Refer to: Lee Y-T N: Carcinoembryonic antigen in patients with breast or colon cancer. West J Med 129:374-380, Nov 1978
Carcinoembryonic Antigen in Patients With Breast or Colon Cancer YEU-TSU N. LEE, MD, Los Angeles
The rationale and results of clinical use of carcinoembryonic antigen (CEA) tests in patients with carcinoma of the breast and colon deserve review. Plasma CEA levels have been found to correlate with the extent of tumor invasion and site of metastatic spread, and CEA titers have diagnostic and prognostic value. Although postresectional serial CEA testing is not as useful in cases of breast carcinoma, in cases of carcinoma of the colon it may indicate recurrence or progression of the lesion. However, there are limitations and CEA results should be interpreted in conjunction with other clinical information. THE TERM carcinoembryonic antigen (CEA) was first used in 1965 by Gold and Freedman' to describe an antigen present in extracts of colonic adenocarcinoma and digestive organs of human embryos. When they noted elevated levels of CEA in plasma in 36 of 37 advanced colon carcinoma cases, it was hoped that a specific test for cancer of the colon had been discovered. This proved not to be the case, as subsequent investigation indicated the presence of CEA in nonentodermal tumors as well as in various nonneoplastic diseases. CEA is a glycoprotein and consists of 45 percent protein and 55 percent carbohydrate. It has a molecular weight of about 200,000 with betaelectrophoretic mobility in immunoelectrophoreSiS. CEA is a constituent of the mucus which is normally secreted into the lumen by epithelial cells of the gastrointestinal tract. As the normal tissue architecture is disrupted, the CEA is released From the Department of Surgery, University of Southern California Medical School and the Tumor Surgery Service, LAC-USC Medical Center, Los Angeles. Submitted, revised, May 1, 1978. Reprint requests to: Yeu-Tsu N. Lee, MD, Dept. of Surgery, USC School of Medicine, 1200 North State Street, Los Angeles, CA 90033.
374
NOVEMBER 1978 * 129 * 5
into underlying tissue and diffuses into the vascular or lymphatic channels. Rapid cellular proliferation and disruption of basement membranes explains the presence of elevated circulating CEA levels in patients with entodermal and nonentodermal malignancies, with various nonmalignant metabolic or inflammatory diseases,2 in surgical trauma and in cases of heavy smoking.3 From 1971 to 1974, the CEA test was evaluated extensively in a collaborative study of 35,000 assays in more than 11,000 patients from over 100 medical institutions. The result showed that 97 percent of healthy nonsmoking subjects had titers of 2.5 ng per ml or below, none above 5 ng per ml (Table 1). Even among chronic smokers (more than one pack a day for at least ten years), 4 percent had CEA titers above 5 ng per ml and only 1 percent over 10 ng per ml. After cessation of smoking, elevated CEA levels declined to nonsmoker range within three months.3 In the absence of malignant disease, CEA titers greater than 5 ng per ml were associated with such conditions as pulmonary emphysema, alcoholic cirrhosis, ulcerative colitis, regional ileitis, granulomatous colitis, gastric and duodenal ulcers,
CARCINOEMBRYONIC ANTIGEN TABLE 1.-Distribution of CEA Levels Among 2,107 Healthy Volunteers* CEA Levels Numnber 2.5 ng >5 ng >10 ng of per ml per ml per ml per ml Patients (Percent) (Percent)(Percent) (Percent)
Condition
Pregnancy Nonsmokers Former smokers Presently smoking ....
.
360 892 235 620
96 97 93 81
4 3 6 18
1 0 2 4
0 0 1 1
2,107
92
8
2
0.5
TABLE 3.-Distribution of CEA Levels Among 1,343 Patients With Carcinoma (All Stages)* Number 2.5 ng >5 ng >10 ng per ml per ml per ml per ml of Patients (Percent) (Percent) (Percent) (Percent)
Entodermal carcinoma Gastric carcinoma Colorectal carcinoma
859 79
27 39
72 61
48 29
31 19
544
28
72
49
35
carcinoma 181 Pancreatic carcinoma .... 55 Nonentodermal carcinoma 468 Breast carcinoma 125 Head and neck carcinoma 128 Other carcinoma . 215
24
76
50
25
9
91
61
35
52 53
48 47
22 27
9 14
48 53
52 47
19 21
5 9
Overall
35
65
38-
23
....
....
Pulmonary ....
CEA = Carcinoembryonic antigen
'Adapted from CEA-Roche Assay, Hoffman-La Roche,
19748
Inc.
....
TABLE 2.-Distribution of CEA Levels Among 3,340 Patients With Nonmalignant Disease* CEA Levels Number 2.5 ng >5 ng > 10 ng of per ml per ml per ml per ml Patients (Percent) (Percent)(Percent) (Percent)
Diagnosis Breast
lesions
115 166 94 39 90 84 146 126
Duodenal ulcer . Gastric ulcer Cholecystitis .... Colorectal polyps Diverticulitis .... Ulcerative colitis Regional ileitis Granulomatous colitis ....... 59 Alcoholic cirrhosis 120 Pulmonary 49 emphysema Otherst. 2,281 ...
...
3,340
85 70 55 77 81
15 30 45 23
4
0
2
19
8 16 6 4
63
37
13
60
40
13
1
1,343
........
CEA = Carcinoembryomic antigen
*Adapted from CEA-Roche Assay, Hoffman-La Roche, Inc. 19748
1
1 2
2
53
47
20
5
29
71
26
2
43
57
20
4
69
31
8
1
67
33
9
1
CEA = Carcinoembryonic antigen
'Adapted from CEA-Roche Assaay, Hoffman-La Roche, Inc. 19748 include heartt disease (289), diabetes (230), myasthenia gravis (183), hyperten sion (156), osteoarthritis (112), pancreatitis (95), and bronchitis (
tMajor categories
....
(61).
release of the obstruction, provided persistent biliary inflammation or liver abscess does not supervene. Some of the elevated CEA levels in patients with inflammatory bowel disease may be due in part to coexisting liver disease. Elevated levels commonly accompany alcoholic pancreatitis. Therefore, correct clinical interpretation requires concomitant assessment of liver status.6'7 In January 1974 reagents for the CEA assay (patented by Hoffman-La Roche) became the first
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immunoassay procedure the colorectal polyps and divierticulitis (Table 2). It is important to note th at most of the "falselevels tend positive" elevations of cir to be lower than those fo und in conditions (Table 3). And ma ny of the nonmalignant conditions associated wit positive assays show transient rather than pers;istent elevations of levels. For instance, CEA titers in patients with nonmalignant colonic pi inflammatory disease usually drop to below 2.5 ng per ml when the polyps are rese.cted diseases in remission.45 More than any other c benign disease, liver disease (especially se alcoholic cirrhosis) levels. Perhaps may cause mildly elevat ed half the patients with beniign obstructive jaundice have elevated CEA titers Nwhich fall after surgical
approved by
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THE WESTERN JOURNAL OF MEDICINE
375
CARCINOEMBRYONIC ANTIGEN
It is emphasized that the CEA test should not be used for screening purposes to detect cancer in the general population. CEA titers are not an absolute test for malignancy, nor for a specific type of malignancy. And CEA levels less than 2.5 ng per ml do not preclude the presence of primary, recurrent or metastatic cancers (Table 3). However, very high CEA levels (above 20 ng per ml) usually indicated metastatic disease. In patients with documented cancer, it is reported that monitoring the level of CEA in the circulation before and after therapy may be useful. In general, decreases in CEA titers were associated with effective therapy. A persistent increase in titers was associated with a lack of response to therapy or a recurrence of disease; in some cases, the titer rise preceded clinical signs for several months. Since CEA tests have been used widely for purposes of follow-up studies in patients with malignant lesions of the breast and colorectum, their rationale, results and limitations are reviewed here in detail.
