|.|l..|_l-|__I _I'l{I_I_I/{I Illi_I'|{/r lls {s_l_Iz!{j__EFffi_I^s_ s__r Carcinoembryonic Antigen New Applications for an Old Marker JEFFREY A. NORTON, M.D. From the Surgical Metabolism Section, Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
UMOR MARKERS ARE circulating factors that are measurable in biologic fluids of patients with cancer and serve as a marker of the disease state. In 1965 Gold and Freedman demonstrated that a fetal antigen (carcinoembryonic antigen, CEA) was present in extracts of tumors from the gastrointestinal tract and fetal gut tissue but not in extracts of adult intestinal tissue. Subsequently this antigen was detected in the circulation of patients with gastrointestinal cancer, but not in the circulation of patients with nonmalignant conditions.' Despite these auspicious beginnings and the fact that radioimmunoassay, enzyme-linked immunoassay, and other immunologic assays can detect minute amounts of tumor markers accurately and reproducibly, tumor markers have not been as useful in the clinical practice of oncology as the initial studies suggested they would be. The potential use of a circulating tumor marker includes screening of populations at risk for the development of tumor, unequivocal diagnosis of the presence of tumor, prognosis, assessment of therapeutic efficacy, and detection of residual or recurrent cancer. Currently the performance of available tumor markers as screening tests for the diagnosis of malignancy in high-risk individuals has been inadequate because of reduced sensitivity and occasional false-positive results. For example the use of serum levels of CEA in individuals with polyposis coli or ulcerative colitis has not detected reliably the presence of small, curable colon cancer.2 Preoperative serum levels of carcinoembryonic antigen do appear to have important prognostic information; in general studies indicate that the higher the preoperative serum level ofthis marker the worse the patient's prognosis." 2 Current, exciting experimental research may provide new insights as to why high CEA production by tumors is associated with increased tumor growth3 and poorer prognosis.",2 Carcinoembryonic T
antigen functions to modulate intercellular adhesion4 and as an accessory adhesion molecule to expedite colon epithelial cell-collagen interactions.5 Because high concentrations of CEA are present in fetal tissue and tumors, it may disrupt the normally operative intercellular or cellcollagen adhesion forces allowing more cell movement and the development of a less ordered tissue architecture and greater cell-cell interaction. The final application for measurement of circulating tumor markers and the area in which tumor markers appear to have the greatest clinical use is as a reflection of treatment efficacy and in follow-up for recurrent disease. In these settings, alterations in serum tumor marker levels may be the primary clinical variable influencing patient management decisions, such as continuing or discontinuing therapy or embarking on efforts to define the extent of disease by imaging studies or exploratory surgery. Unfortunately, even in the follow-up of patients with known diseases such as colon cancer, serum levels of CEA may not always reflect the presence or absence or extent of disease and so the surgeon cannot rely solely on these levels to make patient treatment decisions. In addition agents to treat colon cancer have not been very effective so that real elevations of serum levels of CEA have not necessitated changes in drugs or other agents because few, if any, effective agents are available. Carcinoembryonic antigen and its use in the management of patients with colon cancer is an important topic for surgeons. Colon carcinoma is one of the most common and most lethal cancers. In 1989 approximately 150,000 Americans developed colorectal cancer and 60,000 died of the disease.6 Effective, curative treatment of primary and even recurrent and/or metastatic colon cancer nearly always relies on surgical resection of all tumor mass. As mentioned CEA first was described 25 years ago and its
Address reprint requests to Jeffrey A. Norton, M.D., Surgical Metabolism Section, Surgery Branch, National Cnacer Institute/NIH, Bethesda, MD 20892. Accepted for publication September 17, 1990.
