Japanese Journal of Clinical Oncology 30:12-16 (2000)
© 2000 Foundation for Promotion of Cancer Research
Preoperative Carcinoembryonic Antigen Level as an Independent Prognostic Factor in Colorectal Cancer: Taiwan Experience
1Division of Medical Oncology, Department of Medicine and 2Division of Colorectal Surgery, Department of Surgery, Veterans General Hospital–Taipei and National Yang-Ming University School of Medicine, Taipei, Taiwan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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Background: Preoperative carcinoembryonic antigen (CEA) level is considered as a factor predictive of survival in colorectal cancer patients. Patients with normal (<5 ng/ml) or lower preoperative CEA levels were reported to have significantly longer survival. This study was carried out in an effort to evaluate the prognostic significance of preoperative CEA levels of patients with colorectal cancer in Taiwan.
Methods: Between 1990 and 1994, 218 patients with histologically confirmed colorectal cancers were evaluated retrospectively at the Veterans General Hospital–Taipei. All the patients had undergone potentially curative surgery. Patients with metastatic diseases were not included. 5-Fluorouracil-based adjuvant chemotherapy was administered if the patients had Dukes’ C disease. Reference to the Dukes’ classification was according to the classical criteria described in 1932 for carcinoma of the rectum and adapted for use in colonic tumors. Data on gender, age, degree of tumor differentiation, location of the tumor, tumor size, lymph node metastasis, penetration of the bowel wall and preoperative CEA levels were analyzed to determine their association with survival. Blood samples for CEA measurement were taken a few days before operation and were analyzed using the radioimmunoassay method. Multivariate analysis by Cox’s proportional hazards regression model was performed to determine the most important predictors of survival among all of the possible variables.
Results: By univariate analysis, the size of the tumor (p = 0.012), lymph node metastases (p = 0.007), penetration of the bowel wall (p < 0.001) and preoperative CEA levels (p < 0.001) were found to be significant prognostic factors, while gender, age, degree of tumor differentiation and location of the tumor were not significant. By multivariate Cox analysis, lymph node metastases (p = 0.003), penetration of the bowel wall (p = 0.0001) and preoperative CEA levels (p = 0.0001) were found to be independent prognostic factors in colorectal cancer patients.
Conclusions: The data from our study indicate that in addition to lymph node metastases and penetration of the bowel wall, the preoperative CEA levels are also an independent prognostic factor in non-metastatic colorectal cancer patients after curative surgery. This could serve as an appropriate modification to the initial Dukes’ scheme in colorectal cancer.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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Colorectal cancer is among the leading causes of cancer-related morbidity and mortality in Taiwan. Therefore, searching the prognostic factors for survival in colorectal patients is of interest to us. Since its discovery by Gold and Freedman in 1965, the carcinoembryonic antigen (CEA) has been investigated extensively to test its clinical value in the management of colorectal cancer (1). CEA is of no value in colorectal cancer screening because of its lack of sensitivity and specificity (2,3). In general, the clinical value of CEA in the management of colorectal cancer can be divided into two parts: preoperative assessment of the extent and outcome of the tumor and postoperative monitoring of recurrence. The relationship between the preoperative CEA level and survival has been studied previously but without a definite conclusion. It is justifiable to embark on this subject and investigate its possible existence in Taiwanese patients. To determine if the preoperative CEA level is an independent prognostic factor in colorectal cancer, we evaluated 218 patients who had undergone potentially curative resection of the tumor. Several variables, including the preoperative CEA levels, were analyzed through univariate and multivariate methods to determine independent prognostic factors in colorectal cancer patients.
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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Patients
Between 1990 and 1994, 218 patients with histologically confirmed adenocarcinoma of the colon or rectum operated on at the Veterans General Hospital–Taipei were evaluated retrospectively for the study. All the patients had surgically proven Dukes’ A, B or C disease. Patients with metastatic (or Dukes’ D) diseases were not enrolled. Reference to the Dukes classification was according to the classical criteria described in 1932 for carcinoma of the rectum and adapted for use in colonic tumors (4). Astler and Coller’s modification of the Dukes’ scheme was used to subdivide patients on the basis of the depth of penetration into the bowel wall (5). A ‘B1’ or ‘C1’ lesion refers to a tumor that had not penetrated the entire thickness of the bowel wall, whereas a ‘B2’ or ‘C2’ tumor manifested full thickness penetration of the bowel wall. 5-Fluorouracil-based adjuvant chemotherapy was administered for patients with Dukes’ C disease (tumor located in the colon) and Dukes’ B2 or Dukes’ C disease (tumor located in the rectum). Data on gender, age, location of the tumor (colon or rectum), size of the tumor, degree of tumor differentiation, status of lymph node metastases, penetration of the bowel wall and preoperative CEA levels were analyzed to determine their association with survival. Blood samples for CEA measurements were taken a few days before operation. The blood samples were sent to the Department of Nuclear Medicine of the Veterans General Hospital–Taipei and the CEA value was measured using a radioimmunoassay (RIA) kit manufactured by CIS (France). A CEA value of >5 ng/ml was considered abnormal. All patients were followed up until death and the duration from the CEA determination until death was recorded.
