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1 Department of Nuclear Medicine, St Vincent’s University Hospital, Dublin 4, and Department of Surgery and Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin 4, Ireland.
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Abstract |
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 Top Abstract IntroductionStructure and Biological...Factors Affecting Serum CEA...CEA as a Marker...Surveillance of Patients with...Monitoring Chemotherapy in...ConclusionReferences |
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Methods: The literature relevant to the clinical value of CEA in colorectal cancer was reviewed. Particular attention was paid to studies involving metaanalyses and guidelines issued by Expert Panels.
Results: Although of little use in detecting early colorectal
cancer, high preoperative concentrations of CEA correlate with adverse
prognosis. Serial CEA measurements can detect recurrent colorectal
cancer with a sensitivity of 
80%, a specificity of 70%, and can
provide a lead time of 5 months. CEA is the most frequent indicator
of recurrence in asymptomatic patients and currently is the most
cost-effective test for the preclinical detection of resectable
disease. CEA is most useful for the early detection of liver metastasis
in patients with diagnosed colorectal cancer. Overall, however, little
evidence is available that monitoring of all patients with diagnosed
colorectal cancer leads to enhanced patient outcome or quality of life.
Conclusions: Currently, the most useful application of CEA is in the detection of liver metastasis from colorectal cancers. Because of the relative success of surgery in resecting hepatic metastases, serial determinations of the marker are recommended for detecting cancer spread to the liver. In the future, preoperative concentrations of CEA may be included with the standard staging procedures for assessing prognosis.
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Introduction |
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TopAbstractIntroductionStructure and Biological...Factors Affecting Serum CEA...CEA as a Marker...Surveillance of Patients with...Monitoring Chemotherapy in...ConclusionReferences |
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In one of the first reports on CEA in serum, Thomson et al. (4) found increased concentrations in 35 of 36 patients with colorectal cancer. In contrast, high values were not found in "normal" subjects, pregnant women, patients with nongastrointestinal cancers, or in patients with miscellaneous benign gastrointestinal diseases.
Although these findings were not confirmed, they nevertheless prompted widespread use of CEA as a marker for colorectal cancer. Thirty years after its initial detection in serum, CEA is one of the most widely used tumor markers worldwide and certainly the most frequently used marker in colorectal cancer. The aim of this report is to provide a critical and updated review on the value of CEA as a marker for colorectal cancer, with a introductory discussion on the structure and biological function of the CEA molecule.
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Structure and Biological Function of CEA |
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TopAbstractIntroductionStructure and Biological...Factors Affecting Serum CEA...CEA as a Marker...Surveillance of Patients with...Monitoring Chemotherapy in...ConclusionReferences |
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When isolated from liver metastasis, CEA is a glycoprotein
consisting of 60% carbohydrate and a molecular mass of
180–200 kDa (5). CEA exhibits considerable
heterogeneity, which appears to be attributable to variations in its
carbohydrate side chains (5). Most of the carbohydrate is
composed of mannose, galactose, N-acetylglucosamine, fucose,
and sialic acid (5).
As mentioned above, CEA is a member of the immunoglobulin superfamily. Two types of immunoglobulin domains are found: an N-terminal domain of 108 amino acids homologous to the immunoglobulin variable domain (IgV-like) and six domains homologous to the immunoglobulin constant domain of the C-2 set (IgC2-like) (6)(7). CEA is attached to the cell membrane by a glycosyl phosphatidylinositol anchor and probably is released as a soluble form by a phospholipase C or phospholipase D (6).
Structural similarity of CEA to certain immunoglobulin-related proteins, such as ICAM-1 and ICAM-2, initially suggested that CEA might act as an adhesion molecule. In vitro experiments showed that CEA was capable of both homophilic (CEA binding to CEA) and heterophilic (CEA binding to non-CEA molecules) interactions (6)(7)(8). Because alterations in cell adhesion are causally involved in cancer invasion and metastasis, it was further suggested that CEA may play a role in these processes (8). Evidence for a role in cancer dissemination was obtained recently by Hostetter et al. (9), who showed that after transplantation of colorectal tumors into nude mice, the number of liver metastases increased from 2% to 48% following injection of mice with CEA. There is, however, no direct evidence that CEA is causally involved in cancer dissemination.