95
96
NORTON
use in management questions in patients with colon cancer has been studied fairly well. Unfortunately its current use is limited. In this issue of the Annals ofSurgery, Yeatman and associates from the University of Florida suggest a new application of this marker that may improve its
ability to detect liver metastases in patients with colorectal cancer.7 Recent studies indicate that new treatments may be effective in the management of patients with colorectal cancer. Postoperative radiation therapy and chemotherapy can prolong the disease-free interval8 and subsequent survival9 of patients with rectal adenocarcinoma who have undergone complete or curative surgical resection. Furthermore another recent study indicates that patients with Duke's stage C colon carcinoma (positive lymph nodes) have longer disease-free and overall survival intervals if treated with adjuvant fluorouracil (5-FU) and levamisole.'0 Finally highly meaningful improvements in objective response rates of patients with advanced unresectable colorectal cancer have been reported in six of seven recent trials with the use of 5-FU and folinic acid (either leucovorin or citrovorum factor) compared to 5-FU alone and in two of these studies an improvement in survival also was documented.6 Therefore, despite the high incidence of colon cancer and its relatively poor prognosis, results of recent studies indicate new drugs that are active in the treatment ofthe disease and suggest that these agents may be useful in the management of patients with more extensive disease. Occult, synchronous liver metastases are thought to be present in 10% to 30% of patients at the time of diagnosis of colorectal cancer. Because 25% to 30% of liver metastases from colon cancer may be, if detected early, resected for cure or treated with newer, potentially efficacious regimens such as 5-FU with leucovorin, a method to detect precisely liver metastases in patients with colorectal cancer would be very useful." Preoperative imaging of patients with colorectal cancer using computed tomography (CT) and magnetic resonance has been limited in ability to detect and stage disease accurately.'2 With CT, staging accuracy rates as high as 90% have been reported; however other investigations demonstrate accuracy rates as low as 48%. Magnetic resonance imaging is similar, with accuracy rates of approximately 73%. In fact, even with the use of both imaging modalities, smaller, surgically curable lesions are more likely to be missed.'2 Presurgical staging with labeled antibodies to CEA and other markers also have been developed recently to stage patients with colon cancer. Indium-labeled monoclonal anti-CEA antibody imaging studies have been evaluated in patients with a history of colorectal cancer and elevated serum levels of CEA without detectable disease on standard imaging studies, including CT. In one recent study with 13 patients evaluated, anti-CEA imaging correctly detected recurrent tumor in 11 no recurrence in 1, and was incorrect in only ,
Ann. Surg. February 1991 -
1 of 13 patients. '3 However that study had a large proportion of patients with local recurrences and only two patients had liver metastases.'3 Imaging with labeled antibodies to CEA has been less effective in localizing colorectal liver metastases, with a sensitivity rate of only 45% to 64%.14' Because accurate detection of liver metastases in patients with colorectal cancer remains a significant clinical problem, Yeatman and others have described a new method to detect the presence of liver metastases in patients with colorectal cancer. They have been able to measure elevated levels ofCEA in the gall bladder bile of these patients (more than 1O ng/mL). They reason that in the presence of CEA-secreting liver metastases, the concentrating ability of the gall bladder can concentrate CEA in the bile compared to serum levels. In this issue, they describe a perchloric acid extraction to remove the pigment and other bile proteins, allowing a simpler, more rapid radioimmunoassay with a lower detection limit.5 Previously in Annals of Surgery, Yeatman et al." described some important preliminary clinical investigations with this method. None of 7 patients with morbid obesity had elevated bile levels of CEA, and each of 17 patients with documented hepatic metastases from colorectal cancer had markedly elevated bile levels ofCEA, while 2 of these patients had normal serum levels (100% sensitivity). Unfortunately there have been some false-positive results. Six of eight patients with either acute cholecystitis or cholangitis had elevated bile levels of CEA, and one patient with a primary hepatoma had markedly elevated bile levels of CEA. False-positive results in infections of the biliary