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Purpose: To assess the performance and the potential clinical impact of a new antibody imaging agent, CEA-Scan (Immunomedics Inc, Morris Plains, NJ), in 210 presurgical patients with advanced recurrent or metastatic colorectal carcinomas., Methods: CEA-Scan, an anti-carcinoembryonic antigen (CEA) Fab antibody fragment labeled with technetium-99m-pertechnetate (99mTc), was injected intravenously (IV), and external scintigraphy was performed 2 to 5 and 18 to 24 hours later. Imaging with conventional diagnostic modalities (CDM) was also performed, and findings were confirmed by surgery and histology., Results: The sensitivity of CEA-Scan was superior to that of CDM in the extrahepatic abdomen (55% v 32%; P = .007) and pelvis (69% v 48%; P = .005), and CEA-Scan findings complemented those of CDM in the liver. Among 122 patients with known disease, the positive predictive value was significantly higher when both modalities were positive (98%) compared with each alone (68% to 70%), potentially obviating the need for histologic confirmation when both tests are positive. Imaging accuracy also was significantly improved by adding CEA-Scan to CDM. In 88 patients with occult cancer, imaging accuracy was enhanced significantly by CEA-Scan combined with CDM (61% v 33%). Potential clinical benefit from CEA-Scan was demonstrated in 89 of 210 patients. Only two patients developed human antimouse antibodies (HAMA) to CEA-Scan after a single injection, and none of 19 assessable patients after two injections., Conclusion: CEA-Scan affords high-quality, same-day imaging, uses an inexpensive and readily available radio-nuclide, adds clinically significant information in assessing extent and location of disease in colorectal cancer patients, and only rarely induces a HAMA response.

In an effort to identify the site of recurrent colorectal cancer in patients with occult metastasis and increasing serum CEA levels, we conducted two trials using monoclonal antibodies (MoAb) against CEA. The first utilized Indium-111-labeled ZCE-025; an immunoglobulin G1 (IgG1) anticarcinoembryonic antigen (anti-CEA) antibody (Hybritech, San Diego, CA). The second study used Tc-99m-labeled Fab' fragment of IMMU-4 (Immunomedics, Morris Plains, NJ). Eighteen patients were imaged with the ZCE-025 and 14 with the Tc-99m Fab' IMMU-4. True-positive scans, defined as at least one correct correlation of the MoAb scan and surgical/histologic findings, were observed in 12 of 15 patients undergoing exploration or biopsy using the ZCE-025 and 11 of 14 using the IMMU-4. There were no true-negative scans with the ZCE-025 and only 2 of 14 with the IMMU-4. There were 3 false-positive scans with the ZCE-025 and 1 of 14 with IMMU-4. There were no false-negative scans with either ZCE-025 or IMMU-4. Four (31%) of 13 patients undergoing exploration and imaged with ZCE-025 and 5 (36%) of 14 imaged with IMMU-4 had complete tumor resection. Treatment decisions were affected in 3 (16%) of 18 ZCE-025-imaged patients and 3 (21%) of 14 IMMU-4 ones. Two (14%) of 14 patients imaged with IMMU-4 had negative MoAb scans and negative laparotomies. Despite these findings, it is not known whether such early detection and resection will translate into improved survival rates. The authors suggest two randomized studies, one designed to ascertain the role of MoAb added to blind exploratory laparotomy. In that study, patients with increasing CEA levels and a negative workup will be randomized to an exploratory laparotomy preceded by MoAb anti-CEA scans or a straight exploratory laparotomy without the assistance of a MoAb anti-CEA scan. Endpoints will be differences in complete resectability and survival. A second study will examine the merits of blind exploratory laparotomies. In that study, patients with increasing CEA levels and a negative workup would be randomized to MoAb imaging, exploratory laparotomy, and radioimmunoguided surgery, and the other cohort of patients would continue to have conventional radiologic workup. Exploration in this latter group would be performed only when indicated by radiologic or endoscopic studies. The endpoint of the study would compare survival in the two cohorts of patients. These two studies may ultimately settle the debate regarding the correct approach to patients with occult metastatic colorectal cancer and a increasing levels of serum CEA.

Background: Thirty-nine patients with advanced measurable metastatic colorectal carcinoma were entered in a clinical trial of recombinant alpha-2a-interferon (r alpha-2a-IFN) and continuous-infusion 5-fluorouracil (5-FU). Patients had not been treated previously with chemotherapy and had bidimensionally measurable disease., Methods: A course of therapy consisted of a 5-day continuous infusion of 5-FU, 750 mg/m2/day, with r alpha-2a-IFN, 9 x 10(6) IU, subcutaneously, on days 1, 3 and 5 of the 5-FU infusion. A course of therapy was repeated every 15 days, and patients were examined for response after receiving four courses of therapy., Results: One patient had a complete response, and 11 patients experienced partial responses, for an overall response rate of 31% (95% confidence interval [CI], 17-48%). The median duration of response was 7.5 months (range, 2-13 months). Fifty-two percent of the patients entered in this trial are alive at time of this writing, with a median follow-up duration of 12.2 months (range, 6-24 months). Grade 3-4 toxicities included mucositis (nine patients), diarrhea (two patients), granulocytopenia (two patients), and fatigue (three patients)., Conclusion: This regimen of 5-FU with r alpha-2a-IFN administration does not appear to be superior to previously published schedules of 5-FU with r alpha-2a-IFN or to other methods that modulate 5-FU.