CEA in Patients With Breast Cancer In the Roche collaborative study, among 115 patients with benign breast diseases, 15 percent had titers of CEA above 2.5 ng per ml, none above 10 ng per ml (Table 2). Among 125 patients with various stages of carcinoma of the breast, 47 percent had CEA levels above 2.5 ng per ml, 27 percent above 5 ng per ml, and 14 percent above 10 ng per ml (Table 3). In general, CEA levels in patients with breast cancer were lower than those seen in patients with gastrointestinal cancer. Plasma CEA levels did not correlate with the menstrual status of the patient, nor with the size of the primary lesions,'3 nor the presence of estrogen receptor in the tumors. Subsequently, it was found that the proportion of elevated CEA levels increased with increased tumor spread.'5 More patients with lymph node involvement had abnormal levels of CEA than those with lesions limited to the breast; and in over 70 percent of the patients with distant metastasis the concentrations were increased. The incidence of elevated CEA values varied according to the site of metastasis. It ranged from 41 percent in patients with soft-tissue metastasis, 64 percent for osseous, 83 percent for pulmonary, to 93 percent for hepatic metastasis.16 Pronounced elevation of CEA (greater than 25 ng per ml) was observed most frequently in patients with hepatic 376
NOVEMBER 1978 * 129 * 5
and osseous metastasis.'7 In patients with recurrences in the chest wall only there were normal CEA titers, suggesting that the amount of tumor present was usually much less than in patients with visceral involvement.18 Strangely, when metastatic lesions occur -at three or more organ sites, there is a decreased incidence in quantitative CEA levels.17 This is similar to the situation in patients with carcinomas of colon or lung where the CEA level sometimes decreases with very advanced disease.'9 The titer of CEA in patients with early or localized breast cancer, before or after mastectomy, was found to be similar to that in healthy women.9'20 There was no correlation between the actual levels of CEA before mastectomy and recurrence during follow-up. However, CEA determinations ten days after mastectomy had prognostic importance: 20 percent of patients who had CEA values below 2.5 ng per ml had recurrence of the disease in two years as compared with a 65 percent recurrence rate in women with higher CEA levels.20 The timing of postoperative CEA test may be critical, because Tormey and co-workers17 found no direct correlation between postoperative CEA changes and the presence or absence of relapse. They obtained postoperative CEA values at one or more months and found that 23 percent had elevated levels (more than 2.7 ng per ml in nonsmokers and 5 ng per ml in smokers). Chu and Nemoto'G obtained blood samples at 4 and 14 days after mastectomy. They found an increase of CEA values in nine of 21 patients immediately following surgical operation. A similar transient rise was also detected in patients with other tumors and with benign diseases. They found that CEA levels in patients who had undergone mastectomy did not reflect the presence or absence of early metastasis. In patients with advanced mammary carcinoma receiving chemotherapy or hormonal therapy, some investigators reported that a good clinical response to therapy was mirrored by a fall of CEA values to normal levels.17 Others found good correlation only among patients with pronounced regression or progression of the disease, but the overall correlation was not good enough.14 16 A high initial CEA level at the outset of therapy did not necessarily imply a poor prognosis, and a low initial CEA level did not guarantee a good response to therapy.2' Tormey and co-workers17 found that pretherapy CEA levels of over 5 ng per ml were
CARCINOEMBRYONIC ANTIGEN
associated with low response rates and early failure of chemotherapy. The prognostic value of the initial CEA level appeared to be independent of other clinical features such as menopausal status and sites of involvement.
CEA in Patients With Cancer of the Colon General Remarks In initial studies, CEA values in patients with cancer of the colon were reported as being 97 percent positive.22 Such findings were confirmed in patients with "overt" cancer of the colon, many of whom had metastases. In later expanded studies, however, patients with earlier stages of the disease were included, resulting in a fall of positive assays to 72 percent.6 The number of positive assays fell even further to 59 percent in patients seen preoperatively,2' but rose to almost 100 percent among patients with liver metastasis.7 Therefore, CEA levels vary with the extent of disease. In two series, CEA values were greater than 2.5 ng per ml in 14 to 18 percent of patients with Duke A lesions, in 53 to 62 percent with B, in 60 to 65 percent with C, and in 79 percent of patients with D lesions.24'25 Therefore, a preoperatively negative assay (less than 2.5 ng per ml) does not exclude the diagnosis of cancer, but it does make the diagnosis of metastasis less likely. The titers of CEA did not correlate directly with the size of the tumor.4 And it was suggested that the neoplastic cells differed morphologically and could be divided into two types: (1) tissues in which malignant cells secreted CEA in greater or lesser quantity and (2) tissues in which CEA was localized in the cells.29 Within every particular Duke stage, there was a tendency for the higher plasma value to be associated with a worse prognosis.26'27 With a preresectional CEA value of less than 2.5 ng per ml, recurrence has been rare (5 percent). But, when the pretreatment CEA value was greater than 7 ng per ml, in most patients (seven of nine) the disease recurred within eight months.28 Lo Gerfo and Herter26 found that the chance of recurrence or death within three years is 1.8 times greater in patients who had elevated preoperative CEA values. The prognosis for recurrence is greater in patients with elevated preoperative values, regardless of the stage of the disease. Martin and co-workers4 noted an excellent correlation between plasma CEA levels and grade
of tumor of the colon: Well-differentiated tumors showed higher titers. (Denk and co-workers30 found well-differentiated tumors of the colon contained more CEA.) However, Go" said serum CEA levels were not influenced by the grade of differentiation of the tumor. Bivins and associates" noted that plasma CEA correlated better with vessel invasion and necrosis than with other histologic characteristics of cancer of the colon. Zamcheck and co-workers32 found CEA levels tended to be elevated when blood vessel, lymphatic and perineural invasion was present. An inverse correlation was also noted between the preoperative CEA level and the degree of tumor differentiation, and lymphocyte and plasma cell infiltration in the primary tumor of the colon. They suggested that the combined measures had more prognostic values than any single one alone. It is interesting to note that a higher percentage of patients who had cancers of the colon on the left side (splenic flexure, descending colon and sigmoid) had detectable levels of CEA than patients who had cancer of the colon on the right side (cecum, ascending colon, and hepatic flexure). For all stages of the disease, overall incidence of increased values was 47 to 59 percent versus 28 to 41 percent.4'25 However, patients with carcinomas of the rectum had the lowest incidence of elevated values of CEA (24 percent). Sugarbaker33 showed that pretreatment CEA titers in patients with obstructive colorectal cancer were unusually high. And relief of obstruction alone produced pronounced reduction in circulating CEA levels. Resectable Lesions Thomson and co-workers22 reported five cases in which preoperative elevated CEA determinations fell to normal levels after complete resection of the colonic cancer. Many other investigators have confirmed this finding. Lo Gerfo and associates34 found two patterns of postoperative fall in CEA levels after curative surgical operation. In one group an immediate fall to a nadir occurred within two to four days. In another group, the postoperative nadir occurred between 10 and 18 days. Others'8 have noted a more variable pattern of decline of CEA values after curative resection, including a rise in CEA values from normal to abnormal levels. During two or three weeks after operation, CEA produced by the resected tumor might still be present in the circuTHE WESTERN JOURNAL OF MEDICINE