tree may not be a problem because the presentation of patients with biliary infections is dramatically different from patients with colorectal cancer. However the finding of marked elevations of gall bladder bile levels of CEA in a patient with hepatoma may diminish the usefulness of the study in cancer patients because the assay may not discriminate reliably between one type of liver cancer and another. Most worrisome was the finding that of seven patients with colorectal cancer without known liver metastases, three had elevated bile levels of CEA. This may represent a false-positive result because high venous effluent levels of CEA from the primary tumor entering the portal circulation. These high levels may bathe the liver and produce falsely high levels of CEA in the gall bladder bile. To rule out this explanation effectively, bile levels of CEA would have to be determined before and after the primary tumor had been removed. Another possible explanation is that occult, undetectable colorectal liver metastases are present but cannot be ascertained accurately with our current limitations of detection. The best plan to evaluate whether determination of CEA levels in gall bladder bile is helpful to diagpose occult, resectable and/or otherwise treatable liver metastases is a prospective study of serum and bile levels, "
Vol. 213 * No. 2
CARCINOEMBRYONIC ANTIGEN
at varying intervals in patients with primary colon cancer who are at risk of developing hepatic metastatic disease. Presumably gall bladder bile levels of CEA would have to be obtained by percutaneous transhepatic ultrasound or CT-guided repeated aspirations. Although this procedure can be performed safely, its invasive nature must be evaluated prospectively. It also must be determined whether it is cost-effective compared to determination of serum levels of CEA and repeated CT or magnetic resonance imaging studies. If ability to detect early lesions accurately can be corroborated, then subsequent studies may use gall bladder bile levels of CEA in these patients to alter treatment strategies: either exploratory surgery with ultrasound to assess and resect liver metastatic disease, or consideration of alternate therapy regimens. Portal vein infusional chemotherapy has been suggested by some,16 and systemic chemotherapy with 5-FU and leucovorin has been suggested by others.6 Treatment of tumor with yttrium-90-labeled monoclonal antibodies to CEA has prolonged survival markedly in experimental animal models of colon cancer that produce CEA.'7 In addition other recent studies make this approach more feasible in humans by using a second antibody to remove unbound circulating radiolabeled antibody, thus reducing the toxicity without influencing the anti-tumor effect. 18 Early definitive diagnosis of colorectal liver metastases by determination of elevated gall bladder bile levels of CEA may improve treatment efficacy and eliminate treatment failures in an organ in which most treatment failures occur. Although the marker CEA first was described more than 25 years ago, new applications including measurement of levels in gall bladder bile,7"' anti-CEA antibody imaging'3'-5 and treatment, 17,18 and new basic studies that demonstrate its cellular function4' 5 give it renewed emphasis and importance. These recent studies may appear promising but additional prospective, controlled studies will be necessary to determine the exact role of these potentially expensive and invasive procedures in the management of patients with colorectal cancer. References 1. Norton JA, Fraker DL. Malignant neoplasms: The role of specific serum tests in the diagnosis, management and evaluation of re-
2. 3.
4. 5.
6. 7.
8.
9. 10. 11.
12.
97
currence. In Sabiston DC Jr, ed. Textbook of Surgery, Update 2. Philadelphia: WB Saunders, 1989; pp 19-37. Fletcher RH. Carcinoembryonic antigen. Ann Intern Med 1986; 104:66-73. Jessup JM, Giavazzi R, Campbell D, et al. Growth potential of human colorectal carcinomas in nude mice: association with the preoperative serum concentration of carcinoembryonic antigen in patients. Cancer Res 1988; 48:1689-1692. Benchimoi S, Fuks A, Jothy S, et al. Carcinoembryonic antigen, a human tumor marker, functions as an intercellular adhesion molecule. Cell 1989; 57:327-334. Pignatelli M, Durbin H, Bodmer WF. Carcinoembryonic antigen functions as an accessory adhesion molecule mediating colon epithelial cell-collagen interactions. Proc Natl Acad Sci 1990; 87: 1541-1545. Mayer RJ, O'Connell MJ, Tepper JE, Wolmark N. Status of adjuvant therapy for colorectal cancer. J Natl Cancer Inst 1989; 81:13591364. Yeatman TJ, Kimura AK, Copeland EM, Bland KI. Rapid analysis of carcinoembryonic antigen levels in gallbladder bile: identification of patients for high risk for colorectal liver metastasis. Ann Surg 1990; 213:113-117. Holyoke ED, Mittleman A, Panahon A, et al. Prolongation of the disease-free interval in surgically treated rectal carcinoma. N Engl J Med 1985; 312:1465-1472. Douglass HO Jr, Moertel CG, Mayer RJ, et al. Survival after postoperative combination treatment of rectal cancer. N Engl J Med 1986; 315:1294-1295. Moertel CG, Fleming TR, Macdonald JS, et al. Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med 1990; 322:352-358. Yeatman TJ, Bland KI, Copeland EM, et al. Relationship between colorectal liver metastases and CEA levels in gallbladder bile. Ann Surg 1989; 210:505-512. Moss AA. Imaging of colorectal carcinoma. Radiology 1989; 170:
308-310. 13. Doerr RJ, Abdel-Nabi H, Merchant B. Indium 111 ZCE-025 immunoscintigraphy in occult recurrent colorectal cancer with elevated carcinoembryonic antigen level. Arch Surg 1990; 125:226229. 14. Beatty JD, Williams LE, Yamauchi D, et al. Presurgical imaging with indium-labelled anti-carcinoembryonic antigen for colon cancer staging. Cancer Res 1990; 50(Suppl):922s-926s. 15. Haller DG. Monoclonal antibody imaging in the management of patients with colorectal cancer. J Clin Oncol 1988; 6:1213-1215. 16. Taylor I, Machin D, Mullee M, et al. A randomized controlled trial of adjuvant portal vein cytotoxic perjusion in colorectal cancer. Br J Surg 1985; 72:359-363. 17. Hyams DM, Esteban JM, Beatty BG, et al. Prolongation of survival of nude mice bearing human colon cancer. Arch Surg 1989; 124: 175-179. 18. Blumenthal RD, Sharkey RM, Snyder D and Goldenberg DM. Reduction by anti-antibody administration of the radiotoxicity associated with '31I-labelled antibody to carcinoembryonic antigen in cancer radioimmunotherapy. J Natl Cancer Inst 1989; 81: 194-199.
UMOR MARKERS ARE circulating factors that are measurable in biologic fluids of patients with cancer and serve as a marker of the disease state. In 1965 Gold and Freedman demonstrated that a fetal antigen (carcinoembryonic antigen, CEA) was present in extracts of tumors from the gastrointestinal tract and fetal gut tissue but not in extracts of adult intestinal tissue. Subsequently this antigen was detected in the circulation of patients with gastrointestinal cancer, but not in the circulation of patients with nonmalignant conditions.' Despite these auspicious beginnings and the fact that radioimmunoassay, enzyme-linked immunoassay, and other immunologic assays can detect minute amounts of tumor markers accurately and reproducibly, tumor markers have not been as useful in the clinical practice of oncology as the initial studies suggested they would be. The potential use of a circulating tumor marker includes screening of populations at risk for the development of tumor, unequivocal diagnosis of the presence of tumor, prognosis, assessment of therapeutic efficacy, and detection of residual or recurrent cancer. Currently the performance of available tumor markers as screening tests for the diagnosis of malignancy in high-risk individuals has been inadequate because of reduced sensitivity and occasional false-positive results. For example the use of serum levels of CEA in individuals with polyposis coli or ulcerative colitis has not detected reliably the presence of small, curable colon cancer.2 Preoperative serum levels of carcinoembryonic antigen do appear to have important prognostic information; in general studies indicate that the higher the preoperative serum level ofthis marker the worse the patient's prognosis." 2 Current, exciting experimental research may provide new insights as to why high CEA production by tumors is associated with increased tumor growth3 and poorer prognosis.",2 Carcinoembryonic T
antigen functions to modulate intercellular adhesion4 and as an accessory adhesion molecule to expedite colon epithelial cell-collagen interactions.5 Because high concentrations of CEA are present in fetal tissue and tumors, it may disrupt the normally operative intercellular or cellcollagen adhesion forces allowing more cell movement and the development of a less ordered tissue architecture and greater cell-cell interaction. The final application for measurement of circulating tumor markers and the area in which tumor markers appear to have the greatest clinical use is as a reflection of treatment efficacy and in follow-up for recurrent disease. In these settings, alterations in serum tumor marker levels may be the primary clinical variable influencing patient management decisions, such as continuing or discontinuing therapy or embarking on efforts to define the extent of disease by imaging studies or exploratory surgery. Unfortunately, even in the follow-up of patients with known diseases such as colon cancer, serum levels of CEA