Statistical Analysis
Survival curves were constructed by the Kaplan–Meier product limit method and the data were analyzed by a log-rank test using a microcomputer (6,7). A multivariate analysis using Cox’s proportional hazards regression model was then performed to determine the most important predictors of survival among all of the possible variables (8).
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RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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The incidence of abnormal preoperative CEA (>5 ng/ml) in patients with different Dukes’ stages are shown in Table 1. Of the 218 patients, 103 (47%) had elevated CEA levels of >5 ng/ml. A higher incidence of abnormal CEA level was found in Dukes’ C disease than in Dukes’ B and A diseases. The incidence of preoperative CEA >5 ng/ml in Dukes’ A, B and C diseases were 25, 39 and 71%, respectively. The median survival for all patients with preoperative CEA <5 and >5 ng/ml were 106 months and 47 months, respectively (p < 0.0001). The results for the analysis of prognostic factors in this study are given in Table 2. By univariate analysis, the size of the primary tumor (p = 0.012), lymph node metastases (p = 0.007), penetration of the bowel wall (p < 0.001) and preoperative CEA levels (p < 0.001) were found to be significant prognostic factors. Degree of tumor differentiation, primary sites of the tumor (colon or rectum), age and gender were not significant. By multivariate Cox analysis, lymph node metastases (p = 0.003), penetration of the bowel wall (p = 0.0001) and preoperative CEA levels (p = 0.0001) were proved to be independent prognostic factors. Preoperative CEA level was among the two ‘best’ predictors of survival (p = 0.0001). Patients with preoperative CEA levels of <5 ng/ml had significantly longer survival than those with preoperative CEA levels of >5 ng/ml (Fig. 1). The situation was especially evident in patients with Dukes’ C1 and C2 diseases (Figs 2 and 3). However, in Dukes’ A, B1 and B2 diseases, the above-mentioned relationship between preoperative CEA and survival was not significant (Figs 4, 5, 6).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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Since the first description in 1965 by Gold and Freedman (1), CEA has remained the most thoroughly investigated tumor marker. The clinical value of CEA in the management of colorectal cancers can be divided into two parts: preoperative assessment of the extent and outcome of the tumor and postoperative monitoring of recurrence. Measurement of the CEA level is not a useful test for screening early and potentially curable colorectal cancer because it lacks sensitivity and specificity.
Many workers have shown that preoperative serum CEA levels correlate with the extent of colorectal cancer (9,10). In 1994, Wang et al. reported 318 patients with colorectal cancer staged from Dukes’ A to D (9). Of these, 133 (42%) had elevated preoperative CEA levels. They identified that the incidence of preoperative CEA levels of >5 ng/ml in Dukes stages A, B, C and D diseases are 0, 32, 48 and 79%, respectively. Similarly, in a report by Ladenson et al., a total of 203 patients with colorectal cancer were enrolled and the authors identified that the incidence of preoperative CEA >5 ng/ml in Dukes’ A, B, C and D diseases were 3, 25, 45 and 65%, respectively (10). The current study confirmed this observation. In our study, the incidence of preoperative CEA >5 ng/ml in Dukes’ A, B and C diseases were 25, 39 and 71%, respectively. The Dukes’ stage is the most important predictor of survival in colorectal cancer and the incidence of abnormal preoperative CEA levels is higher in advanced colorectal cancer (Dukes’ C) than in early-stage diseases (Dukes’ A and B). Whether elevated preoperative CEA levels can serve as an ‘independent’ prognostic factor in colorectal cancer is of interest to us.
In 1978, Wanebo et al. firstly reviewed 172 patients with colorectal cancer treated at the Memorial Sloan Kettering Cancer Center and reported the relationship between preoperative CEA and survival (11). They found that the recurrence rate was higher in patients with Dukes’ B and C diseases who had preoperative CEA levels >5 ng/ml. Wolmark et al. analyzed 706 Dukes’ B and C patients who entered into the clinical trials of the National Surgical Adjuvant Breast and Bowel Project (12). They found that the relative risk of treatment failure for patients with a preoperative CEA value >10 ng/ml compared with those with a CEA value <2.5 ng/ml was 3.24 (p = 0.003) in Dukes’ B lesions and 1.76 (p = 0.05) in Dukes’ C lesions. Chu et al. studied 425 patients and found that the preoperative CEA levels significantly affected the survival rates in their patients with TNM stage II and III disease (p = 0.003 and 0.04 for stage II and III diseases, respectively) (13). Using Cox’s multivariate regression analysis, they confirmed that preoperative CEA levels were independent of stage and other prognostic variables.
