Patients with high risk of hematogenous metastasis and recurrence in colorectal cancer: correlation with histopathologic variables and tumor markers, CEA and CA19-9, in peripheral and draining venous blood

Correlations of hematogenous metastasis with histopathologic variables, preoperative CEA and CA19-9 levels in peripheral (p) venous blood, and those in draining (d) venous blood were examined in 78 patients with colorectal cancer. Out of 10 histopathologic variables, location of venous invasion was most significantly correlated with hematogenous recurrence: the rate (11%) of v0 and/or sm-pm v(+) in 50 patients without the recurrence was significantly lower than that (89%) in 28 patients with the recurrence. On the other hand, the rate (68%) of ss-extra(+) in the latter was significantly higher than that (32%) of the former. The mean values (6 and 14 ng/ml) and positive rates (22 and 48%) greater than 5 ng/ml of p and d-CEA in 50 patients without the recurrence were significantly lower than those (14 and 189 ng/ml, 48 and 96%) in 28 patients with the recurrence. Patients with d-p CEA gradient greater than 5 ng/ml were found, respectively, in 34% of the former and 82% in the latter. The mean value (982 U/l) and positive rate (94%) greater than 37 U/ml of CA19-9 in peripheral blood of 28 patients with the recurrence were significantly higher than those (25 U/ml and 11%) of 50 patients without the recurrence. These results suggest that colorectal cancer patients with high risk of hematogenous metastasis and recurrence are the patients with ss-extra(+), the values of d-CEA, especially d-p CEA gradient, greater than 5 ng/ml and with p-CA19-9 value greater than 37 U/ml.     

Key role of the CEA test in the diagnosis and surgical therapy of recurrent colorectal cancer

Between 1978 and 1984, 87 patients with recurrent colorectal cancer have been operated upon. In 10 of 35 patients with locoregional recurrence and 24 of 52 with distant metastases therapy was potentially curative. Of 87 patients 73 had elevated CEA levels (greater than or equal to 5 ng/ml) at the time of diagnosis. In 65 of 73 patients the CEA increase preceded the recognition of recurrence and in 14 patients the diagnosis could be confirmed only by a second-look operation. Patients with metastases (91.3%) showed CEA elevation more often than those with locoregional recurrence (71.4%). Patients with operable disease had significantly (p less than 0.05) lower CEA values (median 19.7 ng/ml) than those with inoperable recurrent carcinomas (median 36.9 ng/ml).     

Serum CEA levels in patients with gastric carcinoma correlate with the tumorigenicity of their xenografts in nude mice

We examined the correlation among preoperative serum carcinoembryonic antigen (CEA) levels, staining properties of the tumors by CEA immunohistochemistry and the tumorigenicity of their xenografts in nude mice, in 28 patients with gastric cancer. Eleven (40 per cent) of them were positive for serum CEA (greater than or equal to 2.5 ng/ml) and seven (25 per cent) of the xenografts were tumorigenic in nude mice. All the tumorigenic cases were positive for serum CEA (p less than 0.001) and the mean value of the serum CEA level in the patients with tumorigenic neoplasms was 20.8 ng/ml, being significantly higher than that (1.4 ng/ml) in the patients with non-tumorigenic neoplasms (p less than 0.001). Twenty-five of the 28 carcinomas (89 per cent) were positive for CEA staining in their cancer cells by the ABC method and CEA localization correlated with tumorigenicity (p less than 0.05). These results suggest that the serum CEA level in patients is correlated with the tumorigenicity of their gastric carcinoma xenografts in nude mice and may account for the poor prognosis of patients with high serum CEA.     

