AIM: To determine whether serum levels of carcinoembryonic antigen (CEA) correlate with the presence of primary colorectal cancer (CRC), and/or recurrent CRC following radical resection.

METHODS: A total of 413 patients with CRC underwent radical surgery between January 1998 and December 2002 in our department and were enrolled in this study. The median follow-up period was 69 mo (range, 3-118 mo), and CRC recurrence was experienced by 90/413 (21.8%) patients. Serum levels of CEA were assayed preoperatively, and using a cutoff value of 5 ng/mL, patients were divided into two groups, those with normal serum CEA levels (e.g., ≤ 5 ng/mL) and those with elevated CEA levels (> 5 ng/mL).

RESULTS: The overall sensitivity of CEA for the detection of primary CRC was 37.0%. The sensitivity of CEA according to stage, was 21.4%, 38.9%, and 41.7% for stages I-III, respectively. Moreover, for stage II and stage III cases, the 5-year disease-free survival rates were reduced for patients with elevated preoperative serum CEA levels (P < 0.05). The overall sensitivity of CEA for detecting recurrent CRC was 54.4%, and sensitivity rates of 36.6%, 66.7%, and 75.0% were associated with cases of local recurrence, single metastasis, and multiple metastases, respectively. In patients with normal serum levels of CEA preoperatively, the sensitivity of CEA for detecting recurrence was reduced compared with patients having a history of elevated CEA prior to radical resection (32.6% vs 77.3%, respectively, P < 0.05).

CONCLUSION: CRC patients with normal serum CEA levels prior to resection maintained these levels during CRC recurrence, especially in cases of local recurrence vs cases of metastasis.

Globally, colorectal cancer (CRC) is the third most common cancer diagnosed, and is associated with high rates of incidence and mortality for both men and women[1]. Furthermore, despite progress that has been made in the treatment of advanced cases of CRC, the clinical outcome of this disease still remains poor[2]. Carcinoembryonic antigen (CEA) is a classic tumor marker for CRC, and has been used to monitor CRC recurrence and as a prognostic factor for CRC patients. Currently, the serum CEA test is recommended by the American Society of Clinical Oncology[3] and the European Group on Tumor Markers[4] as a prognostic biomarker for recurrent CRC following curative resection. However, the effectiveness of CEA as a preoperative and postoperative marker for CRC remains to be evaluated. In particular, it remains unclear how accurate a negative CEA value is for excluding primary and recurrent CRC, and under what conditions CEA values are inaccurate. Therefore, this study was designed to evaluate the role of serum CEA levels in the diagnosis of primary and recurrent CRC following radical resection.

For a total of 413 patients that were diagnosed with CRC between January 1998 and December 2002 in our department and were enrolled in this retrospective study, serum levels of CEA were assayed prior to surgical resection. Based on a cutoff value of 5 ng/mL, two patient groups were established. One group was associated with elevated levels of serum CEA (e.g., > 5 ng/mL) (n = 153; 37.0%), while the second group was associated with normal levels of serum CEA (e.g., < 5 ng/mL) (n = 260; 63%). The stages of CRC associated with these cases included stage I (n = 70), IIA (n = 140), IIB (n = 35), IIIA (n = 23), IIIB (n = 85), and IIIC (n = 60), according to the 6th International Union Against Cancer (UICC) Tumor Node Metastasis (TNM) staging system[5]. Moreover, elevated serum levels of CEA were detected preoperatively in 21.4% of stage I CRC patients, 38.9% of stage II CRC patients, and in 41.7% of stage III CRC patients, respectively. As a result, preoperative CEA levels were found to correlate with CRC diagnoses according to the UICC TNM staging system (P = 0.01). A comparison of preoperative CEA levels with clinicopathological characteristics of the enrolled patients further detected a significant association between serum CEA levels and tumor size and T category (Table 2). However, serum CEA levels did not correlate with patient age, patient gender, tumor location, tumor differentiation, N category, or lymphovascular invasion.

The median follow-up time for this study was 69 mo (range, 3-118 mo), and the 5-year DFS rate was 67% after patients underwent radical resection. Moreover, univariate and multivariate analysis revealed that preoperative serum levels of CEA were a significant independent prognostic factor for 5-year DFS rates (Table 3). The 5-year DFS rate was also found to significantly differ for stage II and stage III CRC patients independent of serum CEA levels (P < 0.05), yet did not differ for stage I CRC patients following radical resection. When stage II and stage III CRC cases were further subdivided into IIA, IIB, IIIA, IIIB, and IIIC stages, the 5-year DFS rate for normal and elevated levels of serum CEA patient groups were 84% and 62% for stage IIA CRC patients, and 64% and 21% for the stage IIIB CRC patients, respectively in each case (P < 0.05, Figure 1A and B). However, no significant difference in the 5-year DFS rates associated with stage IIB, IIIA, and IIIC CRC was observed.

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Figure 1 Disease-free survival curves for patients with stage IIA colorectal cancer (A) and stage IIIB colorectal cancer (B) based on preoperative serum levels of carcinoembryonic antigen.

Recurrence of CRC was experienced by 90/413 patients, with local recurrence, single CRC metastasis, and multiple CRC metastases occurring in 41/90 (45.6%), 49/90 (54.4%), and 16/90 (17.8%) patients, respectively. The types of metastasis detected included hepatic (n = 17), pulmonary (n = 10), osseous (n = 7), renal (n = 2), adrenal (n = 3), distal lymphatic (n = 2), brain (n = 1), and spinal (n = 1). Serum CEA levels were found to be higher in patients with CRC metastases compared to patients with local recurrent CRC (P < 0.05). Moreover, the percentage of patients with elevated CEA levels and local recurrence was less than that of CRC patients with elevated CEA levels and single or multiple metastases (36.6% vs 66.7% and 75.0%, respectively) (P < 0.05, Table 4). Patients with a history of elevated CEA levels prior to surgery were also associated with elevated CEA levels directly prior to surgery in 77.3% of cases, whereas patients with no prior history of elevated CEA levels exhibited elevated levels of CEA levels directly prior to surgery in 32.6% of cases (Table 5). Univariate and multivariate analysis also revealed that preoperative serum levels of CEA and recurrence patterns were significantly associated with serum levels of CEA detected during recurrence (Table 6).