Four patients with clinically nonresectable unilobar hepatic metastases from colorectal cancer were treated with a sequentially combined approach of intrahepatic arterial chemotherapy followed by surgery. Partial regression (greater than or equal to 50%) induced by chemotherapy and associated with a decline in plasma carcinoembryonic antigen level was followed successfully by a complete hepatic tumor resection in three out of four patients. All three patients continue to be free of disease from 13+ to 21+ months. This combined approach may improve the salvage rate of patients with regionally confined hepatic metastases.

Cisplatin (CDDP) was combined with floxuridine (FUDR) and delivered into the hepatic arteries of 29 patients as induction therapy for colorectal cancer metastatic to the liver. Mitomycin C and FUDR combination was substituted after progression or when response had peaked. Chemotherapy was delivered with an Infusaid pump (Infusaid Corp; Norwood, Mass; 14 patients), Medtronic programmable drug administration device (Medtronic, Inc, Minneapolis; two patients), or percutaneously placed catheters (13 patients). Complete disappearance of liver metastases was observed in four patients and 11 additional patients had a partial remission as determined by computed tomography (CT) scan and substantiated at times by angiography, for a total response rate of 52%. Response as determined by imaging techniques coincided with a concurrent decrease in carcinoembryonic antigen (CEA) and improvement in performance status. The severity of tumor burden was correlated with the response to therapy and survival. Among those patients who responded to arterial chemotherapy, differences in disease severity did not significantly influence survival. Median survival among responders with greater than 25% liver replacement by tumor was 14 months (P = .28), compared with 28 months for those patients with less than 25% liver replacement. In contrast, differences in tumor burden significantly affected survival among patients who failed to respond to chemotherapy; median survival among nonresponding patients with greater than 25% liver replacement was 4 months, compared with 8 months for those who had less than 25% liver replacement (P = .01). The presence of minimal extrahepatic disease at the time of initiation of intraarterial treatment did not seem to have a significant detrimental effect on survival. The study suggests that hepatic tumor response to arterial administration of CDDP and FUDR and mitomycin C and FUDR is clinically significant because it overrides the effect of tumor burden on survival among patients who have colorectal cancer with liver metastases and may offer effective palliation.

In this study of 232 patients with histologically confirmed large bowel carcinoma, patient- and tumor-related characteristics were examined and their effect on prognosis was determined. Serum alkaline phosphatase and albumin concentrations, symptom duration prior to diagnosis of the primary tumor, and the status of the primary tumor showed the strongest relationship to survival after diagnosis of surgically noncurable disease. Patients who had normal serum alkaline phosphatase and albumin concentrations, patients whose symptoms lasted over 12 months before diagnosis, and patients whose primary tumor had been resected before diagnosis of noncurable disease had a good prognosis. Performance status, weight loss, sex, presence of liver metastasis, hemoglobin concentration, and absolute lymphocyte or monocyte counts in the peripheral blood, at time of diagnosis of surgically noncurable disease, were significant factors when examined individually. One hundred seventy-nine patients with metastatic colorectal cancer confined to the liver were selected from 601 patients who received chemotherapy for advanced colorectal cancer over 10-year periods to compare the efficacy of hepatic-artery infusion therapy with that of intravenous 5-fluoropyrimidine--containing chemotherapy. The two groups were similar with respect to prognostic factors. The hepatic-artery infusion chemotherapy produced a higher response rate than intravenous chemotherapy, but did not result in significant prolongation of survival.

