Symposium on New Methods of Treatment of Gastrointestinal Disease

The Use of Carcinoembryonic Antigen in the Clinical Management of Colorectal Cancer Jacob Benjamin Green, III, M.D., and Arthur A. Trowbridge, M.D.

After the plasma assay for carcinoembryonic antigen was first described in 196925 and offered as hope for a specific "cancer test," physicians involved in the care of patients with colorectal cancer eagerly awaited results of clinical trials utilizing this new diagnostic tool. Unfortunately, a growing body of evidence has eroded much of the initial optimism regarding the potential clinical usefulness of levels of carcinembryonic antigen in the care of patients with colorectal cancer in all stages. This brief review will attempt to outline some of the suggested uses of plasma levels of carcinoembryonic antigen, the problems associated with each, and current recommendations for practical applications in patient care.

BIOCHEMISTRY There is now evidence that carcinoembryonic antigen, as defined by the circulating material which binds with the antibodies commonly used in the available radioimmunoassay systems, is a mixture of related glycoproteins." Their estimated molecular weights are in the range of 150,000 to 250,000, and they differ primarily in their variable carbohydrate composition. Using very sensitive radioimmunoassay systems, several investigators have shown that carcinoembryonic antigen may be found in tissues other than gastrointestinal cancers and fetal and embryonic digestive system organs as originally suggested." Thus, it is not surprising that levels of carcinoembryonic antigen may be elevated in numerous pathologic states and seriously complicate interpreFrom the Division of Hematology-Oncology, Scott and White Clinic, Temple, Texas

Surgical Clinics of North America - Vol. 59, No.5, October 1979

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tation of assay results in individual patients. Hepatocellular disease, biliary obstruction, inflammatory bowel disease, pancreatitis, heavy smoking, and advancing age have all been associated with increased circulating levels of carcinoembryonic antigen;" There is ample data to suggest that carcinoembryonic antigen from different organ sources, both benign and malignant, has different antigen specificity. In addition, the carcinoembryonic "antigen" may differ in the primary tumor compared with metastatic lesions in the same patient." A widely accepted standard for use as a reference material is sorely needed to make the assay more reproducible and specific for colorectal carcinoma or other sources of origin.

PLASMA ASSAY FOR CARCINOEMBRYONIC ANTIGEN The most commonly used procedure for measurement of plasma levels of carcinoembryonic antigen is a commercially available radioimmunoassay, CEA-Roche." As mentioned above, the antigen and antibody utilized in this system lack absolute specificity for colorectal carcinoma, and levels may be elevated in many clinical conditions as well as an estimated 10 per cent of the normal population. Despite extensive experience with the assay, there is still considerable debate regarding the upper limits of normal. As a rule, values of 2.5 ng per ml or less are normal, and levels of 2.5 to 5 ng per ml should be considered to be questionable." Persistent elevation above 5 ng per ml is abnormal. The reliability and reproducibility of the carcinoembryonic antigen assay have been studied. It appears that precision of results in any single laboratory can usually be expected, but variation often occurs when comparing results of samples assayed by different laboratories. Thus, in following an individual patient, the same laboratory should be used for serial measurements of carcinoembryonic antigen when possible. In addition, limitations of the assay appear to negate the significance of any change in the levels of carcinoembryonic antigen less than two standard deviations from a prior measurement, and construction of a nomogram for individual laboratory quality control has been suggested." Sudden change in the level of carcinoembryonic antigen may suggest recurrent or metastatic colorectal cancer, as will be discussed below, but physicians should be aware that methodology of the assay (with or without perchloric acid extraction of the plasma) may markedly affect results." Marked variations in assay results should prompt inquiry regarding the methods used in the laboratory.