The clinical usefulness of preoperative CEA determination in gastric cancer

Between 1980 and 1984, preoperative serum carcinoembryonic antigen (CEA) was determined in 468 patients with gastric cancer to evaluate its clinical usefulness. The positive rate of preoperative CEA was 20.9 per cent in these 468 patients. A significantly higher CEA positive rate was obtained in those patients with liver metastasis (69.2 per cent), n3-4 (40.0 per cent), stage IV gastric cancer (37.0 per cent) and Pap, Tub1 histological type (26.3 per cent) (p less than 0.01). It is interesting that the positive rate of the 49 unresectable patients was 51.0 per cent, which was significantly higher than 17.4 per cent of the 419 resectable cases (p less than 0.01). CEA levels in 16 of the 39 patients with liver metastasis were more than 100 ng/ml. In contrast, serosal invasion and peritoneal metastasis were less correlated to the CEA positive rate. In the 419 resected cases, the 5 year survival rate in the higher CEA group of more than 50 ng/ml (35 cases) was 4.4 per cent, which was significantly lower than 64.0 per cent in the negative group (346 cases) (p less than 0.01). These results show that CEA determination in patients with gastric cancer is useful for the prediction of prognosis, as well as for a diagnostic tool to discover the presence of liver or lymph node metastasis.     

Carcinoembryonic antigen (CEA) levels of peripheral and portal blood and tumor histopathology in colorectal cancer

Correlation between CEA levels of peripheral and portal blood and 9 histopathologic variables were examined in 66 patients with colorectal cancer. CEA levels of portal blood (mean 26.6ng/ml and positive rate more than 5ng/ml, 59.1%) were significantly higher than those (8.1ng/ml and 33.3%) of peripheral blood. Elevation of CEA levels in portal and peripheral blood were most highly correlated with the grade of vein invasion and its location in the layer of colorectal wall, although the levels were related to the other 8 histopathologic variables such as tumor size, the grade of node metastases, Dukes stage and so on. CEA levels of portal blood elevated from 19.4ng/ml and 40% to 43.6ng/ml and 90.2% respectively following operative stimuli to cancer lesions with vein invasion, but the levels did not elevated in the lesions without its invasion. CEA levels of peripheral blood were as low as 5ng/ml in 3 out of 8 patients with liver metastases. However, the levels in portal blood were much higher than 5ng/ml in all the patients. These results suggested that CEA might be hematogenously drained by portal system from cancer cells in the invasive veins, but not by thoracic duct of lymphatic system, and also that the measurement of CEA in portal blood might be available to predict the vein invasion of cancer lesions and liver metastases in patients with colorectal cancer.     

Plasma levels of CEA as a prognostic marker in carcinoma of urinary bladder.

Plasma carcinoembryonic antigen (CEA) levels were performed preoperatively by radioimmunoassay in 124 patients with histologically proved bladder carcinoma. The level of CEA was used to determine its prognostic value in patients with bladder cancer. The correlation of CEA levels with the stage of the disease, histology, and resectability was also studied. Values above 2.5 ng/ml were taken as abnormal. Active disease was associated with high CEA levels. All patients with CEA levels greater than 10 ng/ml died in less than 1 1/2 years, while all patients who survived 1 1/2-3 years had preoperative CEA levels less than 10 ng/ml. There was a prognostic significance for patients with transitional cell or squamous cell carcinoma. All patients with squamous cell carcinoma had CEA levels less than or equal to 10 ng/ml, and all patients with transitional carcinoma had preoperative CEA values greater than 10 ng/ml. A correlation between CEA levels and resectability of the primary tumor was found. This study indicates that, in bladder carcinoma patients, preoperative CEA levels greater than 10 ng/ml are of prognostic value, since all of these patients have died and all of the long-term survivors had levels of less than or equal to 10 ng/ml.     

Relationship between colorectal liver metastases and CEA levels in gallbladder bile.