may not always reflect the presence or absence or extent of disease and so the surgeon cannot rely solely on these levels to make patient treatment decisions. In addition agents to treat colon cancer have not been very effective so that real elevations of serum levels of CEA have not necessitated changes in drugs or other agents because few, if any, effective agents are available. Carcinoembryonic antigen and its use in the management of patients with colon cancer is an important topic for surgeons. Colon carcinoma is one of the most common and most lethal cancers. In 1989 approximately 150,000 Americans developed colorectal cancer and 60,000 died of the disease.6 Effective, curative treatment of primary and even recurrent and/or metastatic colon cancer nearly always relies on surgical resection of all tumor mass. As mentioned CEA first was described 25 years ago and its
Address reprint requests to Jeffrey A. Norton, M.D., Surgical Metabolism Section, Surgery Branch, National Cnacer Institute/NIH, Bethesda, MD 20892. Accepted for publication September 17, 1990.
95
96
NORTON
use in management questions in patients with colon cancer has been studied fairly well. Unfortunately its current use is limited. In this issue of the Annals ofSurgery, Yeatman and associates from the University of Florida suggest a new application of this marker that may improve its
ability to detect liver metastases in patients with colorectal cancer.7 Recent studies indicate that new treatments may be effective in the management of patients with colorectal cancer. Postoperative radiation therapy and chemotherapy can prolong the disease-free interval8 and subsequent survival9 of patients with rectal adenocarcinoma who have undergone complete or curative surgical resection. Furthermore another recent study indicates that patients with Duke's stage C colon carcinoma (positive lymph nodes) have longer disease-free and overall survival intervals if treated with adjuvant fluorouracil (5-FU) and levamisole.'0 Finally highly meaningful improvements in objective response rates of patients with advanced unresectable colorectal cancer have been reported in six of seven recent trials with the use of 5-FU and folinic acid (either leucovorin or citrovorum factor) compared to 5-FU alone and in two of these studies an improvement in survival also was documented.6 Therefore, despite the high incidence of colon cancer and its relatively poor prognosis, results of recent studies indicate new drugs that are active in the treatment ofthe disease and suggest that these agents may be useful in the management of patients with more extensive disease. Occult, synchronous liver metastases are thought to be present in 10% to 30% of patients at the time of diagnosis of colorectal cancer. Because 25% to 30% of liver metastases from colon cancer may be, if detected early, resected for cure or treated with newer, potentially efficacious regimens such as 5-FU with leucovorin, a method to detect precisely liver metastases in patients with colorectal cancer would be very useful." Preoperative imaging of patients with colorectal cancer using computed tomography (CT) and magnetic resonance has been limited in ability to detect and stage disease accurately.'2 With CT, staging accuracy rates as high as 90% have been reported; however other investigations demonstrate accuracy rates as low as 48%. Magnetic resonance imaging is similar, with accuracy rates of approximately 73%. In fact, even with the use of both imaging modalities, smaller, surgically curable lesions are more likely to be missed.'2 Presurgical staging with labeled antibodies to CEA and other markers also have been developed recently to stage patients with colon cancer. Indium-labeled monoclonal anti-CEA antibody imaging studies have been evaluated in patients with a history of colorectal cancer and elevated serum levels of CEA without detectable disease on standard imaging studies, including CT. In one recent study with 13 patients evaluated, anti-CEA imaging correctly detected recurrent tumor in 11 no recurrence in 1, and was incorrect in only ,
Ann. Surg. February 1991 -