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CARCINOEMBRYONIC ANTIGEN
lation; therefore, CEA test is of limited usefulness within 30 days after curative surgical operation. By 60 to 90 days there was a definite difference between those patients who remained free of disease and those who relapsed.28 In a prospective study of 102 patients after potentially curative resections of colorectal cancer, in 18 patients elevated levels of circulating CEA developed 2 to 42 (mean 16) months later. Six of these 18 patients had progressively rising CEA values, and all six subsequently had recurrences. It is significant that elevations in CEA were noted up to 29 months before clinical evidence of recurrence.10 In six patients with stable elevations and in six with transiently elevated levels cancer did not develop. None of the 84 patients with CEA levels of less than 2.5 ng per ml had evidence of recurrence during the follow-up period. However, two patients with levels consistently under 2.5 ng per ml were found to have small second primary cancers of the colon at sites distant from the first lesion. Mach and co-workers35 and Mackay and associates27 confirmed that rising CEA levels preceded clinical evidence of recurrence of cancer by two to 18 months. It was noted that an incomplete drop of circulating CEA levels one month after operation had a bad prognostic significance. However, the reverse is not true. Holyoke and associates28 emphasized that at least two consecutive elevated CEA values, the second being higher, must be obtained before considering possible progression of disease. They found elevated plasma CEA levels in 90 percent of the patients at time of recurrence; in about a third of the patients, CEA values rose six or more months before the relapse was otherwise detectable. Alkaline phosphatase and transaminase values correlated poorly with the disease state or the CEA results. But even with sequential testing at one to three month intervals and excluding patients with clear-cut associated benign causes, they encountered false positive results in 10 to 16 percent of their patients.36 Rieger and Wahren37 pointed out that in 70 percent of 20 patients with local recurrence without distant metastases, who were potential candidates for a reoperation for cure, plasma CEA values were raised. However, Moertel and associates38 reported that only nine among 36 patients (25 percent) with proven local recurrent or residual malignant disease in the pelvis after re378
NOVEMBER 1978 * 129 * 5
section of colorectal cancer had abnormal CEA levels greater than 5 ng per ml. Sugarbaker and associates39 compared the relative value of monthly CEA tests, three-monthly physical examinations plus stool test for occult blood, and six-monthly tests of hematocrit, alkaline phosphatase, chest and barium enema roentgenograms, liver scan and sigmoidoscopy in detecting recurrent colorectal cancer. In 12 of the 33 patients studied prospectively recurrent disease developed: in 5 the earliest indications were symptoms or physical findings, in 4 progressively rising CEA titers, in 2 both symptoms and the CEA test, in one surgical reexploration. Among the four patients in whom CEA values rose significantly before other evidence of recurrence appeared, two had retroperitoneal masses and one had liver metastasis. Among 16 patients who had persistent elevation of CEA following surgical operation, 11 remained clinically disease-free after 24 to 48 month (mean 31). Therefore, they concluded that CEA, and other laboratory or radiological tests, should not be a substitute for careful clinical follow-up. Many surgeons have proposed the use of a second-look operation in patients who had a curative resection and in whom elevation of circulating CEA persists without clinical signs of tumor recurrence. Martin and co-workers40'41 suggested that each laboratory should establish 95 percent confidence limits at various CEA levels, so that any value that was two standard deviations greater than the previous test would mean very significant elevation. In three reports utilizing second-look operations for patients with rising CEA values, in 45 of 51 patients (88 percent) recurrent disease was found.73942 In six of 22 patients (27 percent), tumors were resectable.'0 Meeker43 calculated that serial CEA tests, at $30 per single test and with a cost-benefit ratio of about $3,300 per patient benefited, are indicated in follow-up studies of patients after curative resection of cancer of the colon.
Unresectable or Advanced Lesions In patients who had elevated CEA levels caused by localized disease and who received radiation therapy, a pronounced fall in serial CEA levels was noted if all CEA-producing tumor was localized within the radiation portal." Persistently low serial CEA titers after irradiation therapy correlated with control of the disease. Rising serial
CARCINOEMBRYONIC ANTIGEN
CEA levels in patients with known metastatic gastrointestinal cancer and treated with chemotherapy correlated with progression of the disease.28 Persistently low, especially undetectable values were a favorable prognostic sign in patients with cancer of the colon. High or rising levels were unfavorable.45 The limited effectiveness of chemotherapy for gastrointestinal cancer precluded any definitive conclusion regarding the effect of chemotherapeutically induced tumor regression on CEA levels, although there was suggestive evidence that CEA correlated with remission. Ravry and co-workers"' confirmed these general observations, but noted day-to-day -variation of CEA levels in 35 percent of their patients. It is also well-known that some cancers of the colon do not produce CEA, and such lesions may deteriorate without a concomitant rise in blood CEA levels.1" About 10 to 33 percent of patients with extensive recurrent disease do not have elevated circulating CEA titers.27'44 And, in some patients, a preterminal fall rather than a rise in CEA levels may occur. Therefore, it is emphasized that one needs to interpret CEA values cautiously, and only in context with the overall clinical and laboratory findings.
Conclusion Carcinoembryonic antigen (CEA) is a glycoprotein which is normally secreted into the lumen by epithelial cells of the gastrointestinal tract. Blood (plasma) CEA levels have been found to be elevated in patients with various non-malignant, metabolic, or inflammatory diseases, in surgical trauma, and in cases of heavy smoking. Some malignant tissues do not release CEA. In general, high CEA levels above 20 ng per ml usually indicated metastatic disease. However, a negative test of CEA does not rule out the presence of metastatic disease.46 In patients with carcinoma of the breast, the proportion of elevated CEA levels increases with increased tumor spread, and varies among different sites of metastasis. Among patients with operable breast carcinomas, the actual levels of CEA before mastectomy do not correlate with
the incidence of recurrence during follow-up. Some authors reported that patients with an elevated CEA test ten days after mastectomy had a higher chance of recurrence, while others noted no direct correlation between postoperative CEA changes and the presence or absence of relapse.
