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10.1245/ASO.2006.03.090
Annals of Surgical Oncology 13:645-650 (2006)
© 2006 Society of Surgical Oncology
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Original Article

Prognostic Effect of Perioperative Change of Serum Carcinoembryonic Antigen Level: A Useful Tool for Detection of Systemic Recurrence in Rectal Cancer

Yoon-Ah Park, MD, Kang Young Lee, MD, Nam Kyu Kim, MD, Seung Hyuk Baik, MD, Seung Kook Sohn, MD and Chang Whan Cho, MD

Department of Surgery, Yonsei University College of Medicine, 134 Shinchon-dong, Seodaemun-ku, Seoul, Korea

Correspondence: Address correspondence and reprint requests to: Kang Young Lee, MD; E-mail: kylee117{at}yumc.yonsei.ac.kr.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: The prognosis of patients even with the same stage of rectal cancer varies widely. We analyzed the capability of perioperative change of serum carcinoembryonic antigen (CEA) level for predicting recurrence and survival in rectal cancer patients.

Methods: We reviewed 631 patients who underwent potentially curative resection for stage II or III rectal cancer. Patients were categorized into three groups according to their serum CEA concentrations on the seventh day before and on the seventh day after surgery: group A, normal CEA level (≤5 ng/mL) in both periods; group B, increased preoperative and normal postoperative CEA; and group C, continuously increased CEA in both periods. The prognostic relevance of the CEA group was investigated by analyses of recurrence patterns and survival.

Results: Stage III patients showed higher systemic recurrence (P = .001) and worse 5-year survival rates (P < .0001) for group C than for groups A and B. On multivariate analysis, the CEA group was a significant predictor for recurrence (P < .001; relative risk, 2.740; 95% confidence interval, 1.677–4.476) and survival (P = .001; relative risk, 2.174; 95% confidence interval, 1.556–3.308).

Conclusions: The perioperative serum CEA change was a useful prognostic indicator to predict for systemic recurrence and survival in stage III rectal cancer patients.

Key Words: Rectal cancer • Perioperative serum CEA change • Recurrence • Prognosis


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Although the pathologic tumor-node-metastasis stage provides the best prognostic information in rectal cancer patients, the prognosis of patients with the same stage of tumor varies widely, especially in those with stage II and III tumors.1–5 To identify a subset of patients at high risk for recurrence, several prognostic factors, including molecular and biochemical markers, have been investigated.6–9 However, the validity of those markers remains controversial, and their clinical application is limited because of their complexity, the difficulties of standardization, and the high cost of measurement.

Carcinoembryonic antigen (CEA) is the most widely used and readily available tumor marker for the management of colorectal cancer. Increased pre-operative serum CEA levels are associated with an increased risk of recurrence and poor prognosis,10–12 and the prognostic effect of serum CEA levels is independent of the tumor-node-metastasis stage.13–15 However, less work has been performed to evaluate the prognostic significance of early postoperative serum CEA levels after curative resection in combination with preoperative measurements, which reflects the patient status after tumor removal. The purpose of this study was to analyze the capability of perioperative changes in the serum CEA level measured in the preoperative and early postoperative period for predicting recurrence and survival in stage II and III rectal cancer patients.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
A total of 715 patients with stage II and III rectal cancer who had undergone potentially curative resection in the Department of Surgery, Yonsei University College of Medicine, from January 1990 to December 1999 were analyzed retrospectively. Rectal cancer was defined as histologically proven adenocarcinoma within 15 cm from the anal verge and was staged according to the 6th edition of the American Joint Committee on Cancer staging system.16 Excluded from this study were 52 patients who underwent preoperative chemotherapy or radiotherapy, because their preoperative serum CEA levels may have been influenced by preoperative treatment, and 32 patients for whom either the preoperative or postoperative serum CEA data were not available. Thus, 631 patients who underwent curative resection without any preoperative treatment for stage II and III adenocarcinoma of the rectum were included in this study.

Serum CEA levels were measured in the preoperative period and on the seventh postoperative day. All assays were performed in one laboratory by use of the CobasCore immunoassay (Boehringer-Mannheim, Mannheim, Germany) from 1990 to 1994 and, thereafter, by the Elecsys 2010 electrochemiluminescence immunoassay (Roche Diagnostics GmbH, Mannheim, Germany) in which the reference range was ≤5 ng/mL. Patients were categorized into three groups according to their serum CEA concentrations on the preoperative and postoperative seventh day: in group A, the value of the preoperative and postoperative CEA was ≤5 ng/mL; in group B, the value of CEA was >5 ng/mL before surgery and ≤5 ng/mL after surgery; and in group C, both the preoperative and postoperative CEA levels were >5 ng/mL.