While computerized tomographic (CT) scanning and intraoperative exploration are both considered accurate measures of liver involvement with metastatic disease, 10% to 30% of colorectal liver metastases remain undetected. Attempting to improve current methods for detecting colorectal liver metastases, CEA levels in gallbladder bile and serum from patients with known liver metastases were determined. One hundred per cent of patients with single and multiple metastases of various dimensions were observed to have gallbladder bile CEA levels strikingly higher than serum values (4.7 to 259 times greater, p = 0.0009). Linear regression analysis of estimated tumor volume and surface area versus gallbladder bile CEA levels predicted that very small tumors (less than or equal to 1 cm3 in volume) might produce detectable levels (9 to 41 ng/mL) of biliary CEA. For this reason, patients who lack clinical and radiologic evidence of distant metastases at the time of primary colorectal resection but who do have elevated gallbladder bile CEA levels (greater than or equal to 10 ng/mL) are being followed for the appearance of occult hepatic metastases.     

CEA Monitoring Among Patients in Multi-institutional Adjuvant G.I. Therapy Protocols

The Gastrointestinal Tumor Study Group (GITSG) has since 1975 included protocols for monitoring carcinoembryonic antigen (CEA) levels in its colorectal cancer adjuvant trials. Among the 563 patients on the colon cancer study (GI 6175) and the 207 patients on the rectal cancer study (GI 7175), one third had preoperative CEA determinations and more than 90% had some postoperative CEA monitoring. Colon cancer patients whose preoperative CEA was greater than 5 ng/ml had a greater probability of recurring than those whose values were lower (33% versus 18% recurrence with 21 months minimum follow-up; p < 0.05). The prognostic value of preoperative CEA was apparent only in patients with Dukes' C1 colon tumors. Preoperative CEA values were not of prognostic significance among the rectal adenocarcinoma patients. Although elevated levels of CEA after resection of either colon or rectum cancers were strongly associated with subsequent tumor recurrence, no single CEA value, arbitrarily defined as “elevated”, provided an adequate screening test with both high sensitivity and high specificity. Postoperative CEA elevations were more strongly predictive of recurrence when part of a steadily rising trend. In the colon cancer study, the median monthly increase in CEA for disease-free patients was estimated to be zero, and for the relapsed patients 5.8%. The corresponding estimates for patients on the rectal cancer protocol were zero and 7.8%. Only 36 of the 344 disease-free patients on the colon protocol and 14 of the 94 disease-free patients on the rectal protocol (15%) exhibited a rate of increase of CEA as high as 3% per month over the entire period of observation. Two thirds of the relapsed patients on both studies showed a rate of increase this high or higher. The patterns of CEA rise in individual patients were quite varied, however, and monthly rates of increase as established in our study are not to be used as guidelines in patient management.     

The usefulness and limitations of CEA assay in the management of colorectal cancer

We investigated the usefulness and limitations of the measurement of CEA in the evaluation of tumor resection and the detection of recurrence in colorectal cancer patients. Preoperatively, 46 of 90 patients (51.1%) had CEA values of 5.0 ng/ml or higher. The percentage of patients with elevated CEA in whom the CEA values returned to normal one month postoperatively was significantly higher in those who had undergone a curative resection than in those who had undergone a non-curative resection (p<0.02). Among patients with normal CEA values, the changes were nil or only slight in CEA values, one month postoperatively Among 28 with recurrences, 24 (85.7%) had CEA values of 5.0 ng/ml or higher. All 11 with liver recurrences had values of 10.0 ng/ml or higher. In 4 with liver recurrences and in cases where CEA measurements were made, CEA values were found to be abnormal 3 to 10 months before the recurrences and a rapid elvation occurred for a short period. However, 4 out of 10 with local or lymphnode recurrences showed normal CEA values. CEA measurement was useful in detection of liver recurrences, but not so useful in detecting local or lymphnode recurrences.     