In patients with advanced lesions who received chemotherapy or hormonal therapy, some investigators reported a good correlation between response to therapy and decreased CEA levels, whereas others showed good correlation only among patients with marked regression or progression of the disease. Therefore, current data do not indicate that the CEA test is of value in the follow-up of patients with breast cancer. In patients with cancers of the colon, the CEA levels correlate better with the extent of the tumor, and have prognostic implications. High CEA levels, found in more advanced lesions, imply early recurrence and dissemination. After complete removal of the colonic cancer, preoperatively elevated CEA values usually fall to normal levels in about one month. And progressively rising CEA values usually suggest relapses. However, there is a false-positive rate of 10 to 15 percent, and about 10 to 30 percent of patients with recurrent lesions might have unchanged CEA levels. There are indications that metastatic lesions of the liver and retroperitoneum, often unresectable, are more likely to manifest themselves by rising values of CEA, while other early and localized recurrences are less likely to do so. Based on these experiences, and knowing that Duke A lesions rarely relapse, it appears that CEA tests should only be used as an adjunct to careful clinical follow-up of patients who had curative resection of non-Duke A cancers of the colon. For best cost-effectiveness, an initial CEA test can be obtained at two to three months after resection and repeated at six-month intervals. When a test result differs by more than two standard deviations from a previous one, a repeat test should be obtained. Serial rising CEA levels in patients with known metastatic gastrointestinal cancer who receive chemotherapy correlate with progression of the disease. Decreases in CEA titers are usually associated with effective therapy, although in some cases the CEA levels might drop preterminally. For patients with nonmeasurable lesions, the CEA test is useful and should be interpreted and considered with other tests and clinical findings. REFERENCES 1. Gold P, Freedman SO: Demonstration of tumor-specific antigens in human colonic carcinomata by immunological and absorp-
tion techniques. J Exp Med 121:439-459, 1965 2. Costanza ME, Das S, Nathanson L, et al: Carcinoembryonic antigen: Report of a screening study. Cancer 33:583-590, 1974 3. Alexander JC, Silverman NA, Chretien PB: Effect of age and cigarette smoking on carcinoembryonic antigen levels. JAMA 235: 1975-1979, 1976
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CARCINOEMBRYONIC ANTIGEN 4. Martin EW, Kibbey WE, DiVecchia L, et al: Carcinoembryonic antigen: Clinical and historical aspects. Cancer 37:62-81, 1976 5. Moore TL, Kantrowitz PA, Zamcheck N: Carcinoembryonic antigen (CEA) in inflammatory bowel disease. JAMA 222:944947, 1972 6. Moore TL, Dhar P, Zamcheck N, et al: Carcinoembryonic antigen(s) in liver disease-I. Clinical and morphological studies. Gastroenterology 63:88-94, 1972 7. Zamcheck N: The present status of CEA in diagnosis, prognosis and evaluation of therapy. Cancer 36:2460-2468, 1975 8. CEA-Roche assay, Hoffman-La Roche, Inc., 1974 9. Reynoso G, Chu TM, Holyoke D, et al: Carcinoembryonic antigen in patients with different cancers. JAMA 220:361-365, 1972 10. Sorokin JJ, Sugarbaker PH, Zamcheck N, et al: Serial carcinoembryonic antigen assays: Use in detection of cancer recurrence. JAMA 228:49-53, 1974 11. Go VLW: Carcinoembryonic antigen: Clinical application. Cancer 37:562-566, 1976 12. Boyd CR, Bivins BA, Kashmiri R, et al: Plasma carcinoembryonic antigen (CEA), tumor CEA, and tumor histology. Surg Forum 26:124-126, 1975 13. Krebs B, Turchi P, Bonet C, et al: Carcinoembryonic antigen assay in breast and bronchus cancers. Eur J Cancer 13:375376, 1977 14. Borthwick NM, Wilson DW, Bell PA: Carcinoembryonic antigen (CEA) in patients with breast cancer. Eur J Cancer 13: 171-176, 1977 15. Tomey DC, Waalkes TP, Ahmann D, et al: Biological markers in breast carcinoma-I. Incidence of abnormalities of CEA, HCG, three polyamines and three minor nucleosides. Cancer 35:1095-1100, 1975 16. Chu TM, Nemoto T: Evaluation of carcinoembryonic antigen in human mammary carcinoma. J Nat Cancer lnst 51:11191122, 1973 17. Tormey DC, Waalkes TP, Synder JJ, et al: Biological markers in breast carcinoma-IlI. Clinical correlations with carcinoembryonic antigen. Cancer 39:2397-2404, 1977 18. Meeker WR, Kashmiri R, Hunter L, et al: Clinical evaluation of carcinoembryonic antigen test. Arch Surg 107:266-274, 1973 19. Ravry M, Moertel CG, Schutt AJ, et al: Usefulness of serial serum carcinoembryonic antigen (CEA) determinations during anti-cancer therapy of long-term follow-up of gastrointestinal carcinoma. Cancer 34:1230-1234, 1974 20. Wang DY, Bulbrook RD, Hayward JL, et al: Relationship between plasma carcinoembryonic antigen and prognosis in women with breast cancer. Eur J Cancer 11:615-618, 1975 21. Steward AM, Nixon D, Zamcheck N, et al: Carcinoembryonic antigen in breast cancer patients: Serum levels and disease progress. Cancer 33:1246-1252, 1974 22. Thompson DMP, Krupey J, Freedman SO, et al: The radioimmunoassay of circulating carcinoembryonic antigen of the human digestive system. Proc Nat Acad Science 64:161-167, 1969 23. Dhar P, Moore TL, Zamcheck N, et al: Carcinoembryonic antigen (CEA) in colonic cancer: Use in preoperative and postoperative diagnosis and prognosis. JAMA 221:31-35, 1972 24. A collaborative study of a test for carcinoembryonic antigen (CEA) in the sera of patients with carcinoma of the colon and rectum: A Joint National Cancer Institute of Canada/American Cancer Society investigation. Can Med Assoc J 107:25-33, 1972 25. Livingstone AS, Hampson LG, Shuster J, et al: Carcinoembryonic antigen in the diagnosis and management of colorectal carcinoma. Arch Surg 109:259-264, 1974
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26. Lo Gerfo P, Herter FP: Carcinoembryon-c antigen and prognosis in patients with colon cancer. Ann Surg 181:81-84, 1975 27. Mackay AM, Patel S, Carter S, et al: Role of serial plasma CEA assays in detection of recurrent and metastatic colorectal carcinomas. Br Med J 4:382-385, 1974 28. Holyoke ED, Chu TM, Murphy GP: CEA as a monitor of gastrointestinal malignancy. Cancer 35:830-836, 1975 29. Rogalsky VY: Variations in carcinoembryonic antigen localization in tumors of the colon. J Natl Cancer Inst 54:1061-1065, 1975 30. Denk H, Tappeiner G, Eckerstorfer R, et al: Carcinoembryonic antigen (CEA) in gastrointestinal and extragastrointestinal tumors and its relationship to tumor-cell differentiation. Int J Cancer lu:262-272, 1972 31. Bivins BA, Meeker WR, Griffen WO, et al: Carcinoembryonic antigen (CEA) levels and tumor histology in colon cancer. J Surg Res 18:257-261, 1975 32. Zamcheck N, Doos WG, Prudente R, et al: Prognostic factors in colon carcinoma. Hum Pathol 6:31-45, 1975 33. Sugarbaker PH: Carcinoembryonic antigen (CEA) assays in obstructive colorectal cancer. Ann Surg 184:752-757, 1976 34. Lo Gerfo P, Krupey J, Hansen HJ: Demonstration of an antigen