Although in vitro data implicate CEA in cell adhesions (6)(7), its localization to the apical surface of mature enterocytes in healthy human colon is difficult to reconcile with this role. In the healthy colon, CEA has been found to bind certain strains of Escherichia coli. According to Thompson et al. (6), this binding may facilitate bacterial colonization of the intestine. Hammarstrom (7), on the other hand, suggested that CEA may play a role in protecting the colon from microbial infection, possibly by binding and trapping infectious microorganisms.
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Factors Affecting Serum CEA Concentrations in Patients with Colorectal Cancer |
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TopAbstractIntroductionStructure and Biological...Factors Affecting Serum CEA...CEA as a Marker...Surveillance of Patients with...Monitoring Chemotherapy in...ConclusionReferences |
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tumor grade
Several studies have shown that well-differentiated colorectal
cancers produce more CEA per gram of total protein than poorly
differentiated specimens (11)(12). For example,
in a recent report (12), mean concentrations of CEA in
well-differentiated, moderately differentiated, and poorly
differentiated colorectal neoplasms were 18.0, 5.5, and 2.2 µg/g of
protein, respectively. Similarly, serum concentrations of CEA tend to
be higher in patients with well-differentiated tumors compared with
those with poorly differentiated tumors (13). A lack of
differentiation or poor differentiation may explain why some patients
with advanced colorectal cancer do not have increased serum CEA values.
liver status
The liver is the primary site for the metabolism of CEA.
Initially, uptake occurs in the Kupffer cells, which modify CEA by
removing its sialic acid residues (5). The asialo CEA is
then endocytosed by liver parenchymal cells where it is degraded
(5). Certain benign liver diseases impair liver function
and, thus, the clearance of CEA. Consequently, CEA can be increased in
serum from patients with nonmalignant liver disease
(5)(14).
tumor site within the colon
Patients with tumors in the left side of the colon generally have
a higher incidence of increased CEA concentrations than those with
malignancies on the right-hand side of the colon
(10)(15).
presence or absence of bowel obstruction
Sugarbaker (16) showed that bowel obstruction per se
gives rise to higher CEA concentrations in patients with colorectal
malignancy. Decompression alone reduced serum CEA values
(16).
smoking
In a recent study of >700 apparently healthy volunteers, the
median CEA values for male smokers and nonsmokers were 6.2 and 3.4
µg/L, respectively. The median concentrations for female smoker and
nonsmokers were 4.9 and 2.5 µg/L, respectively (17). Thus,
smoking appears to almost double the serum concentration of CEA.
ploidy status of tumor
Patients with aneuploid colorectal cancers have been shown to
produce higher concentrations of CEA than those with tumors with a near
diploid pattern (18).
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CEA as a Marker for Colorectal Cancer |
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TopAbstractIntroductionStructure and Biological...Factors Affecting Serum CEA...CEA as a Marker...Surveillance of Patients with...Monitoring Chemotherapy in...ConclusionReferences |
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diagnosis
As in screening, lack of sensitivity and specificity limit the
application of CEA in diagnosing colorectal cancer, especially early
disease. As mentioned above, at a cutoff of 2.5 µg/L, sensitivity
ranges from 30% to 80%, depending on the stage of disease.
However, as pointed out by Fletcher (19), sensitivity in
symptomatic subjects is likely to be higher than in asymptomatic
patients because the former group is likely to have more advanced
disease.