Some investigators have reported that higher preoperative CEA levels are associated with poorer prognosis only in Dukes’ C disease. Goslin et al. (14) studied 113 patients who had undergone curative resection with follow-up for 36–72 months. They did not find an adverse impact of abnormal CEA level on survival among 65 Dukes’ B patients. However, the recurrence rate correlated significantly with preoperative CEA value (p < 0.005) among their Dukes’ C group. Similarly, Lewi et al. (15) studied 217 Dukes’ B and C colorectal cancer patients and found that there was no consistent correlation between survival and preoperative CEA values in patients with Dukes’ B disease (p = 0.65). However, in the Dukes’ C patients, a preoperative CEA value of >10 ng/ml was associated with a significantly decreased 5-year survival rate (p < 0.05). In contrast, after reviewing 563 colorectal cancer patients, Staab et al. (16) reached a different conclusion. They reported that the differences between survival curves based on preoperative CEA ranges of <5 and >5 ng/ml are significant for patients with TNM stage II tumors (p < 0.02) but not for patients with lymph node metastasis (p = 0.1).
A study by the Gastrointestinal Tumor Study Group concluded that only in patients with one to four lymph nodes involving preoperative CEA values of >5 ng/ml are associated with a significantly greater risk of recurrence (42 vs 14%, p < 0.02) (17). Moertal et al. studied 272 patients who had undergone resection at the Mayo Clinic. They argued that preoperative CEA was a significant and independent prognostic determinant only in patients with involvement of four or more lymph nodes. In this group (n = 29), the 5-year survival rates for patients with CEA levels <10 ng/ml was 37% compared with no survivors among patients with CEA > 10 ng/ml (p = 0.028) (18). However, in a later study of the same patient group using Cox’s multivariate analysis model, Scott et al. reported a preoperative CEA level of >10 ng/ml to be an independent prognostic variable (p = 0.027) (19).
There are several reasons that may account for such confusing and even contradictory results. First, some reports with negative results did not have a large enough sample size after stratification. Second, the different statistical methods used may have resulted in different conclusions. Third, different definitions of abnormal CEA levels or different CEA kits were used. The current study of 218 patients treated at a single institution confirmed that an elevated preoperative CEA level of >5 ng/ml is associated with a poorer prognosis only in Dukes’ C colorectal cancer.
Besides malignant diseases, elevated serum CEA levels >5 ng/ml are frequently found in other benign disorders. For example, smokers have been reported to have a higher circulating CEA concentration than non-smokers (20). Furthermore, because the liver is the major site for clearance of CEA, moderate to significant elevation of serum CEA levels can be observed in a variety of benign liver diseases, including hepatitis, cirrhosis, cholelithiasis, obstructive jaundice and cholangitis (20). There is a high prevalence of hepatitis B virus infection in Taiwan. Whether an elevated preoperative CEA level is an independent prognostic factor in colorectal cancer or a factor associated with hepatobiliary disorders is of interest to us. In our study, survival analysis was carried out to identify the influence on survival of impaired liver function tests, hepatobiliary tract diseases and smoking habit. Using univariate analysis, the above-mentioned factors were not identified as having significant influence on survival (Table 2).
In our study, besides preoperative CEA levels, the existence of penetration of the bowel wall was identified as another independent prognostic factor of colorectal cancer. The Dukes’ classification scheme proposed in 1932 failed to subdivide patients with positive nodes on the basis of the depth of tumor penetration. At the time of formation of the Dukes’ classification, it was commonly believed that lymph node metastases occurred only when there was full thickness penetration of the bowel wall and once nodal metastases were in evidence, it was theorized that the depth of tumor penetration was of little prognostic significance. By introducing a subdivision of the Dukes’ C category, Astler and Coller clearly found that tumors with penetration of the bowel wall had a poor prognosis that was independent of the presence of nodal metastases (21). According to their definition, a ‘C1’ lesion referred to a tumor that had not penetrated the entire thickness of the bowel wall, whereas a ‘C2’ tumor manifested full thickness penetration. In our study, by multivariate analysis, patients with penetration of the bowel wall survived significantly shorter than those without bowel wall penetration (p = 0.0001).
In summary, the data from our study indicate that preoperative CEA level is an independent prognostic factor in colorectal cancer. The relationship is especially evident in Dukes’ C disease. In our opinion, preoperative CEA levels could serve as appropriate modifications of the initial Dukes’ scheme. It is recommended that stratification for further clinical trials in colorectal cancer patients should be carried out according to preoperative CEA levels.
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Acknowledgments |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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This work was supported by a grant from the Yen Tjing-Ling Medical Foundation.
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FOOTNOTES |
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+ For reprints and all correspondence: Po-Min Chen, Division of Medical Oncology, Department of Medicine, Veterans General Hospital–Taipei, Taipei 11217, Taiwan. E-mail: pmchen@vghtpe.gov.twAbbreviations: CEA, carcinoembryonic antigen; LFT, liver function test; RIA, radioimmunoassay
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REFERENCES |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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Received August 9, 1999; accepted October 7, 1999.
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