common to several varieties of neoplasia: Assay using zirconyl phosphate gel. N EngI J Med 285:138-141, 1971 35. Mach JP, Jaeger P, Bartholet MM, et al: Detection of recurrence of large bowel carcinoma by radioimmunoassay of circulating carcinoembryoniic antigen (CEA). Lancet 2:535-540, 1974 36. Herrera MA, Chu TM, Holyoke ED: Carcinoembryonic antigen (CEA) as a prognostic and monitoring test in clinically complete resection of colorectal carcinoma. Ann Surg 183:5-9, 1976 37. Rieger A, Wahren B: CEA levels at recurrence and metastases; importance for detecting secondary disease. Scand J Gastroenterol 10:869-874, 1975 38. Moertel CG, Schutt AJ, Go VLW: Carcinoembryonic antigen test for recurrent colorectal carcinoma: Inadequacy for early detection. JAMA 239:1065-1066, 1978 39. Sugarbaker PH, Zamcheck N, Moore ED: Assessment of serial carcinoembryonic antigen (CEA) assays in postoperative detection of recurrent colorectal cancer. Cancer 38:2310-2315, 1976 40. Martin EW, James KK, Hurtubise PE, et al: The use of CEA as an early indicator for gastrointestinal tumor recurrence and second-look procedures. Cancer 39:440-446, 1977 41. Balz JB, Martin EW, Minton JP: CEA as an early indicator for second-look procedure in colorectal carcinoma. Rev Surg 34: 1-4, 1977 42. Mavligit GM, Gutterman JU, Burgess MA, et al: Adjuvant immunotherapy and chemoimmunotherapy in colorectal cancer of the Duke's C classification: Preliminary clinical results. Cancer 36:2421-2427, 1975 43. Meeker WR: The use and abuse of CEA test in clinical practice. Cancer 41:854-862, 1978 44. Sugarbaker PH, Skarin AT, Zamcheck N: Patterns of serial CEA assays and their clinical use on management of colorectal cancer. J Surg Oncol 8:523-538, 1976 45. Skarin AT, Delwiche R, Zamcheck N, et al: Carcinoembryonic antigen: Clinical correlation with chemotherapy for metastatic gastrointestinal cancer. Cancer 33:1239-1245, 1974 46. Gold P, Freedman SO: Tests for carcinoembryonic antigen: Role in diagnosis and management of cancer. JAMA 234: 190-192, 1975
Carcinoembryonic Antigen in Patients With Breast or Colon Cancer YEU-TSU N. LEE, MD, Los Angeles
The rationale and results of clinical use of carcinoembryonic antigen (CEA) tests in patients with carcinoma of the breast and colon deserve review. Plasma CEA levels have been found to correlate with the extent of tumor invasion and site of metastatic spread, and CEA titers have diagnostic and prognostic value. Although postresectional serial CEA testing is not as useful in cases of breast carcinoma, in cases of carcinoma of the colon it may indicate recurrence or progression of the lesion. However, there are limitations and CEA results should be interpreted in conjunction with other clinical information. THE TERM carcinoembryonic antigen (CEA) was first used in 1965 by Gold and Freedman' to describe an antigen present in extracts of colonic adenocarcinoma and digestive organs of human embryos. When they noted elevated levels of CEA in plasma in 36 of 37 advanced colon carcinoma cases, it was hoped that a specific test for cancer of the colon had been discovered. This proved not to be the case, as subsequent investigation indicated the presence of CEA in nonentodermal tumors as well as in various nonneoplastic diseases. CEA is a glycoprotein and consists of 45 percent protein and 55 percent carbohydrate. It has a molecular weight of about 200,000 with betaelectrophoretic mobility in immunoelectrophoreSiS. CEA is a constituent of the mucus which is normally secreted into the lumen by epithelial cells of the gastrointestinal tract. As the normal tissue architecture is disrupted, the CEA is released From the Department of Surgery, University of Southern California Medical School and the Tumor Surgery Service, LAC-USC Medical Center, Los Angeles. Submitted, revised, May 1, 1978. Reprint requests to: Yeu-Tsu N. Lee, MD, Dept. of Surgery, USC School of Medicine, 1200 North State Street, Los Angeles, CA 90033.
374
NOVEMBER 1978 * 129 * 5
into underlying tissue and diffuses into the vascular or lymphatic channels. Rapid cellular proliferation and disruption of basement membranes explains the presence of elevated circulating CEA levels in patients with entodermal and nonentodermal malignancies, with various nonmalignant metabolic or inflammatory diseases,2 in surgical trauma and in cases of heavy smoking.3 From 1971 to 1974, the CEA test was evaluated extensively in a collaborative study of 35,000 assays in more than 11,000 patients from over 100 medical institutions. The result showed that 97 percent of healthy nonsmoking subjects had titers of 2.5 ng per ml or below, none above 5 ng per ml (Table 1). Even among chronic smokers (more than one pack a day for at least ten years), 4 percent had CEA titers above 5 ng per ml and only 1 percent over 10 ng per ml. After cessation of smoking, elevated CEA levels declined to nonsmoker range within three months.3 In the absence of malignant disease, CEA titers greater than 5 ng per ml were associated with such conditions as pulmonary emphysema, alcoholic cirrhosis, ulcerative colitis, regional ileitis, granulomatous colitis, gastric and duodenal ulcers,
CARCINOEMBRYONIC ANTIGEN TABLE 1.-Distribution of CEA Levels Among 2,107 Healthy Volunteers* CEA Levels Numnber 2.5 ng >5 ng >10 ng of per ml per ml per ml per ml Patients (Percent) (Percent)(Percent) (Percent)
Condition
Pregnancy Nonsmokers Former smokers Presently smoking ....
.
360 892 235 620
96 97 93 81
4 3 6 18
1 0 2 4
0 0 1 1
2,107
92
8
2
0.5
TABLE 3.-Distribution of CEA Levels Among 1,343 Patients With Carcinoma (All Stages)* Number 2.5 ng >5 ng >10 ng per ml per ml per ml per ml of Patients (Percent) (Percent) (Percent) (Percent)
Entodermal carcinoma Gastric carcinoma Colorectal carcinoma
859 79
27 39
72 61
48 29
31 19
544
28
72
49
35
carcinoma 181 Pancreatic carcinoma .... 55 Nonentodermal carcinoma 468 Breast carcinoma 125 Head and neck carcinoma 128 Other carcinoma . 215
24
76
50
25
9
91
61
35
52 53
48 47
22 27
9 14
48 53
52 47
19 21
5 9
Overall
35
65
38-
23
....
....
Pulmonary ....
CEA = Carcinoembryonic antigen
'Adapted from CEA-Roche Assay, Hoffman-La Roche,
19748
Inc.
....
TABLE 2.-Distribution of CEA Levels Among 3,340 Patients With Nonmalignant Disease* CEA Levels Number 2.5 ng >5 ng > 10 ng of per ml per ml per ml per ml Patients (Percent) (Percent)(Percent) (Percent)
Diagnosis Breast
lesions
115 166 94 39 90 84 146 126
Duodenal ulcer . Gastric ulcer Cholecystitis .... Colorectal polyps Diverticulitis .... Ulcerative colitis Regional ileitis Granulomatous colitis ....... 59 Alcoholic cirrhosis 120 Pulmonary 49 emphysema Otherst. 2,281 ...
...
3,340
85 70 55 77 81
15 30 45 23
4
0
2
19
8 16 6 4
63
37
13
60
40
13
1
1,343
........
CEA = Carcinoembryomic antigen
*Adapted from CEA-Roche Assay, Hoffman-La Roche, Inc. 19748
1
1 2
2
53
47
20
5
29
71
26
2
43
57
20
4
69
31
8
1
67
33
9
1
CEA = Carcinoembryonic antigen
'Adapted from CEA-Roche Assaay, Hoffman-La Roche, Inc. 19748 include heartt disease (289), diabetes (230), myasthenia gravis (183), hyperten sion (156), osteoarthritis (112), pancreatitis (95), and bronchitis (
tMajor categories
....