Regarding specificity, it is important to mention that CEA can be increased in most types of advanced adenocarcinomas as well as in multiple benign disorders (14)(21). Frequently, the benign conditions with increased concentrations are disorders that require differentiation from cancer. Benign diseases, however, only rarely give rise to serum values >10 µg/L. Therefore, in patients with appropriate symptoms, a highly increased concentration (e.g., >5 times the upper limit of normal) should be considered strongly suggestive for the presence of cancer in that particular patient (22). In this situation, which is likely to be found in the presence of advanced disease, additional tests are necessary to establish a definite diagnosis (22).
assessing prognosis
The Dukes’ staging system, either in its original form or as one
of its modifications (Table 1
), has for many decades been the gold standard for predicting
outcome in patients with newly diagnosed colorectal cancer [for
review, see Ref. (23)]. For a new prognostic factor to be
clinically useful in colorectal cancer it should (a) provide
information that is independent of existing staging systems,
(b) be a stronger indicator of patient outcome than the
existing systems, or (c) provide prognostic information
within the subgroups of the existing systems. Additional prognostic
factors are particularly required for the Dukes’ B (stage II or
node-negative) category of patients. Approximately 40–50% of patients
from this subgroup have aggressive disease and thus might benefit from
adjuvant chemotherapy. Although several studies have shown that
adjuvant chemotherapy extends survival in Dukes’ C colon cancer
patients, the effectiveness of this therapy is less clear for the
Dukes’ B group (20). Rather than administer adjuvant
chemotherapy to all patients with Dukes’ B disease, it would be
desirable to have a marker capable of differentiating patients with
aggressive from those with indolent disease within this group. Patients
with aggressive disease could then be considered for treatment with
adjuvant chemotherapy, whereas those likely to have a good outcome
could be spared the costs and side effects of the cytotoxic agents.
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Multiple studies have shown that patients with high preoperative
concentrations of CEA have a worse outcome than those with low
concentrations of the marker [for review, see Refs.
(24)(25)]. In at least seven different reports,
the prognostic impact of the marker was investigated in either
node-negative or Dukes’ B patients (10)(26)(27)(28)(29)(30)(31)
(Table 2
). In five of these
(10)(26)(28)(30)(31),
including the only two prospective studies
(30)(31), high CEA concentrations predicted
adverse prognosis. In the remaining two
(27)(29), however, no significant relationship
was found between marker concentrations and patient outcome. In one of
these negative studies (27), only a subset of the Dukes’ B
patients was analyzed, i.e., those with stage B2 disease or where tumor
invaded into or through the serosa or perirectal fat. In the other
negative study (29), although CEA alone was not prognostic
in Dukes’ B patients, when combined with CA 242, the two markers
together yielded significant prognostic information in this subgroup of
patients. Thus, the majority of studies suggest that preoperative CEA
can provide prognostic data in patients with Duke’s B colorectal
cancer. CEA may thus be able to help identify the subset of patients
with aggressive disease who might benefit from adjuvant chemotherapy.
However, it is important to point out that there currently are no
reports showing a benefit from the use of adjuvant therapy based solely
on an increased preoperative CEA concentration.
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It is of interest that the American Joint Committee on Cancer at a recent Consensus Conference suggested that CEA be added to the TNM staging system for colorectal cancer (31)(32). The CEA concentration should be designated as follows: CX, CEA cannot be assessed; CO, CEA not increased (<5 µg/L) or CEA1, CEA increased (>5 µg/L). It should be pointed out that these suggestions were for the purpose of discussion only and are not yet formal proposals (31)(32).
A College of American Pathologists Expert Groups ranked preoperative serum CEA concentration as a category I prognostic marker for colorectal cancer (33). Category I factors include those "definitely proven to be of prognostic import based on evidence from multiple statistically robust published trials and generally used in patient management". Also included in the category I group were local extent of tumor assessed pathologically (i.e., TNM staging), regional lymph node metastasis, blood or lymphatic vessel invasion, and residual tumor following surgery with curative intent (33).
Although less work has been carried out to investigate the prognostic value of postoperative CEA concentrations, the available evidence suggests that high concentrations at this time also predict adverse outcome. After successful surgical resection of colorectal cancer, an increased CEA concentration should return to normal within 4–6 weeks (34). Failure of an increased preoperative value to decrease to normal concentrations within 6 weeks of surgery frequently is associated with early recurrent disease (34).
