Carcinoembryonic Antigen (CEA) Assays in Obstructive Colorectal Cancer PAUL H. SUGARBAKER, M.D.,*

Four of 40 patients with resectable colon or rectal cancer had tumors causing acute large bowel obstruction with colonic dilatation; all 4 patients had preoperative CEA titers above 10 ng/ml with a mean of 28 ng/ml. Thirty-six cancer patients without acute colon obstruction had a mean CEA titer of 4.5 ng/ml; only 6 of 36 patients had circulating CEA titers 10 ng/ml or greater. This suggested that pre-treatment CEA titers in patients with obstructing cancer are unusually high. Multiple CEA assays were performed on two of the 4 patients with colonic obstruction before and after bowel decompressive procedures and prior to their definitive treatment. Relief of obstruction alone produces marked reduction in circulating CEA; this suggested that not only the extent of disease but also the pathophysiological changes associated with obstruction influenced circulating CEA levels. CARCINOEMBRYONIC ANTIGEN (CEA) may be pro-

duced in large amounts by some colon and rectal cancers,3 in small amounts by other diseased gastrointestinal organs,19 and in minimal amounts by normal tissue.14 Herrera, Chu and Murphy9 presented important data suggesting that preoperative CEA determinations correlated with the extent of disease; however, some patients were exceptions having high preoperative CEA values with localized disease. Livingstone et al.1" reported that patients who had no detectable circulating CEA may at post mortem examination have high antigen titers in the tumor mass itself. It seems that circulating CEA may vary markedly for incompletely under-

From the Department of Surgery of Peter Brent Brigham Hospital at Harvard Medical School

stood reasons in some patients even if tumors are of similar histology and stage. We report high circulating CEA values in 4 patients with acute colonic obstruction from colorectal cancer. The data suggest that the level of circulating CEA depends not only on its production by tumor and its metabolism by the liver,'6 but that other pathophysiological factors associated with obstruction may be important. Material and Methods

The pre-treatment CEA values of all patients who underwent a potentially curative surgical procedure for colorectal cancer in 1973 and 1974 on one of three general surgical services at the Peter Bent Brigham Hospital, and all patients who underwent preoperative radiation therapy for rectal cancer followed by potentially curative surgery, are plotted on Fig. 1. The tumors were classified by stage as described by Dukes.5 All CEA determinations were performed by the Hansen method as modified by Kupchik'0 with reagents provided by Roche Laboratories. The indirect assay was used to obtain all values. Submitted for publication February 4, 1976. Unusually High CEA Titers In Patients With Colonic Reprint requests: Paul H. Sugarbaker M.D., Surgery Branch, NIH, Dilatation: Four patients had acute large bowel obstrucBldg. 10, lON-116 Bethesda, Md. 20014. tion with colonic dilatation requiring prompt intestinal * Surgical research trainee supported by PHS Grant No. 5 TOI GMO 1561-08. Also supported by grant IM-18C from the American decompression. The obstruction caused abdominal pain Cancer Society. and gross abdominal distention. Barium enema examina-

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PRE-TREATMENT CEA(ng/ml) o No Colonic Obstruction * Colonic Obstruction A Poorly Differentiated, No Obstruction

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753 location of tumor, tumor pathology and size of the primary tumor as obtained from pathology reports. Relationship Between CEA Levels Of 10 nglml Or Greater And Tumor Location: Median pre-treatment CEA titers for 8 right-sided tumors was 3.9 ng/ml (range 2.6-140 ng/ml); 3 of the 8 patients had unusually high CEA levels of 10 ng/ml or greater. Median pretreatment CEA for 6 transverse colon tumors was 1.5 ng/ml (range 0.5-10.1 ng/ml); one of the 6 patients had a CEA of 10.3 ng/ml. Thirteen left colon tumors had a median pre-treatment CEA of 3.9 ng/ml (range 0.540 ng/ml); 3 of the 13 had a CEA of 10 ng/ml or greater. Thirteen rectal tumors had a median pretreatment CEA of 3.4 ng/ml (range 0.1-50 ng/ml); 3 of the 13 had a CEA of 10 ng/ml or greater. By chi square analysis, unusually high (10 ng/ml or greater) pretreatment CEA values were not associated with tumors in different locations with statistically different frequency.

