Colorectal cancer (CRC) is now the fifth most common malignancy in men, the fourth most common in women, and the fifth most common cause of death from cancer in Korea [1]. The liver is the most common site for CRC metastases, because of the enteric venous drainage via the portal circulation. Up to 50% of CRC patients develop liver metastases, and 25% of patients with newly diagnosed CRC already have metastases. Furthermore, the liver is the sole site of metastasis in 35% of cases. Several studies have shown that 10% to 30% of patients with synchronous liver-limited colorectal metastases (sCRLM) have potentially resectable disease at the 0point of detection and can be treated surgically [2]. Surgical resection of hepatic metastases has been shown to significantly improve survival, with reported 5-year survival rates of 30%–40% in some centers. Recent advances in surgical technique for partial hepatectomy, indications for liver resection, imaging modalities, and perioperative neoadjuvant chemotherapy, have increased the number of patients suitable for simultaneous surgical resection [34]. However, hepatic tumor recurrence rates remain high, at around 60%–65%. Therefore, identifying patients who are more likely to have recurrence after surgery is important for guiding treatment.

Recently, it has been shown that the inflammatory response (IR) plays a key role in the survival of cancer patients. The neutrophil-to-lymphocyte ratio (NLR), an IR marker, has been reported to be associated with patients' prognosis for various types of cancer, including breast [5] stomach [6], pancreatic [7], and hepatocellular carcinoma [8]. Several recent studies have reported on the role of NLR as a prognostic factor for CRC patients [9]. Moreover, NLR is also a predictor in CRLM after surgery [10]. However, few studies have investigated the prognostic value of NLR in resectable sCRLM.

Serum CEA is an adhesion molecule of the immunoglobulin cell and is known to be increased in several cancers, including CRC [11]. CEA is also widely accepted as a clinically significant prognostic indicator for both recurrence and therapeutic benefit in CRC [12]. CEA mediates metastasis and IRs by binding to its receptor, hnRNP, in the liver [13]. One study on the correlation between CEA and colorectal metastasis found that CEA was associated with higher liver metastasis but not with other organ metastasis or nonmetastatic CRC [14]. However, the prognostic value of CEA in CRC with liver metastasis remains uncertain. A meta-analysis showed that low preoperative CEA level (less than 50 ng/mL) was associated with a significantly better survival time following liver metastasis resection. Another meta-analysis using a cut-off of 200 ng/mL to stratify the 2 groups, also demonstrated improved survival time with lower CEA level [15].

There have been no studies until now that have explored the prognostic role of combined detection of preoperative NLR and CEA levels in patients with sCRLM. Therefore, the aim of this study was to evaluate each prognostic utility of preoperative NLR or CEA levels in patients undergoing simultaneous surgery for sCRLM, and was to determines the predictive ability of combining of preoperative NLR and CEA levels in sCRLM patients.

Our study revealed that in combination high NLR and CEA levels might be an independent prognostic biomarker that correlates with survival and prognosis in patients with sCRLM. This is the first study evaluating the effectiveness of this metric in patients with resectable sCRLM. Since Walsh et al. [9] first reported that NLR was a prognostic indicator in patients with CRC, many studies have confirmed the correlation of NLR and prognosis [161718]. However, only a few studies have reported that combining NLR and CEA levels correlated with prognosis in CRCM [19]. Moreover, most of the previous studies included patients at all stages of CRC or included inoperable stage IV CRC group [20]. Chiang et al. [18] demonstrated that NLR and CEA levels predict the survival of stage I-III CRC patients who received curative surgery. Zhan et al. [21] reported on combined detection of NLR and CEA as an independent prognostic factor in stage II and III CRC patients. Halazun et al. [16] documented that elevation of NLR predicts survival of patients who were included in both synchronous and metachronous groups for CRLM after hepatic resection. However, they only evaluated NLR by itself. Moreover, in metachronous liver metastasis, tumor biology could be changed due to primary tumor resection and adjuvant chemotherapy.

In the present study, colon cancer lymph-node metastasis, postoperative inflammatory complications, and high NLR were shown, when used independently, to be poor prognostic factors for both overall and recurrence-free survival in multivariate analysis. Previous commonly used clinicopathological factors, such as patient age, colon cancer location, T stage, microvascular invasion, and number of liver metastases showed no significant correlation with high NLR [2]. More aggressive histology and length of stay in hospital were significantly correlated with high NLR. Some studies also showed that histopathologic factors such as differentiation, angio-invasion, and tumor infiltrating inflammation of primary CRC and metastatic lesion were independent risk factor for recurrence after hepatic resection in CRLM [22]. These results suggest that elevated NLR and inflammatory complications have an important role in the aggressiveness of tumors.

Recently, inflammation as a protective response that paradoxically plays a critical role in tumor development has attracted great interest. One inflammatory marker, NLR, has been reported as a powerful index of the systemic IR. Because neutrophilia and lymphopenia occur during systemic inflammation, NLR is an important marker which represents a balance between pro-tumor inflammatory pathways and the immune systems antitumor functions. Increased NLR means that elevations in inflammatory cells, affect tumor growth in the microenvironment. Furthermore, they suppress cell-mediated immunity, thereby facilitating the immune escape of tumor cells [23]. High NLR is correlated with tumor invasiveness, angiogenesis and metastasis [24]. Elevated NLR was correlated with OS in several types of cancer including CRC [5678910].