Since Gold et al[6] first described and characterized CEA in 1965, it has become the one of the most widely known tumor markers for gastrointestinal tract diseases, especially for CRC. However, although 90% of CRCs produce CEA[7], elevated serum levels of CEA are not often detected at the time of diagnosis. In this study, normal serum levels of CEA (e.g., < 5 ng/mL) were detected in 67% of the CRC patients assayed, and in 79% of stage I CRC patients. While a correlation between stage of CRC and preoperative CEA levels has previously been observed, a low sensitivity is associated with serum CEA assays in the detection of early stage CRC[8-10]. Accordingly, the usefulness of serum CEA assays for screening of CRC is limited. Despite this, a semi-quantitative relationship between CEA levels and tumor volume has previously been described[11], suggesting that elevated serum levels of CEA detected preoperatively may indicate a larger tumor burden. In the present study, preoperative levels of serum CEA were found to be significantly associated with tumor size and T category, but not with N category or tumor differentiation. Moreover, preoperative CEA levels also correlated with stage of disease, while providing a prognostic determinant of survival. These results are consistent with other studies[12-14], and also confirmed that elevated levels of serum CEA represent an independent prognostic factor for 5-year DFS, especially for cases of stage IIA and IIIB CRC.

In colon cancer, CEA modulates intercellular adhesion, functions as a promoter of cellular aggregation, regulates the innate immune system, and mediates signal transduction[15-17]. Accordingly, it is hypothesized that CEA plays an important role in tumor invasion and metastasis. In this study, the 5-year DFS rate of stage II CRC patients with elevated levels of serum CEA were compared with stage III CRC patients with normal levels of serum CEA, and no significant difference was found (data not shown). This finding is consistent with another study[18], and suggests that a diagnosis of CRC accompanied by elevated levels of serum CEA may be an indicator for tumor restaging even after surgery. Furthermore, it has been shown that genetic vaccines targeting CEA may be a feasible strategy for the treatment of CRC[19]. For example, Ogata et al[20] observed that stage II CRC patients with elevated levels of CEA may be candidates for adjuvant chemotherapy following curative resection.

CRC recurrence has been reported for 30%-40% of patients who undergo curative resection. During the follow-up period of surgical resection, CEA monitoring is typically performed. However, the accuracy and efficacy of CEA monitoring is not always consistent. For example, in the present study, only 54.5% of patients experiencing recurrence had elevated serum levels of CEA. Moreover, these results are consistent with previously reported findings[21]. Typically, elevated levels of CEA detected postoperatively have a high probability of indicating tumor recurrence, while normal levels of CEA detected postoperatively are not useful for excluding the probability of recurrence[22,23]. Therefore, the need for monitoring CEA levels in patients who initially exhibit normal levels of CEA remains to be determined[24]. In the present study, according to the preoperative CEA levels assayed, 77% of recurrent CRC patients had elevated CEA levels, while 32% had normal CEA levels. These results indicate that normal CEA levels may be associated with the relatively early stages of tumor progression, and also with the presence of a non-CEA producing tumor. For example, production of CEA may be reduced in poorly differentiated adenocarcinomas. Furthermore, some studies[25,26] have reported an inverse relationship between tumor grade and CEA levels among patients with nodal metastases and unresectable disease.

Another consideration is the rate of rise for CEA levels that can vary depending on the site of recurrence. It has previously been proposed that monitoring of serum CEA levels is useful for the detection of liver metastases, yet is not useful for the detection of local recurrence or other types of metastasis[27]. In the present study, patients with CRC metastasis, especially multiple metastases, were associated with higher CEA levels, whereas those with local recurrent CRC had a lower CEA level during recurrence (75.0% vs 36.6%, respectively, P < 0.05). In combination, these results suggest that CEA alone should not determine whether “second-look” surgeries are performed, or whether CT scan or other imaging tools should be required to identify precise sites of recurrence.

As a retrospective study, the limitations associated with this work include the absence of a standard adjuvant therapy protocol and monitoring strategy. For example, CRC monitoring was not at regular time intervals, resulting in a sensitivity bias. In comparison, the cut-off values used to determine elevated CEA levels in other studies have ranged from 3-15 ng/mL[28-30], thereby affecting the sensitivity of serum CEA assays for tumor detection. Furthermore, since CEA levels were found to be associated with T stage and tumor size in the present study, additional large-scale studies are needed to establish the specific cut-off value needed, according to different tumor burden volumes, in order to facilitate the detection of primary and recurrent CRC.

Currently, an ideal tumor marker for CRC is not available[31]. For example, although CEA is a well-known tumor marker for CRC, the detection of serum CEA levels has not proven to be sufficiently sensitive for detecting primary CRC, especially early stage CRC. However, preoperative serum levels have been found to be an independent prognostic factor for patients with CRC following curative resection. Moreover, CRC patients with normal serum levels of CEA have a higher probability of maintaining these levels during CRC recurrence, especially during local recurrence compared with metastasis. Therefore, monitoring of serum CEA levels can facilitate the detection of primary and recurrent CRC; however, this assay must be complemented by other clinical and laboratory assessments.