Significance of CEA in gastric and colorectal cancer

The determination of serum CEA (Sandwich method) and CEA staining (PAP method) of excised specimens were performed in patients with gastric or colorectal cancer, and the biological characteristics of each cancer and the factors to increase serum CEA were studied with the following results: As colonic cancer has strong CEA productivity, serum CEA can be useful for the detection of cancer, and especially effective for the postoperative observation. Gastric cancer has weak CEA productivity, and serum CEA is not so useful in the detection of cancer and the judgement of resectability. The CEA positive rate of tissue with CEA staining was 80% in gastric cancer, 100% in colonic cancer, and were nearly equal to the CEA positive rate of serum in the group of terminal stage. In the mode of CEA staining of cancerous cells, IV type was observed most frequently in gastric cancer, and I type in colonic cancer. Among the resected cases showing more than 7ng/ml serum CEA, differentiated type, lymph node metastasis (+), the degree of tissue staining with CEA staining, the mode of cell staining O or I type in gastric cancer and I type in colonic cancer were observed in common.     

The clinical usefulness of preoperative CEA determination in gastric cancer

Between 1980 and 1984, preoperative serum carcinoembryonic antigen (CEA) was determined in 468 patients with gastric cancer to evaluate its clinical usefulness. The positive rate of preoperative CEA was 20.9 per cent in these 468 patients. A significantly higher CEA positive rate was obtained in those patients with liver metastasis (69.2 per cent), n_3–4 (40.0 per cent), stage IV gastric cancer (37.0 per cent) and Pap, Tub₁ histological type (26.3 per cent) (p<0.01). It is interesting that the positive rate of the 49 unresectable patients was 51.0 per cent, which was significantly higher than 17.4 per cent of the 419 resectable cases (p<0.01). CEA levels in 16 of the 39 patients with liver metastasis were more than 100 ng/ml. In contrast, serosal invasion and peritoneal metastasis were less correlated to the CEA positive rate. In the 419 resected cases, the 5 year survival rate in the higher CEA group of more than 50 ng/ml (35 cases) was 4.4 per cent, which was significantly lower than 64.0 per cent in the negative group (346 cases) (p<0.01). These results show that CEA determination in patients with gastric cancer is useful for the prediction of prognosis, as well as for a diagnostic tool to discover the presence of liver or lymph node metastasis.     

The usefulness of CEA as an indicator for early detection and a guide to the treatment of recurrent gastric cancer

The usefulness of carcinoembryonic antigen (CEA) as an indicator for recurrence and a guide to the treatment was evaluated from a retrospective analysis of 88 patients with recurrent gastric cancer. Sixty-two of these patients (70.5 per cent), 25 of whom had a preoperative positive assay, and 37 a negative assay, had elevated levels of CEA after disease progression. Averaged CEA level in patients with liver metastasis was significantly higher (872 ng/ml) than in those with peritoneal metastasis (68 ng/ml), with lymph node metastasis (103 ng/ml) or with local metastasis (93 ng/ml) (p less than 0.01). An elevation of CEA was found prior to the clinical manifestation of recurrence, and the average lead time was 4 months. In 25 patients with a lead time of more than 4 months, survival time after CEA elevation was 13.3 months, which was longer than the 6.5 months of 28 patients with less than 4 months. Thirty-seven of the 88 patients were treated after recurrence. The average survival period after the detection of recurrence was 9.4 months in patients with surgical treatments followed by chemotherapy, 5.9 months in those with chemotherapy alone and 3.8 months in those with surgery alone. The average survival period of 26 patients with positive CEA assays in recurrence was 5.1 months longer than of patients with negative assays. This fact suggested that early detection of recurrence followed by various treatments, in the elevated CEA group, contributes to favorable results.     

Histopathologic and immunohistochemical studies on the elevation mechanism of carcinoembryonic antigen (CEA) in gastric cancer patients