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DUKES CLASSIFICATION

FIG. 1. Pre-treatment CEA values of 40 patients, four of whom had obstructing colorectal cancer. CEA titers are plotted according to their Dukes classification.5 None of these patients had disseminated disease at the time of surgical resection. Patients 1 and 2 had both obstructed and non-obstructed CEA values plotted.

tion showed no flow of contrast material beyond the tumor. No increase in pressure to force contrast material through the obstruction was used. All four patients had CEA titers above 10 ng/ml drawn while they had obstructive symptoms. Mean CEA titer prior to decompression was 28 ng/ml with a range of 10.3-50 ng/ml. Thirty-six patients had colonic cancer without colonic dilatation. Two of these patients had small bowel obstruction; one from cancer of the ileocecal valve and another from a localized colonic perforation. CEA titers prior to intestinal decompression were 7.3 and 3.7 ng/ml respectively. The other 34 patients had no marked bowel dilatation when pre-treatment CEA titers were obtained. Taking these 36 patients as a group, mean pretreatment CEA titer was 4.5 ng/ml. One patient's pretreatment CEA titer of 140 ng/ml was excluded being markedly outside the normal range. Six of these 36 patients had pre-treatment CEA titers of 10 ng/ml or greater. Search For Other Clinical Correlations: In an attempt to find other possible correlations besides colonic

obstruction with unusually high CEA values, the clinical histories of these 40 patients were reviewed. In addition to presence or absence of obstruction and Dukes classification, other variables were tabulated including

Relationship Between CEA Levels Of 10 nglml or Greater and Tumor Pathology: Pathologic examination of specimens from ten patients with pre-treatment CEA levels of 10 ng/ml or greater revealed 6 patients classified as Dukes B and 4 patients as Dukes C (Fig. 1). All tumors were well differentiated or moderately well differentiated as were 90Wo of the tumors in this group of patients. As indicated in Fig. 2, four patients with

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FIG. 2. A linear correlation of tumor volume and pretreatment CEA values was found if one unusually high titer and four titers in patients with poorly differentiated cancer are omitted. Pre-treatment CEA values in three patients with colonic obstruction defined a regression line that was significantly above the regression line defined by values obtained from patients without colonic obstruction (P = 0.016). Patients 1 and 2 had both obstructing and non-obstructing CEA values plotted.

Ann. Surg. * December 1976 SUGARBAKER 754 Patient 1: (Fig. 3) A 47-year-old woman had severe abdominal poorly differentiated tumor had normal or minimally cecal dilation produced by obstructing cancer of the elevated CEA values despite large tumor volume. This pain from flexure with a competent ileocecal valve. Initial CEA level splenic supports the findings of Martin and Martin13 and Denk was 10.3 ng/ml. The patient was not vomiting and was not

et al.4 who showed that the CEA content was lowest in poorly differentiated tumors by both extraction and immunofluorescence procedures. Relationship Between CEA Level And Tumor Size: In 29 patients, including 3 of the 4 patients with acute colonic obstruction, the tumor mass was not altered by radiation therapy or fulguration prior to excision so that tumor volume could be assessed. To calculate volume, the dimensions of the tumor obtained from pathology reports were multiplied to obtain cm3. If all pretreatment CEA values are plotted against tumor volume in cm3 as in Fig. 2, there is no statistically significant correlation (P = 0.07). However, if the patient with pretreatment CEA value of 160 ng/ml and 4 patients with poorly differentiated tumor are omitted, there is a highly significant correlation (P < 0.001). Pre-treatment CEA values in three patients with colonic obstruction defined a regression line that was significantly above the regression line defined by values obtained from patients without colonic obstruction (P = 0.016).

Case Reports Patients I and 2 showed that bowel decompression alone reduced the CEA levels significantly.