POTENTIAL CLINICAL USES OF CARCINOEMBRYONIC ANTIGEN IN THE MANAGEMENT OF COLORECTAL CARCINOMA Screening for Colorectal Cancer It was natural to hope that measurement of plasma carcinoembryonic antigen would be useful as a screening tool for colorectal can-

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ce~. However, it soon became evident that levels are elevated in numerous other malignant diseases, benign diseases, and even a significant number of the normal population. Such findings, and the realization that the majority of patients with early stage colorectal cancer have normal levels of carcinoembryonic antigen, have rendered measurement of plasma carcinoembryonic antigen totally useless as a screening test. Unfortunately, studies continue to suggest that plasma carcinoembryonic antigen is still used for this purpose!" - a practice which should be emphatically discouraged. There is currently some interest in screening colonic secretions for levels of carcinoembryonic antigen, and it has been suggested that this procedure could facilitate early detection." Further studies are needed to evaluate this method.

Assessing the Prognosis of Patients with Colorectal Cancer Preoperative assessment of plasma carcinoembryonic antigen has been reported to assist in establishing prognosis in individual patients. One of the largest studies has been reported by Wanebo and coworkers who examined the relation of preoperative levels of carcinoembryonic antigen to time, site, and extent of recurrence in 358 patients with colorectal cancer." In patients with Duke's Band C lesions, preoperative levels of carcinoembryonic antigen greater than 5 ng per ml were associated with increased recurrence rates, and recurrences occurred earlier with increasing levels. There is also data to suggest that failure of postoperative levels of carcinoembryonic antigen to fall into the normal range is associated with an adverse prognosis. Oh and MacLean have reported a definite increase in recurrence rates at 6, 12, and 18 months following surgery in patients who had preoperative levels of carcinoembryonic antigen greater than 2.5 ng per ml which persisted following surgery;" It should be noted that these findings were not correlated with stage, histologic grade of tumor, or other known prognostic factors. In general, patients without preoperative elevation of carcinoembryonic antigen have a greater proportion of early (Duke's A) lesions, less risk of recurrence, and a longer disease-free interval. Obviously, the intriguing aspect of this data relates to the question of whether or not preoperative elevation of carcinoembryonic antigen might identify that group of patients most likely to benefit from adjuvant chemotherapy or radiotherapy. Carefully designed clinical trials will be necessary to answer this question. One note of caution is in order. Significant bowel obstruction appears to be a cause of elevated plasma levels of carcinoembryonic antigen not related to high risk disease, and a decrease in the level of carcinoembryonic antigen may be seen following relief of obstruction without tumor resection;" Under such circumstances increased carcinoembryonic antigen could certainly not be used as a prognostic factor. Detection of Recurrence in Colorectal Cancer The use of serial postoperative plasma levels for the possible early detection of recurrent colorectal cancer is currently the most active area of clinical investigation related to carcinoembryonic antigen. In spite of this emphasis, there is no definitive data from controlled pros-