Patients were followed up every 3 months for the first 3 years after surgery, every 6 months for the next 2 years, and yearly thereafter. Each visit included a medical history, a physical examination, including a rectal examination, and measurement of the serum CEA concentration. Routine radiological examinations consisting of chest radiography, abdominopelvic computed tomography or ultrasonography, whole-body bone scintigraphy, and colonoscopy or double-contrast barium enema were performed 6 months after surgery and annually thereafter, as well as on suspicion of recurrence. The main patterns of recurrence were recorded as the first site of detectable failure at the time of diagnosis. Determination of recurrence was made by clinical and radiological examinations or by histological confirmation. Recurrences were classified into locoregional (disease within the pelvis), systemic (disease outside the pelvis), or combined. The patients were followed up until death or the cutoff date (December 31, 2003). Overall, 10 patients (1.6%) were lost to follow-up. There were two operative mortalities within 30 days of surgery. The median duration of follow-up at the cutoff date was 74.7 months (range, 10.6–167.8 months).

Data analyses were performed by using SPSS version 10.0 for Windows (SPSS, Inc., Chicago, IL). The intergroup comparisons of clinicopathologic variables were performed by using the analysis of variance test for continuous variables and the two-tailed {chi}2 test for discrete variables. The lost cases and operative mortality cases were treated as censored data for the analysis of survival rates. The overall survival rate was estimated and compared according to the Kaplan-Meier method and log-rank test, respectively. Multivariate analyses using logistic regression analysis and Cox’s proportional hazard model were used to identify the independent risk factors that influenced recurrence and survival, respectively. A P value <.05 was considered statistically significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Comparison of Clinicopathologic Features
The clinicopathologic features of the three CEA groups categorized by preoperative and early postoperative serum CEA concentrations are summarized in Table 1Go. The patient distribution in the groups was 381 patients in group A, 166 in group B, and 84 in group C. There were no significant differences among the groups with regard to age, sex, or location of the tumor, whereas tumor size, perirectal fat invasion, and the number of metastatic lymph nodes showed significant differences. Tumor size and perirectal fat invasion were stratified according to preoperative CEA levels. Tumor size was significantly larger for groups B (5.61 cm) and C (5.63 cm) than for group A (5.04 cm; P = .001). Perirectal fat invasion was more common in groups B (94.7%) and C (94.1%) than in group A (90.2%; P < .001). However, the mean number of metastatic lymph nodes was stratified according to postoperative CEA levels, which were higher for group C (5.45) than for groups A (2.46) and B (2.51; P < .001). There was no significant difference in the number of retrieved lymph nodes and adjuvant treatment among the three groups.


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  		TABLE 1. Clinicopathologic features in patients with stage II and III rectal cancer according to CEA groupa
 
Recurrence Patterns According to CEA Group and Risk Factors for Recurrence
Of 268 stage II and 363 stage III rectal cancer patients, 65 (24.3%) and 152 (41.9%) patients developed recurrence, respectively. According to CEA group, 114 (29.9%) group A, 58 (34.9%) group B, and 45 (53.6%) group C patients developed recurrent disease (P < .001; Table 1Go). For stage III patients, systemic recurrence was significantly higher in group C (47.5%) than in groups A (24.4%) and B (22.2%; P = .001), whereas, for stage II patients, no significant difference was observed among the three groups (group A, 13.7%; group B, 13.3%; group C, 28.0%; P = .077). In terms of locoregional recurrence, there was no significant difference among the three groups in stage II (P = .939) and III (P = .420) patients (Figs. 1Go and 2Go). Logistic regression analysis revealed that perirectal fat invasion, lymph node metastasis, and CEA group were correlated independently with postoperative recurrence (Table 2Go).


Figure 1
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  		FIG. 1. Recurrence patterns in patients with stage II rectal cancer according to carcinoembryonic antigen group. There were no significant differences in locoregional (P = .939) and systemic (P = .077) recurrence rates among the three groups.

 

Figure 2
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  		FIG. 2. Recurrence patterns in patients with stage III rectal cancer according to carcinoembryonic antigen group. There were no significant differences in locoregional recurrence rates among the three groups (P = .420). However, the systemic recurrence rate was significantly higher in group C than in groups A and B (P = .001).

 

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  		TABLE 2. Logistic regression analysis of risk factors for recurrence
 
Survival Rate According to CEA group and Predictors for Survival
For stage III patients, group C (35.4%) had a lower 5-year survival rate than groups A (64.1%) and B (54.1%; P < .0001), whereas there was no significant difference among the three groups for stage II patients (P = .552; Figs. 3Go and 4Go). Cox’s proportional hazard model analysis showed that age, histological grade, perirectal fat invasion, lymph node metastasis, and CEA group were the independent prognostic factors (Table 3Go).


Figure 3
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  		FIG. 3. Survival curves in patients with stage II rectal cancer according to carcinoembryonic antigen group. There were no significant differences in 5-year survival rates among the three groups (group A, 79.1%; group B, 71.0%; group C, 66.0%, P = .552).

 

Figure 4
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  		FIG. 4. Survival curves in patients with stage III rectal cancer according to carcinoembryonic antigen group. The 5-year survival rate was significantly lower in group C (35.4%) than in groups A (64.1%) and B (54.1%; P < .0001).