CEA may also provide prognostic data in patients who develop liver
metastasis following curative resection for colorectal cancer. The
liver is the main site for metastatic disease from colorectal cancer,
with 60% of patients developing metastasis in this organ
(35). In 40% of patients who die from colorectal cancer,
the liver appears to be the only site of metastatic disease
(35). Approximately 25% of these patients are candidates
for hepatic resection, and the 5-year survival for patients who undergo
surgery is 21–48% (36). Hepatic resection is thus the most
successful and currently the only potential curative form of treatment
for metastatic colorectal cancer (36).
Unfortunately, 50–80% of patients who undergo hepatic resection
develop further recurrences. It is therefore important to have
preoperative prognostic factors that might predict those patients
likely to develop recurrent disease. In a review of the literature,
Cromheecke et al. (36) (Table 3
) found that high concentrations of preoperative CEA predicted a
poor outcome in 8 of 11 studies reviewed. High concentrations of CEA
1–3 months after hepatectomy has also been shown to correlate with
adverse prognosis (37)(38).
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Surveillance of Patients with Diagnosed Colorectal Cancer |
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TopAbstractIntroductionStructure and Biological...Factors Affecting Serum CEA...CEA as a Marker...Surveillance of Patients with...Monitoring Chemotherapy in...ConclusionReferences |
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80% (range, 17–89%) and specificity of 70%
[range, 34–91%; for review, see Ref. (19)]. The wide
ranges of sensitivities and specificities are likely to be attributable
to factors such as frequency of CEA assay and definition of a CEA
increase. 60% (30). Despite this
limited sensitivity for locoregional disease, Pietra et al.
(41) recently showed in a prospective randomized trial that
CEA was superior to endoscopy, computerized tomography, and ultrasound
in diagnosing local recurrences. On the basis of the above findings, we can conclude that CEA currently is the most cost-effective and sensitive method for diagnosing recurrent disease in patients with previously diagnosed colorectal cancer. An important question therefore is: do these results justify the routine assay of CEA in patients who undergo curative resection for colorectal cancer? To answer this question it would be necessary to carry out a large prospective randomized trial comparing patient outcome, quality of life, and cost of care in patients with and without CEA monitoring. To my knowledge, results from such a study have never been published.
In the absence of data from a large randomized trial, a metaanalysis of small randomized or nonrandomized studies provides the most reliable data. In 1998, Rosen et al. (43) reported the results of such an analysis based on a review of the published literature from 1972 to 1996. The aim of this study was to compare outcomes in patients with intensive follow-up vs those with no follow-up. Intensive follow-up was defined as (a) at least history, physical examination, and serial CEA assays; (b) an interval for these follow-up periods of at least three times per year for the first 2 years; and (c) mean follow-up after initial resection of at least 2 years. The control group had no routine follow-up, with physicians responding only to changes in symptoms. From the literature review, two randomized and three comparative cohort studies, comprising 2005 patients, met the above criteria. After evaluation in a metaanalysis, the following conclusions emerged:
Although this metaanalysis concluded that intensive follow-up diagnosed a greater number of resectable recurrences and led to enhanced patient outcome, it did not investigate the specific benefit of CEA. However, in a separate metaanalysis based on seven nonrandomized studies with a total of 3283 patients, Bruinvels et al. (44) showed that patients who underwent intensive follow-up had a 9% better 5-year survival rate than those with minimal or no follow-up only when the intensive follow-up group had CEA assayed.
The value of CEA, or indeed of any other procedure for the preclinical
detection of recurrent/metastatic disease, depends primarily on whether
outcome is improved as a result of early diagnosis. As mentioned above,
hepatic resection for isolated liver metastasis achieves long-term
survival in 20–50% of patients and may be the only curative
therapy for metastatic colorectal cancer. Because of the success of
surgery in treating liver metastasis from colorectal cancer, an
American Society of Clinical Oncology panel recommended CEA
monitoring in "only those patients who would be willing and able to
undergo a hepatic resection for recurrent disease" (25).