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pective studies to show that monitoring levels of carcinoembryonic antigen is cost effective or necessary if used in conjunction with routine careful clinical follow-up. Obviously, the goal of early detection is discovery of recurrent disease when additional therapy will still result in cure. There is general agreement that serial measurement of plasma carcinoembryonic antigen in the postoperative patient may allow earlier detection of recurrences.": 21 However, conflicting data exist regarding whether or not such early detection often yields resectable disease." 14. 15 For the most part, anecdotal data abound in recommending measurements of carcinoembryonic antigen every one to three months postoperatively in the hope of detecting resectable recurrences, and prospective studies are planned by the Cooperative Oncology Groups to confirm or refute this recommendation. If the physician chooses to systematically follow postoperative levels of carcinoembryonic antigen, several important observations must be kept constantly in mind. First, at least two or more successive elevations of levels of carcinoembryonic antigen over a two to three month period are required to be significant. This is necessary because of the inherent variability in the assay procedure as well as a significant incidence of transient unexplained postoperative elevation of carcinoembryonic antigen which do not reflect recurrent disease. IS A substantial portion of patients' with preoperative elevations of carcinoembryonic antigen which fall after surgery will also have recurrences unassociated with rising levels of carcinoembryonic antigen." Thus, use of carcinoembryonic antigen routinely as a monitor can only be recommended, if at all, in conjunction with standard clinical follow-up. One group of investigators has reported that the rate of increase of levels of carcinoembryonic antigen should determine how aggressively one should consider a second-look surgical procedure in the hope of finding a resectable recurrence. According to their findings, slow rises in carcinoembryonic antigen correlate with local often resectable recurrences, whereas rapid rises predicted unresectable disease." Monitoring Therapy in Colorectal Cancer There are numerous reports of the efficacy of serial measurements of carcinoembryonic antigen in assessing the response of recurrent or metastatic colorectal cancer to radiation therapy or chemotherapy. One of the earliest studies investigating the use of carcinoembryonic antigen to monitor therapy was reported by Vider and coworkers who found that changes in carcinoembryonic antigen correlated "in general" with response to therapy, that is, decreased carcinoembryonic antigen with shrinkage of tumor and increased carcinoembryonic antigen with progressive disease unresponsive to treatment." It should be emphasized, however, that this particular study included a variety of malignant diseases, and the total number of colorectal patients was not large. The most disturbing data relating to changes in levels of carcinoembryonic antigen correlated with response to therapy has been presented by Shani et ale In their investigation, significant discordance was. found between antitumor response and changes in the level of carcinoembryonic antigen, that is, no decrease or an increase

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with measurable antitumor response and vice versa." In addition, changes in levels of carcinoembryonic antigen did not correlate as well with survival as did objective response to treatment. Levels of carcinoembryonic antigen were of predictive value in terms of progression of disease in this study, showing an increase from 5 to 20 weeks before progression could be detected clinically. Still, simple and less expensive clinical measurements such as alkaline phosphatase were just as accurate in following hepatic metastases. Thus, the cost effectiveness of serial levels of carcinoembryonic antigen in their study was seriously questioned. Though of dubious benefit in following response to therapy in most patients with metastatic or recurrent colorectal cancer, there are clinical situations in which the monitoring of carcinoembryonic antigen may be useful. Although certainly not a totally reliable parameter, the level of carcinoembryonic antigen correlates in general with the amount of tumor mass present in most cases. When elevated, repeat assays during and following therapy may be helpful to assess the response in patients with metastatic or recurrent colorectal cancer which is not clinically measurable." This may be particularly helpful during irradiation therapy to assure that the bulk of the tumor producing carcinoembryonic antigen is in the treatment field. 22 Detection of Site-Specific Metastatic Disease in Colorectal Cancer Plasma levels of carcinoembryonic antigen may occasionally be useful to confirm site-specific metastatic disease in patients with known colorectal carcinoma. In clinical practice, the physician is often confronted with patients who have a prior history of colorectal carcinoma and findings highly suspicious .of, though not diagnostic for, metastatic disease. Probable or possible liver metastases are particularly troublesome in this regard. The use of plasma levels of carcinoembryonic antigen in combination with a liver scan may be helpful in such situations. Often, the liver scan can only be described as "abnormal" or "suggestive." When such is the case, a plasma level of carcinoembryonic antigen greater than 9 ng per ml has been reported to be virtually diagnostic of liver metastasis." Very high levels of carcinoembryonic antigen are also suggestive of hepatic involvement with tumor. However, as previously stated, benign hepatic disease and hepatobiliary obstruction can occasionally lead to elevated levels of carcinoembryonic antigen, but usually not of the magnitude seen with metastatic disease. It is not clear why levels of carcinembryonic antigen are elevated to such high levels. Both increased production of carcinoembryonic antigen by the liver and decreased degradation of carcinoembryonic antigen by a diseased liver has been suggested as possible explanations. Measurement of carcinoembryonic antigen in ascitic and pleural fluid may occasionally confirm metastatic colorectal carcinoma in patients with a past history of the disease and no other accessible metastases. There are no large studies yet reported, but it appears that levels of carcinoembryonic antigen in pleural fluid or ascitic fluid may be