1 of 13 patients. '3 However that study had a large proportion of patients with local recurrences and only two patients had liver metastases.'3 Imaging with labeled antibodies to CEA has been less effective in localizing colorectal liver metastases, with a sensitivity rate of only 45% to 64%.14' Because accurate detection of liver metastases in patients with colorectal cancer remains a significant clinical problem, Yeatman and others have described a new method to detect the presence of liver metastases in patients with colorectal cancer. They have been able to measure elevated levels ofCEA in the gall bladder bile of these patients (more than 1O ng/mL). They reason that in the presence of CEA-secreting liver metastases, the concentrating ability of the gall bladder can concentrate CEA in the bile compared to serum levels. In this issue, they describe a perchloric acid extraction to remove the pigment and other bile proteins, allowing a simpler, more rapid radioimmunoassay with a lower detection limit.5 Previously in Annals of Surgery, Yeatman et al." described some important preliminary clinical investigations with this method. None of 7 patients with morbid obesity had elevated bile levels of CEA, and each of 17 patients with documented hepatic metastases from colorectal cancer had markedly elevated bile levels ofCEA, while 2 of these patients had normal serum levels (100% sensitivity). Unfortunately there have been some false-positive results. Six of eight patients with either acute cholecystitis or cholangitis had elevated bile levels of CEA, and one patient with a primary hepatoma had markedly elevated bile levels of CEA. False-positive results in infections of the biliary tree may not be a problem because the presentation of patients with biliary infections is dramatically different from patients with colorectal cancer. However the finding of marked elevations of gall bladder bile levels of CEA in a patient with hepatoma may diminish the usefulness of the study in cancer patients because the assay may not discriminate reliably between one type of liver cancer and another. Most worrisome was the finding that of seven patients with colorectal cancer without known liver metastases, three had elevated bile levels of CEA. This may represent a false-positive result because high venous effluent levels of CEA from the primary tumor entering the portal circulation. These high levels may bathe the liver and produce falsely high levels of CEA in the gall bladder bile. To rule out this explanation effectively, bile levels of CEA would have to be determined before and after the primary tumor had been removed. Another possible explanation is that occult, undetectable colorectal liver metastases are present but cannot be ascertained accurately with our current limitations of detection. The best plan to evaluate whether determination of CEA levels in gall bladder bile is helpful to diagpose occult, resectable and/or otherwise treatable liver metastases is a prospective study of serum and bile levels, "
Vol. 213 * No. 2
CARCINOEMBRYONIC ANTIGEN
at varying intervals in patients with primary colon cancer who are at risk of developing hepatic metastatic disease. Presumably gall bladder bile levels of CEA would have to be obtained by percutaneous transhepatic ultrasound or CT-guided repeated aspirations. Although this procedure can be performed safely, its invasive nature must be evaluated prospectively. It also must be determined whether it is cost-effective compared to determination of serum levels of CEA and repeated CT or magnetic resonance imaging studies. If ability to detect early lesions accurately can be corroborated, then subsequent studies may use gall bladder bile levels of CEA in these patients to alter treatment strategies: either exploratory surgery with ultrasound to assess and resect liver metastatic disease, or consideration of alternate therapy regimens. Portal vein infusional chemotherapy has been suggested by some,16 and systemic chemotherapy with 5-FU and leucovorin has been suggested by others.6 Treatment of tumor with yttrium-90-labeled monoclonal antibodies to CEA has prolonged survival markedly in experimental animal models of colon cancer that produce CEA.'7 In addition other recent studies make this approach more feasible in humans by using a second antibody to remove unbound circulating radiolabeled antibody, thus reducing the toxicity without influencing the anti-tumor effect. 18 Early definitive diagnosis of colorectal liver metastases by determination of elevated gall bladder bile levels of CEA may improve treatment efficacy and eliminate treatment failures in an organ in which most treatment failures occur. Although the marker CEA first was described more than 25 years ago, new applications including measurement of levels in gall bladder bile,7"' anti-CEA antibody imaging'3'-5 and treatment, 17,18 and new basic studies that demonstrate its cellular function4' 5 give it renewed emphasis and importance. These recent studies may appear promising but additional prospective, controlled studies will be necessary to determine the exact role of these potentially expensive and invasive procedures in the management of patients with colorectal cancer. References 1. Norton JA, Fraker DL. Malignant neoplasms: The role of specific serum tests in the diagnosis, management and evaluation of re-
2. 3.