markedly dehydrated; emergency right transverse colostomy resulted in a prompt fall in CEA level to 2.6 ng/ml. It remained between 2.6 and 5.3 ng/ml until left colectomy was done two and a half weeks later. CEA level fell after surgery to I ng/ml but then regained its minimally elevated preoperative level where it has remained. A liver biopsy specimen obtained at the time of surgery showed mild portal fibrosis. The patient has at present no evidence of malignancy 3 years following treatment. Decompression of the right colon appeared to have a greater effect in decreasing the elevated CEA than did removal of the tumor itself. In fact, there is little or no evidence that tumor removal decreased the CEA at all, for postoperative CEA titers remained persistently elevated after a transient decline. Patient 2: (Fig. 4) A 50-year-old woman sought medical advice for abdominal pain and distention from an obstructing cancer of the right colon. Vomiting prior to hospitalization produced moderate dehydration. Because of an incompetent ileocecal valve, complete small bowel and cecal decompression was possible with a long intestinal tube. CEA level fell from 12.7 to 5.2 ng/ml with intestinal suctioning and intravenous fluid replacement. Initially, all liver function tests were normal except for an LDH of 302 International Units (upper limit of normal = 186). Right colectomy removed all gross disease but did not further decrease the CEA level. At the time of surgery the liver was carefully inspected and was found to be free of tumor. Eight months postoperatively, the liver scan, which had been normal preoperatively, showed a central filling defect; CEA level at this time had increased to 10 ng/ml. Treatment with cyclophosphamide plus adriamycin resulted in a fall in CEA to 3 ng/ml

Age 47 V Dukes B

Obstructing Cancer, Splenic Flexure 12

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FIG. 3. Forty-seven-yearold woman with obstructing cancer of the splenic flexure requiring emergency right transverse colostomy. Decompression of this patient's obstruction resulted in a fall in CEA from 10.0 to 4.5 ng/ ml (average of 5 values).

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MILLER ABBOT TUBE

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Age 50 V Dukes C Obstructing Cancer, Right Colon

DECOMPRESSION

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woman with cancer of the

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and a normal liver scan. Chemotherapy was discontinued because of toxicity; CEA 3 years postoperatively was 140 ng/ml. Bowel decompression was associated with a decline in CEA titer to less than half its initial level. In fact, colonic obstruction was accompanied by higher CEA levels than were observed with the liver metastases diagnosed eight months later. Impaired liver function did not account for the initial high CEA, for liver function tests were essentially normal. Baseline CEA values of 4.46.6 ng/ml postoperatively might have been related to non-tumor CEA production since they did not decline further with removal of the bulky right colon tumor. Unfortunately clinical data available in the other two patients with colonic obstruction do not allow an assessment of the role tumor mass alone versus tumor mass plus obstruction played in causing elevated CEA values. However, Patients 3 and 4 call attention to unusually high preoperative CEA values seen in the presence of colonic obstruction and are presented as indirect evidence that obstruction may influence circulating CEA titers. Patient 3 had acute obstruction from a sigmoid cancer and underwent emergency resection with exteriorization of proximal and distal colon. CEA titer decreased from 39 ng/ml to less than I ng/ml where it has remained for three years. Patient 4 had acute obstruction from a rectal cancer treated by naso-gastric suction plus emergency radiation therapy; this resulted in a decrease of CEA from 50 to 4 ng/ml. Similar reductions in CEA titer in patients undergoing

ng/ml or greater without clinical or radiologic evidence of colonic dilatation. The clinical features of all 10 patients with unusually high CEA titers are shown in Table 1. Comment: Four patients with cancer causing acute large bowel obstruction with colonic dilatation had significantly higher pre-treatment circulating CEA titers than did patients without colon obstruction. In Patients 1 and 2 when the obstruction was relieved, CEA titers fell to less than half their former level without a reduction in tumor mass. In Patients 3 and 4, although pre-treatment CEA values were unusually high, the fall in CEA attributable to decompression could not be separated from that of tumor resection or radiation therapy. These preliminary data suggest that colonic obstruction is associated with elevation of pre-treatment circulating CEA titers and decompression with a reduction. Booth et al.2 and Herrera, Chu and Holyoke9 showed that a high preoperative CEA level usually indicated cancer of advanced stage which recurred soon after resection. Although this is true for most patients,

radiation therapy for localized colorectal cancer have been reported.17

other factors besides the extent or stage of the tumor may influence CEA levels. Undoubtedly the large mass of the obstructing cancers contributed to the high CEA levels with which they were associated in the patients with colonic dilatation. However, in correlating pretreatment CEA values and tumor volume, titers in

At abdomo-perineal resection there was invasion of the urethra; the patient died one year later with CEA over 500 ng/ml.

Patients With CEA 10 nglml Or Greater With NonObstructing Cancer: Six patients had CEA titers of 10

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TABLE 1. Clinical Features of Ten Patients wtith Pre-treatment CEA Titers Greater Than 10 nglml

Pt. No.