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elevated in some cases even when cytology is negative." Pancreatitis may cause elevation of carcinoembryonic antigen in pleural fluid, and this should be taken into consideration in the individual patient. As is the case in the use of levels of carcinoembryonic antigen to confirm hepatic metastasis, analysis of fluid probably is benefical only in patients with a known diagnosis of colorectal cancer to substantiate metastatic disease if other studies are negative. Screening of Patients at High Risk for Colorectal Cancer Since the best hope for improving the dismal survival figures for colorectal cancer is earlier diagnosis, there has been interest in using levels of carcinoembryonic antigen to screen high-risk patients. Patients with familial polyposis, sporadic adenomatous or villous polyps, and inflammatory bowel disease are all at increased risk for colorectal cancer. Selected groups of each have been studied in terms of levels of carcinoembryonic antigen and their correlation with existing or future malignant disease. It does not appear that carcinoembryonic antigen is very useful in these situations. Patients with familial polyposis and their primary relatives show a 20 per cent incidence of increased plasma levels of carcinoembryonic antigen, but the increase is very small and does not correlate with malignant disease.' Increased levels of carcinoembryonic antigen have been suggested as an indicator of a "high risk" category for patients with sporadic colonic polyps, that is, a high risk for concomitant or eventual invasive colorectal cancer," However, confirmatory evidence is lacking. Carcinoembryonic antigen is often elevated in inflammatory bowel disease and levels may correlate with disease activity, but the development of invasive carcinoma of the large bowel is often not associated with increased levels of carcinoembryonic antigen. Thus, screening for cancer with plasma levels of carcinoembryonic antigen cannot be recommended even in high-risk patients.

RECOMMENDATIONS FOR THE USE OF CARCINOEMBRYONIC ANTIGEN IN THE CLINICAL MANAGEMENT OF PATIENTS WITH COLORECTAL CANCER Based on the data in the literature as reviewed briefly above, we believe that reasonable recommendations can be made for the use of plasma levels of carcinoembryonic antigen in the management of patients with colorectal cancer. 1. Levels of carcinoembryonic antigen should not be used as a screening test for colorectal cancer. The assay is too insensitive and nonspecific and may lead to a false sense of security, or to an array of needless diagnostic studies that are both unpleasant and expensive for the patient. 2. If serial measurements of carcinoembryonic antigen are made for any reason, the same laboratory should perform all assays. Interla-

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boratory variation in results is often quite significant and may render interpretation impossible. 3. Preoperative measurement of carcinoembryonic antigen in patients with colorectal cancer is indicated in the absence of obvious metastatic disease. Elevated values, especially if marked, suggest hepatic metastasis and would indicate the need for a liver scan or possible biopsy prior to subjecting the patient to the morbidity of a laparotomy. It is important to reemphasize that elevated levels of carcinoembryonic antigen preoperatively in patients who have colonic obstruction may not be indicative of advanced disease. The question of whether or not postoperative levels of carcinoembryonic antigen should be measured is a more difficult one. If the physician chooses to measure the postoperative levels of carcinoembryonic antigen, the assay should be done at least four weeks postoperatively. It has been shown that levels do not reach their lowest level until this point in most patients. If one chooses to subscribe to the theory that identification of the high-risk patient (failure of carcinoembryonic antigen to return to normal) with subsequent early detection of metastatic disease increases the likelihood of response to chemotherapy or radiation therapy, then postoperative levels of carcinoembryonic antigen should be measured routinely in most patients. However, there are no data in the literature to suggest that any currently available chemotherapeutic program is efficacious enough to warrant its routine use; therefore, one must seriously question the routine use of postoperative values of carcinoembryonic antigen until more effective therapy is available for metastatic disease. 4. We do not believe that there is sufficient data to justify routine measurement of serial plasma levels of carcinoembryonic antigen in patients who have undergone potentially curable surgery for colorectal cancer. The cost is not insignificant, and it has not yet been shown that second-look surgery in patients with rising levels of carcinoembryonic antigen leads to cures or even prolonged survival. Studies are currently underway in an attempt to resolve this issue. 5. Serial measurements of carcinoembryonic antigen may be very useful to monitor response to chemotherapy and radiotherapy in patients with unmeasurable disease. This is true both in patients with primary disease not amenable to surgery and with metastatic or locally recurrent disease which cannot be accurately measured clinically. 6. In patients with a history of colorectal cancer, measurement of levels of carcinoembryonic antigen in ascitic or pleural fluid is reasonable and may be helpful if the cause is uncertain and there is no other clinical evidence of metastatic disease.