(61).
release of the obstruction, provided persistent biliary inflammation or liver abscess does not supervene. Some of the elevated CEA levels in patients with inflammatory bowel disease may be due in part to coexisting liver disease. Elevated levels commonly accompany alcoholic pancreatitis. Therefore, correct clinical interpretation requires concomitant assessment of liver status.6'7 In January 1974 reagents for the CEA assay (patented by Hoffman-La Roche) became the first
biological
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rculating
CEA
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as
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follows: 0.5
A
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immunoassay procedure the colorectal polyps and divierticulitis (Table 2). It is important to note th at most of the "falselevels tend positive" elevations of cir to be lower than those fo und in conditions (Table 3). And ma ny of the nonmalignant conditions associated wit positive assays show transient rather than pers;istent elevations of levels. For instance, CEA titers in patients with nonmalignant colonic pi inflammatory disease usually drop to below 2.5 ng per ml when the polyps are rese.cted diseases in remission.45 More than any other c benign disease, liver disease (especially se alcoholic cirrhosis) levels. Perhaps may cause mildly elevat ed half the patients with beniign obstructive jaundice have elevated CEA titers Nwhich fall after surgical
approved by
Food and
was
results.9'°0
time of day when the
age,
level.
Among
and
or
of cancer-do not in-
carcinoma, there
tumor CEA
found that
drawn, and the presence
family history CEA
Go"
17
was
serum
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CEA
with
correlation
levels.'2
THE WESTERN JOURNAL OF MEDICINE
375
CARCINOEMBRYONIC ANTIGEN
It is emphasized that the CEA test should not be used for screening purposes to detect cancer in the general population. CEA titers are not an absolute test for malignancy, nor for a specific type of malignancy. And CEA levels less than 2.5 ng per ml do not preclude the presence of primary, recurrent or metastatic cancers (Table 3). However, very high CEA levels (above 20 ng per ml) usually indicated metastatic disease. In patients with documented cancer, it is reported that monitoring the level of CEA in the circulation before and after therapy may be useful. In general, decreases in CEA titers were associated with effective therapy. A persistent increase in titers was associated with a lack of response to therapy or a recurrence of disease; in some cases, the titer rise preceded clinical signs for several months. Since CEA tests have been used widely for purposes of follow-up studies in patients with malignant lesions of the breast and colorectum, their rationale, results and limitations are reviewed here in detail.
CEA in Patients With Breast Cancer In the Roche collaborative study, among 115 patients with benign breast diseases, 15 percent had titers of CEA above 2.5 ng per ml, none above 10 ng per ml (Table 2). Among 125 patients with various stages of carcinoma of the breast, 47 percent had CEA levels above 2.5 ng per ml, 27 percent above 5 ng per ml, and 14 percent above 10 ng per ml (Table 3). In general, CEA levels in patients with breast cancer were lower than those seen in patients with gastrointestinal cancer. Plasma CEA levels did not correlate with the menstrual status of the patient, nor with the size of the primary lesions,'3 nor the presence of estrogen receptor in the tumors. Subsequently, it was found that the proportion of elevated CEA levels increased with increased tumor spread.'5 More patients with lymph node involvement had abnormal levels of CEA than those with lesions limited to the breast; and in over 70 percent of the patients with distant metastasis the concentrations were increased. The incidence of elevated CEA values varied according to the site of metastasis. It ranged from 41 percent in patients with soft-tissue metastasis, 64 percent for osseous, 83 percent for pulmonary, to 93 percent for hepatic metastasis.16 Pronounced elevation of CEA (greater than 25 ng per ml) was observed most frequently in patients with hepatic 376
NOVEMBER 1978 * 129 * 5
and osseous metastasis.'7 In patients with recurrences in the chest wall only there were normal CEA titers, suggesting that the amount of tumor present was usually much less than in patients with visceral involvement.18 Strangely, when metastatic lesions occur -at three or more organ sites, there is a decreased incidence in quantitative CEA levels.17 This is similar to the situation in patients with carcinomas of colon or lung where the CEA level sometimes decreases with very advanced disease.'9 The titer of CEA in patients with early or localized breast cancer, before or after mastectomy, was found to be similar to that in healthy women.9'20 There was no correlation between the actual levels of CEA before mastectomy and recurrence during follow-up. However, CEA determinations ten days after mastectomy had prognostic importance: 20 percent of patients who had CEA values below 2.5 ng per ml had recurrence of the disease in two years as compared with a 65 percent recurrence rate in women with higher CEA levels.20 The timing of postoperative CEA test may be critical, because Tormey and co-workers17 found no direct correlation between postoperative CEA changes and the presence or absence of relapse. They obtained postoperative CEA values at one or more months and found that 23 percent had elevated levels (more than 2.7 ng per ml in nonsmokers and 5 ng per ml in smokers). Chu and Nemoto'G obtained blood samples at 4 and 14 days after mastectomy. They found an increase of CEA values in nine of 21 patients immediately following surgical operation. A similar transient rise was also detected in patients with other tumors and with benign diseases. They found that CEA levels in patients who had undergone mastectomy did not reflect the presence or absence of early metastasis. In patients with advanced mammary carcinoma receiving chemotherapy or hormonal therapy, some investigators reported that a good clinical response to therapy was mirrored by a fall of CEA values to normal levels.17 Others found good correlation only among patients with pronounced regression or progression of the disease, but the overall correlation was not good enough.14 16 A high initial CEA level at the outset of therapy did not necessarily imply a poor prognosis, and a low initial CEA level did not guarantee a good response to therapy.2' Tormey and co-workers17 found that pretherapy CEA levels of over 5 ng per ml were
CARCINOEMBRYONIC ANTIGEN
associated with low response rates and early failure of chemotherapy. The prognostic value of the initial CEA level appeared to be independent of other clinical features such as menopausal status and sites of involvement.