Our study showed that inflammatory postoperative complications, such as anastomosis leakage and wound complication, are independent prognostic factors of survival and recurrence in multivariate analysis. Many studies have also reported a correlation between cancer-associated inflammation and survival and prognosis in various cancers, for which there are several possible explanations. Tumor-associated inflammation induces crosstalk between nonmalignant and malignant cells through mediators such as cytokines, chemokines, and prostaglandins. The tumor microenvironment under inflammatory conditions leads to tumor progression and metastasis, and this microenvironment provides a source of extracellular matrix-modifying enzymes that facilitate angiogenesis, invasion, and metastasis [25]. Major host cell types involved in inflammation are macrophages, myeloid cells, lymphocytes, and mesenchymal cells. Neutrophils may also contribute to progression and dissemination of cancer with a number of studies suggesting an important role. Neutrophil extracellular trap (NET) are networks of extracellular DNA derived from neutrophils. They trap circulating tumoral cells and subsequently increase the mature metastatic-disease burden. Studies have shown that NET products in vitro are increased in CRC patients [26]. Human neutrophil peptides-1, -2, and -3 (HNP 1, -2, and -3) were upregulated in CRC patients when compared to normal colon tissue. HNP levels can be applied as important markers in patients with lymph node or liver metastasis [27]. Neutrophils induce granulocyte-colony stimulating factor release from tumor cells through the release of interleukin (IL)-1 and tumor necrosis factor (TNF)-alpha. Neutrophilia increases inflammatory markers, such as vascular endothelial growth factor, CXCL8, proteases (metalloproteinase tissue inhibitors), and antiapoptotic markers (nuclear factor-kappa B [NF-κB]), which are associated with tumor growth and progression [25]. Chronic inflammation plays an important role in the proliferation and metastasis of tumor cells. In addition, many studies suggest that cancer-associated inflammation affects cancer development and progression. Transcription factors, including NF-κB and STAT3, and inflammatory cytokines, such as IL-1β, IL-6, IL-23, and TNF-α, are associated with cancer-related inflammation. Further supporting the link, some studies have shown that COX-2 inhibitors and nonsteroidal anti-inflammatory drugs reduce not only CRC incidence but also metastasis and overall mortality [28].

In our study, high CEA showed a strong trend with lower OS and DFS in univariate analysis. CEA is also a widely accepted prognostic indicator of therapeutic response and monitoring of recurrence in CRC, and the CEA level is recommended as a gold standard for follow-up by the American Society of Clinical Oncology and European Society for Medical Oncology [2930]. However, in CRC with liver metastasis, especially resectable sCRLM, the value of CEA has been less well understood. Some reports showed low CEA levels (less than 200 ng/mL) were correlated with better survival. They reported a 5-year survival of 48.9%, compared to 0% for high CEA levels. A previous meta-analysis demonstrated that preoperative CEA level less than 50 ng/mL was associated with better survival after liver resection [15]. Although the optimal cutoff value remains uncertain, (many studies have used cutoff values ranging from 20 to 200 ng/mL) 100 ng/mL was used in this study. We have also shown that, compared to patients with lower NLR, patients with high NLR were significantly correlated with high CEA levels measured at the preoperational stage (CEA <100 or >100 ng/mL). As shown in Fig. 1, the CEA level was correlated with OS and DFS, and the combination of NLR and CEA was a better prognosticator for resectable sCRLM patients than NLR or CEA alone. There are several advantages to the use of serum NLR and CEA levels, because they are easily measured in blood test and routinely checked in all CRC patients. The combination of NLR and CEA not only reflects the tumor characteristics, but also represents the inflammatory and immune status of tumors. Zhan et al. [21] also demonstrated that COCN (combination of CEA and NLR) is a more powerful independent predictor than NLR or CEA alone in patients with stage II or III CRC.

Our study has several limitations. First, although patients were selected only if they had resectable sCRLM, because of working within a single institution and using a retrospective design, selection bias such as heterogenicity of chemotherapy regimens and duration could not be excluded completely. Second, the total number of patients was small, and the lack of standardization of clinical assays are an important problem. Third, some important pathological reports, such as perineural invasion, were not included in the study because they were not documented. Further well-designed prospective studies are needed. However, all patients involved were synchronously diagnosed and operated on for lesions of colon and liver; therefore, the biases were minimized.

In summary, elevated preoperative NLR is strongly correlated with both survival and recurrence in patients who have been diagnosed with resectable synchronous CRC with liver metastases. Combined NLR and CEA levels could be a more powerful prognostic marker than NLR alone. Preoperatively, measurement of NLR and CEA level may a provide simple method for identifying patients with a poorer prognosis in resectable sCRLM. Further it will allow optimization for selecting patients who will need further treatment, such as inflammatory and immune modulation, which could improve their long-term outcomes.