SUMMARY Measurement of plasma levels of carcinoembryonic antigen, though not infrequently helpful in the management of patients with

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colorectal cancer, has serious limitations in terms of specificity and sensitivity. Many benign conditions may cause elevations of carcinoembryonic antigen, and even far advanced metastatic large bowel cancer may be associated with normal levels. Major treatment decisions should rarely, if ever, be based on plasma levels of carcinoembryonic antigen alone. Studies are currently underway to assess the value of serial levels of carcinoembryonic antigen in the early detection of recurrent disease with the hope of identifying patients who might be cured by secondary resections.

REFERENCES 1. AIm, T., and Wahren, B.: Carcinoembryonic antigen in hereditary adenomatosis of the colon and rectum. Scand. J. Gastroenterol., 10:875--879, 1975. 2. Alpert, E.: The immunochemical complexity of carcinoembryonic antigen. Cancer, 42:1585-1588,1978. 3. Doos, W. G., Wolff, W. 1., Shinya, H., et al.: Carcinoembryonic antigen levels in patients with colorectal polyps. Cancer, 36: 1996-2003, 1975. 4. Evans, J. T., Mittelman, A., Chu, M., et al.: Pre-and postoperative uses of carcinoembryonic antigen. Cancer, 42:1419-1421,1978. 5. Gold, P., Shuster, J., and Freedman, S. 0.: Carcinoembryonic antigen (CEA) in clinical medicine. Cancer, 42 :1399-1405, 1978. 6. Herrera, M. A., Chu, T. M., Holyoke, E. D., et al.: Carcinoembryonic antigen monitoring of palliative treatment for colorectal carcinoma. Ann. Surg., 185:23-30, 1977. 7. Jubert, A. V., Talbott, T. M., and Maycroft, T. M.: Characteristics of adenocarcinomas of the colorectum with low levels of preoperative plasma carcinoembryonic antigen. Cancer, 42 :635-639, 1978. 8. Loewenstein, M. S., Kupchik, H. Z., and Samcheck, N.: Disparity between CEA-Roche "indirect" and "direct" carcinoembryonic antigen values: Clinical relevance. New Engl. J. Med., 294:1123, 1976. 9. Lowenstein, M. S., Rittgers, R. A., Feinerman, A. E., et al.: Carcinoembryonic antigen assay of ascites and detection of malignancy. Ann. Intern. Med., 88:635-638, 1978. 10. Lowenstein, M. S., and Zamcheck, N.: Carcinoembryonic antigen levels in benign gastrointestinal disease states. Cancer, 42: 1412-1418, 1978. 11. Martin, E. W., Jr., James, K. K., Hurtubise, P. E., et al.: The use of CEA as an early indicator for gastrointestinal tumor recurrence and second-look procedures. Cancer, 39:440-446, 1977. 12. McCartney, W. H., and Hoffer, P. B.: Carcinoembryonic antigen assay in hepatic metastases detection. J.A.M.A., 236:1023-1027, 1976. 13. Meeker, W. R., Jr.: The use and abuse of carcinoembryonic antigen test in clinical practice. Cancer, 41 :854-862,1978. 14. Minton, J. P., James, K. K., Hurtubise, P. E., et al.: The use of serial carcinoembryonic antigen determinations to predict recurrence of carcinoma of the colon and the time for a second-look operation. Surge Gynecol. Obstet., 147 :208-210, 1978. 15. Moertel, C. G., Schutt, A. J., and Go, V. L. W.: Carcinoembryonic antigen test for recurrent colorectal carcinoma. J.A.M.A., 239:1065-1066, 1978. 16. Molnar, 1. G., Vandevoorde, J. P., and Gitnick, G. L.: Carcinoembryonic antigen levels in fluids bathing gastrointestinal tumors. Gastroenterology, 70:513-515, 1976. 17. Oh, J. H., and MacLean, L. D.: Prognostic use of preoperative and immediate postoperative carcinoembryonic antigen determinations in colonic cancer. Canad. J. Surg., 20:64--67, 1977. 18. Rittgers, R. A., Steele, G., Jr., Zaincheck, N., et al.: Transient carcinoembryonic antigen elevations following resection of colorectal cancer: A limitation in the use of serial carcinoembryonic antigen levels as an indicator for second-look surgery. J. Nat. Cancer Inst., 61 :315-318,1978. 19. Roche Diagnostics: Procedure manual for CEA-Roche carcinoembryonic antigen assay. Nutley, New Jersey, Hoffman-LaRoche, Inc., 1974. 20. Shani, A., O'Connell, M. J., Moertel, C. G., et al.: Serial plasma carcinoembryonic measurements in the management of metastatic colorectal carcinoma. Ann. Intern. Med., 88:627-630,1978.