CEA in Patients With Cancer of the Colon General Remarks In initial studies, CEA values in patients with cancer of the colon were reported as being 97 percent positive.22 Such findings were confirmed in patients with "overt" cancer of the colon, many of whom had metastases. In later expanded studies, however, patients with earlier stages of the disease were included, resulting in a fall of positive assays to 72 percent.6 The number of positive assays fell even further to 59 percent in patients seen preoperatively,2' but rose to almost 100 percent among patients with liver metastasis.7 Therefore, CEA levels vary with the extent of disease. In two series, CEA values were greater than 2.5 ng per ml in 14 to 18 percent of patients with Duke A lesions, in 53 to 62 percent with B, in 60 to 65 percent with C, and in 79 percent of patients with D lesions.24'25 Therefore, a preoperatively negative assay (less than 2.5 ng per ml) does not exclude the diagnosis of cancer, but it does make the diagnosis of metastasis less likely. The titers of CEA did not correlate directly with the size of the tumor.4 And it was suggested that the neoplastic cells differed morphologically and could be divided into two types: (1) tissues in which malignant cells secreted CEA in greater or lesser quantity and (2) tissues in which CEA was localized in the cells.29 Within every particular Duke stage, there was a tendency for the higher plasma value to be associated with a worse prognosis.26'27 With a preresectional CEA value of less than 2.5 ng per ml, recurrence has been rare (5 percent). But, when the pretreatment CEA value was greater than 7 ng per ml, in most patients (seven of nine) the disease recurred within eight months.28 Lo Gerfo and Herter26 found that the chance of recurrence or death within three years is 1.8 times greater in patients who had elevated preoperative CEA values. The prognosis for recurrence is greater in patients with elevated preoperative values, regardless of the stage of the disease. Martin and co-workers4 noted an excellent correlation between plasma CEA levels and grade
of tumor of the colon: Well-differentiated tumors showed higher titers. (Denk and co-workers30 found well-differentiated tumors of the colon contained more CEA.) However, Go" said serum CEA levels were not influenced by the grade of differentiation of the tumor. Bivins and associates" noted that plasma CEA correlated better with vessel invasion and necrosis than with other histologic characteristics of cancer of the colon. Zamcheck and co-workers32 found CEA levels tended to be elevated when blood vessel, lymphatic and perineural invasion was present. An inverse correlation was also noted between the preoperative CEA level and the degree of tumor differentiation, and lymphocyte and plasma cell infiltration in the primary tumor of the colon. They suggested that the combined measures had more prognostic values than any single one alone. It is interesting to note that a higher percentage of patients who had cancers of the colon on the left side (splenic flexure, descending colon and sigmoid) had detectable levels of CEA than patients who had cancer of the colon on the right side (cecum, ascending colon, and hepatic flexure). For all stages of the disease, overall incidence of increased values was 47 to 59 percent versus 28 to 41 percent.4'25 However, patients with carcinomas of the rectum had the lowest incidence of elevated values of CEA (24 percent). Sugarbaker33 showed that pretreatment CEA titers in patients with obstructive colorectal cancer were unusually high. And relief of obstruction alone produced pronounced reduction in circulating CEA levels. Resectable Lesions Thomson and co-workers22 reported five cases in which preoperative elevated CEA determinations fell to normal levels after complete resection of the colonic cancer. Many other investigators have confirmed this finding. Lo Gerfo and associates34 found two patterns of postoperative fall in CEA levels after curative surgical operation. In one group an immediate fall to a nadir occurred within two to four days. In another group, the postoperative nadir occurred between 10 and 18 days. Others'8 have noted a more variable pattern of decline of CEA values after curative resection, including a rise in CEA values from normal to abnormal levels. During two or three weeks after operation, CEA produced by the resected tumor might still be present in the circuTHE WESTERN JOURNAL OF MEDICINE
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CARCINOEMBRYONIC ANTIGEN
lation; therefore, CEA test is of limited usefulness within 30 days after curative surgical operation. By 60 to 90 days there was a definite difference between those patients who remained free of disease and those who relapsed.28 In a prospective study of 102 patients after potentially curative resections of colorectal cancer, in 18 patients elevated levels of circulating CEA developed 2 to 42 (mean 16) months later. Six of these 18 patients had progressively rising CEA values, and all six subsequently had recurrences. It is significant that elevations in CEA were noted up to 29 months before clinical evidence of recurrence.10 In six patients with stable elevations and in six with transiently elevated levels cancer did not develop. None of the 84 patients with CEA levels of less than 2.5 ng per ml had evidence of recurrence during the follow-up period. However, two patients with levels consistently under 2.5 ng per ml were found to have small second primary cancers of the colon at sites distant from the first lesion. Mach and co-workers35 and Mackay and associates27 confirmed that rising CEA levels preceded clinical evidence of recurrence of cancer by two to 18 months. It was noted that an incomplete drop of circulating CEA levels one month after operation had a bad prognostic significance. However, the reverse is not true. Holyoke and associates28 emphasized that at least two consecutive elevated CEA values, the second being higher, must be obtained before considering possible progression of disease. They found elevated plasma CEA levels in 90 percent of the patients at time of recurrence; in about a third of the patients, CEA values rose six or more months before the relapse was otherwise detectable. Alkaline phosphatase and transaminase values correlated poorly with the disease state or the CEA results. But even with sequential testing at one to three month intervals and excluding patients with clear-cut associated benign causes, they encountered false positive results in 10 to 16 percent of their patients.36 Rieger and Wahren37 pointed out that in 70 percent of 20 patients with local recurrence without distant metastases, who were potential candidates for a reoperation for cure, plasma CEA values were raised. However, Moertel and associates38 reported that only nine among 36 patients (25 percent) with proven local recurrent or residual malignant disease in the pelvis after re378
NOVEMBER 1978 * 129 * 5
section of colorectal cancer had abnormal CEA levels greater than 5 ng per ml. Sugarbaker and associates39 compared the relative value of monthly CEA tests, three-monthly physical examinations plus stool test for occult blood, and six-monthly tests of hematocrit, alkaline phosphatase, chest and barium enema roentgenograms, liver scan and sigmoidoscopy in detecting recurrent colorectal cancer. In 12 of the 33 patients studied prospectively recurrent disease developed: in 5 the earliest indications were symptoms or physical findings, in 4 progressively rising CEA titers, in 2 both symptoms and the CEA test, in one surgical reexploration. Among the four patients in whom CEA values rose significantly before other evidence of recurrence appeared, two had retroperitoneal masses and one had liver metastasis. Among 16 patients who had persistent elevation of CEA following surgical operation, 11 remained clinically disease-free after 24 to 48 month (mean 31). Therefore, they concluded that CEA, and other laboratory or radiological tests, should not be a substitute for careful clinical follow-up. Many surgeons have proposed the use of a second-look operation in patients who had a curative resection and in whom elevation of circulating CEA persists without clinical signs of tumor recurrence. Martin and co-workers40'41 suggested that each laboratory should establish 95 percent confidence limits at various CEA levels, so that any value that was two standard deviations greater than the previous test would mean very significant elevation. In three reports utilizing second-look operations for patients with rising CEA values, in 45 of 51 patients (88 percent) recurrent disease was found.73942 In six of 22 patients (27 percent), tumors were resectable.'0 Meeker43 calculated that serial CEA tests, at $30 per single test and with a cost-benefit ratio of about $3,300 per patient benefited, are indicated in follow-up studies of patients after curative resection of cancer of the colon.
Unresectable or Advanced Lesions In patients who had elevated CEA levels caused by localized disease and who received radiation therapy, a pronounced fall in serial CEA levels was noted if all CEA-producing tumor was localized within the radiation portal." Persistently low serial CEA titers after irradiation therapy correlated with control of the disease. Rising serial
CARCINOEMBRYONIC ANTIGEN
CEA levels in patients with known metastatic gastrointestinal cancer and treated with chemotherapy correlated with progression of the disease.28 Persistently low, especially undetectable values were a favorable prognostic sign in patients with cancer of the colon. High or rising levels were unfavorable.45 The limited effectiveness of chemotherapy for gastrointestinal cancer precluded any definitive conclusion regarding the effect of chemotherapeutically induced tumor regression on CEA levels, although there was suggestive evidence that CEA correlated with remission. Ravry and co-workers"' confirmed these general observations, but noted day-to-day -variation of CEA levels in 35 percent of their patients. It is also well-known that some cancers of the colon do not produce CEA, and such lesions may deteriorate without a concomitant rise in blood CEA levels.1" About 10 to 33 percent of patients with extensive recurrent disease do not have elevated circulating CEA titers.27'44 And, in some patients, a preterminal fall rather than a rise in CEA levels may occur. Therefore, it is emphasized that one needs to interpret CEA values cautiously, and only in context with the overall clinical and laboratory findings.