Correlation between carcinoembryonic antigen (CEA) levels of peripheral and draining venous blood, and 11 histopathologic and 2 immunohistochemical variables, was examined in 53 gastric cancer patients and 8 patients with benign diseases. CEA levels of draining blood (with a mean of 136.5 ng/ml and positive rate greater than 5 ng/ml, 58, 3%) were significantly higher than those (30.3 ng/ml, 22.9%) of peripheral blood in patients with CEA producing cancer. However, CEA levels of draining blood were as low as 5 ng/ml and were not different from those of peripheral blood in all of the patients with CEA non-producing cancer and benign diseases. Elevation of CEA levels in draining and peripheral blood was most highly correlated with the venous invasion, although the levels in draining blood were related to other histopathologic variables including tumor size, macro- and microscopic types, invasive layer of gastric wall, peritoneal dissemination, liver and node metastasis, lymphatic invasion and stage classification except tumor location. These variables relating to CEA elevation in the blood were highly correlated with venous invasion. However, tumor location was not found the relation with venous invasion. These results suggest that CEA may be haematogenously drained by the portal system via the draining vein from the CEA producing cancer cells in the invasive veins but not by the thoracic duct of the lymphatic system, and that histopathologic CEA elevation-relating variables may affect secondarily the CEA elevation in the blood in association with the venous invasion.     

Carcinoembryonic antigen (CEA) assays in obstructive colorectal cancer.

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.     

Preoperative high CEA level in lung cancer patients: significant of measurement of serum CEA level among preoperative and postoperative course in long time observed patient]

We measured pre- and postoperative CEA level in 330 patients who underwent resection for lung cancer at Kyushu Cancer Center Hospital between 1983 and 1986 using RIA method. There were 93 patients with high preoperative serum CEA level above 5 ng/ml. The interrelationships among preoperative serum CEA level, prognostic factors, outcome, and postoperative change of CEA level were investigated in the 93 patients. Five-year survival rate of patients with preoperative serum CEA level ranging from 5.0 to 10.0 ng/ml (N = 53) was 60.0%, while that of patients with preoperative CEA level over 10.1 ng/ml (N = 40) was 24.6% (P less than 0.05). Recurrent rate was higher in patients with preoperative CEA level over 10.1 ng/ml, especially in those with lung cancer at stages I or II. However, patients with preoperative CEA level about 50 ng/ml, showed good outcome after curative resection. All 12 patients in whom postoperative serum CEA level did not return to normal died within 4 years, indicating that normalization of CEA level is an important factor in prognosis. This study indicates that among lung cancer patients with high serum CEA level, the preoperative CEA level and postoperative change of CEA level are apparently prognostic factors.     

Use of CEA as an Indicator of Early Recurrence and as a Guide to a Selected Second-look Procedure in Patients with Colorectal Cancer

The usefulness of the CEA as an indicator of recurrence and a guide to selected second-look surgery was evaluated from a retrospective analysis of 358 patients with colorectal cancer and from a prospective experience with 16 patients all of whom had been admitted for second-look surgery because of postoperative elevations of CEA only. Our previous experience had shown that after curative resection the CEA usually returned to normal levels (less than 5 ng/ml) within one month, but became elevated at time of clinically obvious recurrence being very high in patients with liver metastases, but only moderately elevated or normal in patients with local recurrence. All 16 patients had previously had curative resection of colorectal cancer; 13 in the rectum or rectosigmoid and three in the right colon. There were 13 Dukes' C and three Dukes' B cancers. All had been followed clinically and by CEA testing at three monthly intervals and were considered free of disease (NED) at time of CEA elevation.

The median disease free interval was 13 months (range 4-57 months) and the median CEA prompting admission for second-look operation was 21 ng/ml (range 10-56 ng/ml). The sites of recurrence were liver in six, lung in two and localized disease in six. Two patients had negative exploration for recurrence and were found to have cholelithiasis only (one of these later died of metastases). Resection for cure was done in seven and palliative resection or biopsy only was done in nine patients. At this time, four patients are NED (12-37 months), five are living with disease (10-16 months) and seven have died of disease (2-12 months). The CEA test provides a method of early detection of recurrence and may permit surgical retrieval in selected patients and earlier initiation of palliation in other patients. The longterm effects in patient salvage remain to be defined.