Pre-treat CEA (ng/ml)

1 2 3 4 5 6 7 8 9 10

10.3 12.7 39 50 27 18 140 14.0 12.2 10.0

Tumor Location

Splenic flexure Right colon Desc. colon Rectum Rectosigmoid

Sigmoid Right colon Right colon Rectum Rectum

Colonic Dil.

Colon Obst by Ba E

Tumor Size

(1-4+)

(1-4+)

(Cm3)

4+ 4+ 4+ 4+ 0 0 0 0 0 0

4+ 4+ 4+ 4+ 3+ 2+ 2+ 2+

72 16 144

1+ 1+

85 75.6 94 147 36

Dukes Class B C B B C C B B C B

Post-treat Baseline CEA mean & SD 2.47 6.26 1.17 25.8 3.37 3.55 5.21 4.68 1.50 1.08

± ± ± ± ± ± ± ± ± ±

0.97 1.61 0.75 6.43 3.2 0.91 0.71 1.45 0.62 0.45

Highest Post-treat CEA* (ng/ml)

Clinical Course

4.3 140 2.6 500 770 1500 6.2 6.9 420 39.0

NED Ca 3 years living w/recur Ca 3 years NED (a 3 years died a 1 year died @6 1 year living w/recur @: 3 years NED @ 18 months NED Ca 18 months died @4 2 years living w/recur Ca 1 year

* After post-treatment baseline CEA values reached.

patients with colon obstruction were significantly higher than non-obstructing titers. Other factors besides tumor mass including the rate of absorption of CEA from a tumor mass, and its possible reabsorption by inflamed colonic mucosa above an obstructing cancer, may be important. Ackerman,1 using an experimental model for intestinal obstruction in dogs, found lymph flow increased 4-5 times control values when mechanical factors simulating colonic obstruction were induced. This increased lymph flow may cause an increased absorption of CEA from tumor tissue. As Ackerman points out, it may also be responsible for the poor prognosis of patients with obstructing colorectal cancer.'5 Internal cleansing of the gastrointestinal tract after bowel decompression and in preparation for surgery may also have played a role in the decline of circulating CEA prior to tumor resection. Freed and Taylor,7 Elias et al.,6 Winawer et al.,18 and Go et al.8 reported CEA in feces and colonic washings of normal individuals and in large amounts in patients with colonic cancer. Retention of CEA-rich material behind an obstructing cancer may have resulted in reabsorption of CEA through inflamed colonic mucosa proximal to an obstructing cancer. Rehydration with intravenous fluids may also tend to decrease circulating CEA. However, in Patient 2 such replacement of fluids and electrolytes was accomplished within 24 hours while CEA fell more gradually with colonic decompression. In Patient 1, rapid colonic decompression with a colostomy led to a more rapid decline in CEA. In studying preoperative CEA titers in large numbers of colorectal cancer patients, Livingstone et al." and Martin et al.'2 determined that left colon tumors produced elevated CEA titers more frequently than did rightsided tumors. Our observation that colonic obstruction can increase circulating CEA titers may help explain such regional differences in CEA positivity, since left colon

cancer generally causes more constriction of the colonic lumen than right colon cancer. Although all patients with obstructing cancer in this patient population had pre-treatment CEA titers greater than 10 ng/ml, all obstructing cancers will not have such high circulating CEA levels. Small cicatrizing tumors causing obstruction may produce only small amounts of CEA, and not cause substantially elevated CEA levels. Also some tumors, especially poorly differentiated ones, do not produce CEA at all, so that even fecal CEA has occasionally been found absent.7 It is unlikely that colonic obstruction alone without colorectal cancer produces such marked CEA elevations. We found no reports of markedly elevated CEA values in patients with intestinal obstruction of non-malignant causes. Although all four patients with colon obstruction had pre-treatment CEA values over 10 ng/ml, 6 of 36 patients had high CEA titers without colonic dilatation; no consistent clinical or histopathological features were uncovered to explain them. Undoubtedly the level of circulating CEA is controlled by many pathophysiological processes, including production of CEA by the tumor, release of antigen into surrounding tissue and then entrance into lymphatics and the blood stream, metabolic degradation and excretion by the liver, and reabsorption of antigen from within the colonic lumen. Further study of these mechanisms will increase our knowledge of the pathophysiology of CEA and may improve its usefulness as a clinical tool.