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21. Staab, H. J~, Anderer, F. A., Stumpf, E., et al.: Carcinoembryonic follow-up and selection of patients for second-look operation in management of gastrointestinal carcinoma. J. Surg. Oncol., 10:273-282, 1978. 22. Sugarbaker, P. H., Bloomer, W. D., Corbett, E. D., et al.: Carcinoembryonic antigen monitoring of radiation therapy for colorectal cancer. Am. J. Roentgenol., 127 :641644,1976. 23. Sugarbaker, P. H.: Carcinoembryonic antigen assays in obstructive colorectal cancer. Ann. Surg., 184:752-757, 1976. 24. Taylor, R. N., Fulford, K. M., and Huong, A. Y.: Results of a nationwide proficiency test for carcinoembryonic antigen. J. Clin. Microbiol., 5 :433-438, 1977. 25. Thompson, D. M. P., Krupey, J., Freeman, S. 0., et al.: The radio-immunoassay of circulating carcinoembryonic antigen of the human digestive system. Proc. Nat. Acad. Sci., 64 :161-167, 1969. 26. Vider, M., Kashmiri, Meeker, W. R., et al.: Carcinoembryonic antigen monitoring in the management of radiotherapeutic and chemotherapeutic patients. Am. J. Roentgenol. Radium Ther. Nucl. Med., 124 :630-635, 1975. 27. Vrba, R., Alpert, E., and Isselbacher, K. J.: Immunochemical difference between plasma and tumor carcinoembryonic antigen. Fed. Proc., 34:513, 1975. 28. Wanebo, H. J., Bhaskar, R., Pinsky, C. M., et al.: Preoperative carcinoembryonic antigen level as a prognostic indicator in colorectal cancer. New Engl. J. Med. 299:448-451, 1978. Division of Hematology-Oncology Scott and White Clinic Temple, Texas 76501

The use of carcinoembryonic antigen in the clinical management of colorectal cancer.

Symposium on New Methods of Treatment of Gastrointestinal Disease The Use of Carcinoembryonic Antigen in the Clinical Management of Colorectal Cancer...
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