     

Serum CEA levels in patients with gastric carcinoma correlate with the tumorigenicity of their xenografts in nude mice

We examined the correlation among preoperative serum carcinoembryonic antigen (CEA) levels, staining properties of the tumors by CEA immunohistochemistry and the tumorigenicity of their xenografts in nude mice, in 28 patients with gastric cancer. Eleven (40 per cent) of them were positive for serum CEA (≧2.5 ng/ml) and seven (25 per cent) of the xenografts were tumorigenic in nude mice. All the tumorigenic cases were positive for serum CEA (p<0.001) and the mean value of the serum CEA level in the patients with tumorigenic neoplasms was 20.8 ng/ml, being significantly higher than that (1.4 ng/ml) in the patients with nontumorigenic neoplasms (p<0.001). Twenty-five of the 28 carcinomas (89 per cent) were positive for CEA staining in their cancer cells by the ABC method and CEA localization correlated with tumorigencity (p<0.05). These results suggest that the serum CEA level in patients is correlated with the tumorigenicity of their gastric carcinoma xenografts in nude mice and may account for the poor prognosis of patients with high serum CEA.     

The usefulness of CEA as an indicator for early detection and a guide to the treatment of recurrent gastric cancer

The usefulness of carcinoembryonic antigen (CEA) as an indicator for recurrence and a guide to the treatment was evaluated from a retrospective analysis of 88 patients with recurrent gastric cancer. Sixty-two of these patients (70.5 per cent), 25 of whom had a preoperative positive assay, and 37 a negative assay, had elevated levels of CEA after disease progression. Averaged CEA level in patients with liver metastasis was significantly higher (872 ng/ml) than in those with peritoneal metastasis (68 ng/ml), with lymph node metastasis (103 ng/ml) or with local metastasis (93 ng/ml) (p<0.01). An elevation of CEA was found prior to the clinical manifestation of recurrence, and the average lead time was 4 months. In 25 patients with a lead time of more than 4 months, survival time after CEA elevation was 13.3 months, which was longer than the 6.5 months of 28 patients with less than 4 months. Thirty-seven of the 88 patients were treated after recurrence. The average survival period after the detection of recurrence was 9.4 months in patients with surgical treatments followed by chemotherapy, 5.9 months in those with chemotherapy alone and 3.8 months in those with surgery alone. The average survival period of 26 patients with positive CEA assays in recurrence was 5.1 months longer than of patients with negative assays. This fact suggested that early detection of recurrence followed by various treatments, in the elevated CEA group, contributes to favorable results.     

Prognostic value of postoperative carcinoembryonic antigen concentration and extent of invasion of resection margins after hepatic resection for colorectal metastases.

OBJECTIVE: To evaluate the prognostic value of postoperative concentration of carcinoembryonic antigen (CEA) and extent of surgical margins after resection of liver metastases from colorectal cancer. DESIGN: Retrospective study. SETTING: Teaching hospital, Switzerland. SUBJECTS: 49 patients with hepatic metastases after primary colorectal cancer. INTERVENTIONS: Resection of hepatic metastases MAIN OUTCOME MEASURES: Assessment of prognostic value of variables by univariate and multivariate analysis. RESULTS: Median survival was 24 months (range 5-86 months). Resection margins were clear (> 1-cm) in 10, close (< 1-cm) in 25 and invaded in 9 patients. On univariate analysis, a postoperative concentration of CEA of <4ng/ml was correlated with prolonged survival (p < 0.001), but the width of the resection margin was not of prognostic importance. There was no correlation between width of resection margins and postoperative concentration of CEA (p = 0.5). On multivariate analysis, postoperative concentrations of CEA of 4 ng/ml or more were associated with increased risk of death (relative risk 7.3; 95% confidence interval (CI) 2.8-18.7, p < 0.001). CONCLUSION: Postoperative CEA offers better prognostic discrimination than the width of resection margins after resection of liver metastases from colorectal tumours. Some patients with invaded resection margins did survive for 3 years, but no patient did whose CEA concentration was 4 ng/ml or more. The definition of a potentially curative hepatic resection should include a postoperative CEA concentration of <4 ng/ml (within the reference range).