For this subset of patients, it was recommended that CEA testing be
performed every 2–3 months for at least 2 years after diagnosis.
Testing was to be confined to those patients with stage II (Dukes’ B)
and III (Dukes’ C) disease. Patients with Dukes’ A disease were
excluded from CEA monitoring because the probability of developing
recurrences is low in this subgroup.
Finally, it is important to address (a) the proportion of
patients who are likely to benefit from CEA monitoring, and
(b) the cost of this monitoring. On the basis of the
assumptions that 50% of patients with colorectal cancer develop
liver metastasis, that 25% of these patients are candidates for
resection, and that 25% of these have 5-year survival rates,
Ballantyne and Modlin (45) calculated that at most only 3%
of patients with colorectal cancer benefit from surgical resection of
liver metastasis. Similar conclusions were also reached by other
authors (46)(47).
Regarding costs, Kievit and van de Velde (48) in 1990 concluded that monitoring with CEA provided a minor improvement in survival but at a high cost ($22 936 to $4 888 208 per quality-adjusted life-years saved). A further analysis in 1999 estimated a cost of $500 000 per cure of recurrence (49). Despite these apparently high costs, it is important to point out that monitoring with CEA is likely to be cheaper and more convenient to patients than either radiology or endoscopy.
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Monitoring Chemotherapy in Patients with Advanced Disease |
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TopAbstractIntroductionStructure and Biological...Factors Affecting Serum CEA...CEA as a Marker...Surveillance of Patients with...Monitoring Chemotherapy in...ConclusionReferences |
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Despite this, an American Society of Clinical Oncology Panel (25) recommended the following with respect to the use of CEA in monitoring therapy in patients with advanced colorectal cancer: (a) a baseline CEA value before treatment; and (b) serial monitoring every 2–3 months while on active treatment (if no other simple test is available to indicate a response). According to the Panel, two values above the baseline are adequate to document progressive disease and discontinuation of therapy, even in the absence of corroborating radiological evidence.
It is important to mention that administration of fluorouracil-based therapy can cause transient increases in CEA concentrations in the absence of disease progression. For example, in a study by Moertel et al. (53), among 99 patients who developed liver toxicity while on chemotherapy, 19 had false-positive CEA increases. These CEA values ranged from 5.1 to 34 µg/L and returned to normal after cessation of therapy.
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Conclusion |
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TopAbstractIntroductionStructure and Biological...Factors Affecting Serum CEA...CEA as a Marker...Surveillance of Patients with...Monitoring Chemotherapy in...ConclusionReferences |
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The question therefore remains whether CEA should be used in the surveillance of patients who have undergone curative resection for colorectal cancer. According to Macdonald (54), monitoring may be of benefit if the subject is a potential candidate for aggressive curative surgery if metastases were to develop. It was mentioned above that removal of liver metastases from patients with no extra metastatic deposits produces 5-year survivals of 21–48%. Consequently, the American Society of Clinical Oncology Guidelines have recommended CEA monitoring in patients if resection of liver metastasis would be clinically indicated.
Finally, it should be mentioned that most of the data relating to the use of CEA in the follow-up of patients with colorectal cancer were obtained before the relatively widespread use of chemotherapy for this malignancy. In recent years, both chemotherapy for metastatic disease and adjuvant chemotherapy for patients with Dukes’ C malignancy have found increasing use. Currently, there is no evidence that monitoring these patients with CEA values enhances prognosis. However, should more effective chemotherapy for colorectal cancer become available or should there be an increase in the use of second-line chemotherapy in the future, it is likely that CEA would be used more widely to monitor its effects.
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Footnotes |
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References |
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TopAbstractIntroductionStructure and Biological...Factors Affecting Serum CEA...CEA as a Marker...Surveillance of Patients with...Monitoring Chemotherapy in...ConclusionReferences |
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