because 2.5 or 6 mg/mL was used as a cut-off value, little information was gained regarding the correlation between CEA level and pathologic tumor response.[28], 45, [47],[48]

In our study, meta-analysis showed that the serum CEA level was a predictor of downstaging and complete regression.

It is important to summarize the available data that is driving clinical practice trends. Our findings and statistics are important to report for current practice, and furthermore, they reinforce the urgent need for large-scale studies and establishing prognostic scores for clinical decision making and treatment strategies. However, there are some limitations of the present study. First, the role of meta-analysis for nonrandomized studies has been debated. In our analysis, all of the enrolled studies were retrospective, which may perpetuate the individual biases of each study and give a false impression of cohesion in the literature. Second, because this study adopted meta-analysis which is an analysis method based on available articles. And here had to be some common factor between different articles, thus, our analysis was limited. We could hardly analyze the relationship between NLR and more clinical-pathological characteristics or perform more stratification analysis.

We acknowledge that the retrospective studies currently available in the literature limit our meta-analysis. Nonetheless, the statistical quantification and pooling of results from many studies helps to identify reasons for variability, inconsistency or heterogeneity in the literature, therefore, encouraging further research. Such studies could perform more analysis according to the gender, age, the main treatment, disease stage, and other clinical-pathological characteristics. It is a very meaningful research to compare the predicting efficacy of NLR with that of CEA since its presence can affect the patient outcome and provide clinicians more information for patients' care. We also hope that this paper can get other researchers' attention and give them motivation to conduct further studies, resulting prospective studies and laboratory studies which can help us gain greater insight to the risk of NLR in patients with CRC.


 > Conclusion Top


Elevated pretreatment NLR and CEA are associated with poorer prognosis in CRC patients. NLR is also closely associated with clinicopathological factors. NLR and CEA are easy access and inexpensive biomarker. The usefulness of NLR and CEA level as independent prognostic factors in CRC and determining optimal cut-off values warrant more investigation. Future studies focused on establishing prognostic tools and surveillance programs for treatment strategy and personalized cancer care are greatly needed.

 
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