Conclusion Carcinoembryonic antigen (CEA) is a glycoprotein which is normally secreted into the lumen by epithelial cells of the gastrointestinal tract. Blood (plasma) CEA levels have been found to be elevated in patients with various non-malignant, metabolic, or inflammatory diseases, in surgical trauma, and in cases of heavy smoking. Some malignant tissues do not release CEA. In general, high CEA levels above 20 ng per ml usually indicated metastatic disease. However, a negative test of CEA does not rule out the presence of metastatic disease.46 In patients with carcinoma of the breast, the proportion of elevated CEA levels increases with increased tumor spread, and varies among different sites of metastasis. Among patients with operable breast carcinomas, the actual levels of CEA before mastectomy do not correlate with
the incidence of recurrence during follow-up. Some authors reported that patients with an elevated CEA test ten days after mastectomy had a higher chance of recurrence, while others noted no direct correlation between postoperative CEA changes and the presence or absence of relapse.
In patients with advanced lesions who received chemotherapy or hormonal therapy, some investigators reported a good correlation between response to therapy and decreased CEA levels, whereas others showed good correlation only among patients with marked regression or progression of the disease. Therefore, current data do not indicate that the CEA test is of value in the follow-up of patients with breast cancer. In patients with cancers of the colon, the CEA levels correlate better with the extent of the tumor, and have prognostic implications. High CEA levels, found in more advanced lesions, imply early recurrence and dissemination. After complete removal of the colonic cancer, preoperatively elevated CEA values usually fall to normal levels in about one month. And progressively rising CEA values usually suggest relapses. However, there is a false-positive rate of 10 to 15 percent, and about 10 to 30 percent of patients with recurrent lesions might have unchanged CEA levels. There are indications that metastatic lesions of the liver and retroperitoneum, often unresectable, are more likely to manifest themselves by rising values of CEA, while other early and localized recurrences are less likely to do so. Based on these experiences, and knowing that Duke A lesions rarely relapse, it appears that CEA tests should only be used as an adjunct to careful clinical follow-up of patients who had curative resection of non-Duke A cancers of the colon. For best cost-effectiveness, an initial CEA test can be obtained at two to three months after resection and repeated at six-month intervals. When a test result differs by more than two standard deviations from a previous one, a repeat test should be obtained. Serial rising CEA levels in patients with known metastatic gastrointestinal cancer who receive chemotherapy correlate with progression of the disease. Decreases in CEA titers are usually associated with effective therapy, although in some cases the CEA levels might drop preterminally. For patients with nonmeasurable lesions, the CEA test is useful and should be interpreted and considered with other tests and clinical findings. REFERENCES 1. Gold P, Freedman SO: Demonstration of tumor-specific antigens in human colonic carcinomata by immunological and absorp-
tion techniques. J Exp Med 121:439-459, 1965 2. Costanza ME, Das S, Nathanson L, et al: Carcinoembryonic antigen: Report of a screening study. Cancer 33:583-590, 1974 3. Alexander JC, Silverman NA, Chretien PB: Effect of age and cigarette smoking on carcinoembryonic antigen levels. JAMA 235: 1975-1979, 1976
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CARCINOEMBRYONIC ANTIGEN 4. Martin EW, Kibbey WE, DiVecchia L, et al: Carcinoembryonic antigen: Clinical and historical aspects. Cancer 37:62-81, 1976 5. Moore TL, Kantrowitz PA, Zamcheck N: Carcinoembryonic antigen (CEA) in inflammatory bowel disease. JAMA 222:944947, 1972 6. Moore TL, Dhar P, Zamcheck N, et al: Carcinoembryonic antigen(s) in liver disease-I. Clinical and morphological studies. Gastroenterology 63:88-94, 1972 7. Zamcheck N: The present status of CEA in diagnosis, prognosis and evaluation of therapy. Cancer 36:2460-2468, 1975 8. CEA-Roche assay, Hoffman-La Roche, Inc., 1974 9. Reynoso G, Chu TM, Holyoke D, et al: Carcinoembryonic antigen in patients with different cancers. JAMA 220:361-365, 1972 10. Sorokin JJ, Sugarbaker PH, Zamcheck N, et al: Serial carcinoembryonic antigen assays: Use in detection of cancer recurrence. JAMA 228:49-53, 1974 11. Go VLW: Carcinoembryonic antigen: Clinical application. Cancer 37:562-566, 1976 12. Boyd CR, Bivins BA, Kashmiri R, et al: Plasma carcinoembryonic antigen (CEA), tumor CEA, and tumor histology. Surg Forum 26:124-126, 1975 13. Krebs B, Turchi P, Bonet C, et al: Carcinoembryonic antigen assay in breast and bronchus cancers. Eur J Cancer 13:375376, 1977 14. Borthwick NM, Wilson DW, Bell PA: Carcinoembryonic antigen (CEA) in patients with breast cancer. Eur J Cancer 13: 171-176, 1977 15. Tomey DC, Waalkes TP, Ahmann D, et al: Biological markers in breast carcinoma-I. Incidence of abnormalities of CEA, HCG, three polyamines and three minor nucleosides. Cancer 35:1095-1100, 1975 16. Chu TM, Nemoto T: Evaluation of carcinoembryonic antigen in human mammary carcinoma. J Nat Cancer lnst 51:11191122, 1973 17. Tormey DC, Waalkes TP, Synder JJ, et al: Biological markers in breast carcinoma-IlI. Clinical correlations with carcinoembryonic antigen. Cancer 39:2397-2404, 1977 18. Meeker WR, Kashmiri R, Hunter L, et al: Clinical evaluation of carcinoembryonic antigen test. Arch Surg 107:266-274, 1973 19. Ravry M, Moertel CG, Schutt AJ, et al: Usefulness of serial serum carcinoembryonic antigen (CEA) determinations during anti-cancer therapy of long-term follow-up of gastrointestinal carcinoma. Cancer 34:1230-1234, 1974 20. Wang DY, Bulbrook RD, Hayward JL, et al: Relationship between plasma carcinoembryonic antigen and prognosis in women with breast cancer. Eur J Cancer 11:615-618, 1975 21. Steward AM, Nixon D, Zamcheck N, et al: Carcinoembryonic antigen in breast cancer patients: Serum levels and disease progress. Cancer 33:1246-1252, 1974 22. Thompson DMP, Krupey J, Freedman SO, et al: The radioimmunoassay of circulating carcinoembryonic antigen of the human digestive system. Proc Nat Acad Science 64:161-167, 1969 23. Dhar P, Moore TL, Zamcheck N, et al: Carcinoembryonic antigen (CEA) in colonic cancer: Use in preoperative and postoperative diagnosis and prognosis. JAMA 221:31-35, 1972 24. A collaborative study of a test for carcinoembryonic antigen (CEA) in the sera of patients with carcinoma of the colon and rectum: A Joint National Cancer Institute of Canada/American Cancer Society investigation. Can Med Assoc J 107:25-33, 1972 25. Livingstone AS, Hampson LG, Shuster J, et al: Carcinoembryonic antigen in the diagnosis and management of colorectal carcinoma. Arch Surg 109:259-264, 1974
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NOVEMBER 1978 *
129 * 5
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