4. 5.
6. 7.
8.
9. 10. 11.
12.
97
currence. In Sabiston DC Jr, ed. Textbook of Surgery, Update 2. Philadelphia: WB Saunders, 1989; pp 19-37. Fletcher RH. Carcinoembryonic antigen. Ann Intern Med 1986; 104:66-73. Jessup JM, Giavazzi R, Campbell D, et al. Growth potential of human colorectal carcinomas in nude mice: association with the preoperative serum concentration of carcinoembryonic antigen in patients. Cancer Res 1988; 48:1689-1692. Benchimoi S, Fuks A, Jothy S, et al. Carcinoembryonic antigen, a human tumor marker, functions as an intercellular adhesion molecule. Cell 1989; 57:327-334. Pignatelli M, Durbin H, Bodmer WF. Carcinoembryonic antigen functions as an accessory adhesion molecule mediating colon epithelial cell-collagen interactions. Proc Natl Acad Sci 1990; 87: 1541-1545. Mayer RJ, O'Connell MJ, Tepper JE, Wolmark N. Status of adjuvant therapy for colorectal cancer. J Natl Cancer Inst 1989; 81:13591364. Yeatman TJ, Kimura AK, Copeland EM, Bland KI. Rapid analysis of carcinoembryonic antigen levels in gallbladder bile: identification of patients for high risk for colorectal liver metastasis. Ann Surg 1990; 213:113-117. Holyoke ED, Mittleman A, Panahon A, et al. Prolongation of the disease-free interval in surgically treated rectal carcinoma. N Engl J Med 1985; 312:1465-1472. Douglass HO Jr, Moertel CG, Mayer RJ, et al. Survival after postoperative combination treatment of rectal cancer. N Engl J Med 1986; 315:1294-1295. Moertel CG, Fleming TR, Macdonald JS, et al. Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med 1990; 322:352-358. Yeatman TJ, Bland KI, Copeland EM, et al. Relationship between colorectal liver metastases and CEA levels in gallbladder bile. Ann Surg 1989; 210:505-512. Moss AA. Imaging of colorectal carcinoma. Radiology 1989; 170:
308-310. 13. Doerr RJ, Abdel-Nabi H, Merchant B. Indium 111 ZCE-025 immunoscintigraphy in occult recurrent colorectal cancer with elevated carcinoembryonic antigen level. Arch Surg 1990; 125:226229. 14. Beatty JD, Williams LE, Yamauchi D, et al. Presurgical imaging with indium-labelled anti-carcinoembryonic antigen for colon cancer staging. Cancer Res 1990; 50(Suppl):922s-926s. 15. Haller DG. Monoclonal antibody imaging in the management of patients with colorectal cancer. J Clin Oncol 1988; 6:1213-1215. 16. Taylor I, Machin D, Mullee M, et al. A randomized controlled trial of adjuvant portal vein cytotoxic perjusion in colorectal cancer. Br J Surg 1985; 72:359-363. 17. Hyams DM, Esteban JM, Beatty BG, et al. Prolongation of survival of nude mice bearing human colon cancer. Arch Surg 1989; 124: 175-179. 18. Blumenthal RD, Sharkey RM, Snyder D and Goldenberg DM. Reduction by anti-antibody administration of the radiotoxicity associated with '31I-labelled antibody to carcinoembryonic antigen in cancer radioimmunotherapy. J Natl Cancer Inst 1989; 81: 194-199.