Monoclonal antibodies (MoAbs) against carcinoembryonic antigen (CEA) react with human colorectal cancer cells, and when labeled with a gamma-emitting radioisotope, may help to localize known and occult metastatic disease. We tested ZCE-025 (Hybritech, Inc, San Diego), a high-affinity immune gamma globulin1 (IgG1) MoAb anti-CEA that does not react with normal granulocyte glycoproteins in a phase I/II trial to determine the reagent's toxicity and its maximum efficacy in detecting metastatic colorectal cancer. Increasing doses of unlabeled ZCE-025 were mixed with 1 mg of Indium-111 (111In)-radiolabeled MoAb and administered intravenously (IV) to 34 patients who had metastatic colorectal cancer. Planar nuclear or single photon emission computed tomographic (SPECT) scans were performed 48 to 72 and 120 to 144 hours later. Total dose of MoAb and scanning sensitivity (number of imaged lesions/number of known lesions) were correlated up to 80 mg. At doses of 2.5 to 20 mg, a mean of 22% of the lesions were imaged; at 40 mg, 77% were imaged (P less than .01). Liver metastases were detected as areas of increased activity ("hot") at the 40 mg dose but showed decreased MoAb uptake at lower doses. At the 40 mg dose normal liver parenchymal uptake of the labeled MoAb was lower with respect to blood pool compared with the other doses. At 80 mg, however, sensitivity of detection declined to 21%. One milligram of 111In-labeled ZCE-025 antibody coinfused with 39 mg of unlabeled antibody appeared optimal for detecting metastatic colorectal cancer, particularly in the liver. Although the exact mechanism(s) for this dose effect is currently unknown, a partial "blocking" effect of unlabeled antibody with a change in MoAb biodistribution may be occurring.

Twenty patients with colon cancer metastatic to the liver underwent successful hepatic resection and adjuvant perioperative therapy that included hepatic arterial mitomycin C and floxuridine (FUDR). The median survival for all 20 patients was 51 months: 10 are still alive with a median postoperative follow-up of 49 months; 6 are disease-free with a median postoperative follow-up of 43 months. Among 10 patients in whom the surgical margins of the specimen contained tumor cells, the median survival was 52 months. This survival was comparable to that among 10 patients in whom the surgical margins were tumor free (P = 0.22). Neither the number of metastatic liver deposits nor the disease-free interval between the primary diagnosis of colorectal carcinoma and the development of liver metastases significantly affected survival. A transient chemical hepatitis which resolved before the next scheduled treatment was associated with 50% of arterial chemotherapy cycles (approximately 70% of the patients). Gastric or duodenal ulcerations occurred in 23% of the patients. Surgical complications were either pulmonary such as pleural effusion or atelectasis, or wound infections and subphrenic abscesses. Although these results compare favorably with the results in previously published series, this aggressive adjuvant chemotherapy appears to be particularly justified in patients with tumor positive surgical margins or those with multiple tumor masses and, therefore, are characterized by a poor prognosis.

Fifty-five patients with metastatic colorectal carcinoma confined to the liver were treated with hepatic arterial infusion of floxuridine and mitomycin C. Tumour response rate was 43.4% and median overall survival was 11 months. Prolonged survival was associated with intentional or inadvertent occlusion of the hepatic artery. The median survival of twenty-four patients with arterial occlusion (15 months) was significantly higher than that of thirty-one patients without arterial occlusion (8 months).

Twenty-one patients with inoperable colon cancer in the pelvis were treated with intra-arterial 5-fluorouracil (5-FU) and mitomycin C, given bilaterally into the internal iliac arteries. Seventeen of the 21 patients had failed previous radiation therapy and 15 had also failed systemic intravenous chemotherapy. Eighteen of the 21 patients received intra-arterial treatments because of pelvic pain. Effect of this treatment on the pain could be evaluated in 16 patients. A measurable decrease in pain medication occurred in 8 of 16, whereas a subjective feeling of pain relief was observed in 12 of 16 patients for a mean period of 3.5 months. However, objective tumor response was considered definite only if associated with a greater than 50% decline of an elevated plasma carcinoembryonic antigen level; this was observed in 5 of 11 patients (45%). Reduction in tumor mass as measured by imaging techniques was observed in two of ten patients in whom it was evaluable. Improvement in hydronephrosis was observed in five of seven evaluable patients. Hematuria was present in 12 patients and improved in 10 of those patients. The most significant side effect of chemotherapy was perineal and gluteal skin erythema, which was observed in 36% of the patients after the first course and in 24% during the second course. This frequently escalated to cutaneous vesiculation and desquamation. This side effect was prevented by concurrent administration of steroids. Pelvic arterial infusion of 5-FU and mitomycin C can offer temporary pain relief to patients who have failed other means of therapy. Objective antitumor effects may have also resulted but were much harder to assess in this group of patients.

Two colorectal carcinoma patients with elevated serum carcinoembryonic antigen (CEA) levels are discussed. In the first patient, metastatic disease in the left adrenal gland was diagnosed by computerized tomography scanning. A CEA concentration gradient between the left adrenal artery and the left adrenal vein was detected by selective sampling of the appropriate vessels. After adrenalectomy, the serum CEA level returned to normal. In the second patient, a CEA gradient between the hepatic artery and the left hepatic vein helped localize metastatic disease in the left lobe of the liver, before it became evident by any other means. We conclude that subselective angiography and sampling of serum for CEA levels could serve as an auxiliary method of detecting obscure metastatic colorectal carcinoma in patients with elevated levels of the antigen.