Acknowledgment The authors wish to thank Ms. Caryl Boyden, Laboratory for Surgical Research, Peter Bent Brigham Hospital for her excellent help with the statistical analysis of these data, and Dr. Norman Zamcheck for his review of this manuscript.

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Carcinoma of the Intestine. Surg. Gynecol. Obstet., 138: 677-682, 1974. Booth, S. N., Jamieson, G. C., King, J. P. G., et al.: Carcinoembryonic Antigen in Management of Colorectal Carcinoma. Br. Med. J., 4:183-187, 1974. Burtin, D., von Kleist, S., Sabine, M. C. and King, M.: Immunohistological Localization of Carcinoembryonic Antigen and Non-specific Cross-reacting Antigen in Gastrointestinal Normal and Tumor Tissues. Cancer Res., 33:3299-3305, 1973. Denk, H., Tappeiner, G., Eckerstorfer, R. and Holgner, J. H.: Carcinoembryonic Antigen (CEA) in Gastrointestinal and Extragastrointestinal Tumors and Its Relationship to Tumor Cell Differentiation. Int. J. Cancer, 10:262-272, 1972. Dukes, C. E.: The Classification of Cancer of the Rectum. J. Pathol. Bacteriol., 35:323-332, 1932. Elias, E. G., Holyoke, E. D. and Chu, T. M.: Carcinoembryonic Antigen (CEA) in Feces and Plasma of Normal Subjects and Patients with Colorectal Carcinoma. Dis. Colon Rectum, 17:38-41, 1974. Freed, D. L. J. and Taylor, G.: Carcinoembryonic Antigen in Faeces. Br. Med. J., 1:85-87, 1972. Go, V. L. W., Amnon, H. V., Holtermuller, K. H., et al.: Quantification of CEA-like Activity in Human Gastrointestinal Secretions. Clin. Res., (Abstract) 22:489, 1974. Herrera, M. A., Chu, T. M. and Holyoke, E. D.: Carcinoembryonic Antigen (CEA) as a Prognostic and Monitoring Test in Clinically Complete Resection of Colorectal Carcinoma. Ann. Surg., 183:5-9, 1976. Kupchik, H. Z., Zamcheck, N. and Saravis, C. A.: Immunochemical studies of carcinoembryonic antigen: Methodologic

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considerations and some clinical implications. J. Nat. Cancer Inst., 51:1741-1749, 1973. Livingstone, A. S., Hampson, L. G., Shuster, J., et al.: Carcinoembryonic Antigen in the Diagnosis and Management of Colorectal Carcinoma. Arch. Surg., 109:259-264, 1974. Martin, E. W., Kibbey, W. E., Di Vecchia, L., et al.: Carcinoembryonic Antigen: Clinical and Historical Aspects. Cancer, 37:62-81, 1976. Martin, F. and Martin, M. S.: Radioimmunoassay of Carcinoembryonic Antigen in Extracts of Human Colon and Stomach. Int. J. Cancer, 9:641-647, 1972. Pusztaszeri, G. and Mach, J. P.: Carcinoembryonic Antigen (CEA) in Non-digestive Cancerous and Normal Tissues. Immunochem., 10:197-204, 1973. Ragland, J. J., Londe, A. M. and Spratt, J. S.: Correlation of the Prognosis of Obstructing Colorectal Carcinoma with Clinical and Pathologic Variables. Am. J. Surg., 121:552556, 1971. Shuster, J., Silverman, M. and Gold, P.: Metabolism of Human Carcinoembryonic Antigen in Xenogenic Animals. Cancer Research, 33:65-68, 1973. Sugarbaker, P. H., Bloomer, W. D., Chaffey, J. T., et al.: Carcinoembryonic Antigen (CEA) Monitoring Radiation Therapy for Colorectal Cancer. Am. J. Roent, In Press. Winawer, S. J., Fleisher, M., Melamed, M., et al.: Cytological, Immunological (CEA) and Isotope Labeling Studies Based on Gastrointestinal Endoscopic Lavage. Gastroenterology, (Abstract) 66:800, 1974. Zamcheck, N., Moore, T. L., Dhar, P. and Kupchik, H.: Immunologic Diagnosis and Prognosis of Human Digestive Tract Cancer: Carcinoembryonic antigens. N. Engl. J. Med., 286:83-86, 1972.