 

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  		TABLE 3. Cox’s proportional hazard model analysis of prognostic factors
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The major findings of this study were that rectal cancer patients who had increased preoperative serum CEA levels could be divided into two groups according to their early postoperative serum CEA level. The patients who had continuously increased serum CEA levels both in the preoperative and early postoperative period showed more frequent systemic recurrence and worse survival rates than those who had increased preoperative but normal early postoperative serum CEA levels in stage III rectal cancer.

The locoregional extent of tumor and the regional lymph node status, assessed pathologically, are the standards for staging and are the most useful criteria to plan treatment, project prognosis, and measure outcomes in colorectal cancer.1,17 However, some patients with the same stage of cancer would show different prognostic outcomes and form a heterogeneous group, as with stage II and III rectal cancer.2–5 For this reason, a large number of potential prognostic factors, including molecular and biochemical markers such as p53, K-ras, microsatellite instability, and thymidylate synthase, have been proposed to aid the traditional staging system.7–9,18 However, the clinical application of these markers is not widely available because the methods of detection are complicated, expensive, and not automated and because the reference ranges are not consistent among the study groups.

CEA is the most widely accepted and frequently used tumor marker worldwide in colorectal cancer, and the method of measurement is standardized, readily available, and not costly. Most studies on CEA in colorectal cancer have focused on the prognostic effect of preoperative CEA levels10–15 and on the usefulness of postoperative CEA monitoring for early detection of recurrence after curative surgery and for assessment of response to chemotherapy in metastatic colorectal cancer.19–22

Previous studies reported that an increased pre-operative CEA level was correlated with a high rate of recurrence and that the degree of elevation was also associated with the outcome of patients with Dukes’ B/C colorectal cancer.10–15 In the College of American Pathologists Consensus Statement in 1999, the prognostic factors in colorectal cancer were categorized according to the strength and reliability of the published evidence in the literature. Preoperative CEA elevation is classified into category I, which includes factors definitely proven to be of prognostic import on the basis of multiple statistically robust published trials and generally used in patient management, together with tumor extent, regional lymph node metastasis, blood or lymphatic vessel invasion, and residual tumor after surgery.23 However, the prognostic significance of early postoperative CEA, which reflects the response to surgical treatment, has not been investigated extensively.

Although a few studies evaluated the relationship between the perioperative serum CEA change and prognosis in colorectal cancer patients, those involved only a small number of patients or included both colon and rectal cancer patients.24,25 Moreover, the time of postoperative blood sampling for CEA measurement was not consistent, ranging from 1 week to 4 weeks after surgery,24,25 a variation that may affect the value of postoperative serum CEA.

In this study, we investigated the prognostic value of the perioperative serum CEA change by assessing preoperative and early postoperative concentrations in patients with stage II and III rectal cancer. This study included only rectal cancer patients and involved a relatively large number of patients. Moreover, all the early postoperative serum CEA concentrations were measured on the postoperative seventh day: a time point that took into account the half-life of CEA26 and reduced the possible effects of adjuvant treatment on the postoperative serum CEA levels. We analyzed the pattern of recurrence based on the CEA group, which was not evaluated in the previous studies. According to our results, the patients with increased preoperative serum CEA levels could be divided into two groups: one with normal serum CEA levels in the early postoperative period (group B) and the other with continuously increased serum CEA levels (group C). For stage III rectal cancer patients, those who had normal postoperative serum CEA levels showed a prognosis similar to that of patients with normal preoperative serum CEA levels, whereas patients with increased preoperative and early postoperative serum CEA levels had more frequent systemic failure and worse survival rates. Although the statistical difference was not significant (P = .077), the patients with stage II disease showed a tendency for systemic failure similar to that of stage III patients. Patients with increased preoperative serum CEA that failed to normalize in the early postoperative period showed frequent systemic recurrence compared with those who had normal preoperative or normal early postoperative serum CEA. The marginal statistical difference might come from the small number of recurrences observed in stage II patients, which could be insufficient to differentiate the high-risk group from the low-risk group for recurrence and death.

In summary, perioperative serum CEA change may be a useful tool for prediction of systemic failure after curative resection in stage III rectal cancer. Our findings suggest that a more accurate prediction of prognosis and systemic recurrence can be obtained from early postoperative serum CEA levels, which reflect the status of curative resection, together with preoperative serum CEA values. During postoperative follow-up, careful attention should be given to stage II and III patients with a high probability of systemic failure based on their perioperative CEA levels. In addition, perioperative serum CEA change can be an aid to sort patients into a more homogeneous group for the application of new treatment strategies.

In conclusion, perioperative serum CEA changes in the preoperative and early postoperative period are predictive of systemic recurrence and prognosis in stage III rectal cancer patients. Early postoperative serum CEA combined with the preoperative value could serve as a useful prognostic indicator.


   ACKNOWLEDGMENTS
 
The authors thank Scott Butler, MD, for his editorial comments. This study was supported by Yonsei University Research Fund of 2002.

Received for publication March 22, 2005. Accepted for publication November 3, 2005.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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